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m (→‎Function: task, replaced: The Journal of Investigative Dermatology. Symposium Proceedings / the Society for Investigative Dermatology, Inc. [And] European Society for Dermatological Researc using AWB)
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== Function ==
== Function ==
CARP was originally identified as a YB-1-associating, cardiac-restricted transcription co-repressor in the homeobox NKX2-5 pathway that is involved in [[ventricle (heart)|cardiac ventricular]] chamber specification, maturation and morphogenesis,<ref name="ReferenceB">{{cite journal | vauthors = Zou Y, Evans S, Chen J, Kuo HC, Harvey RP, Chien KR | title = CARP, a cardiac ankyrin repeat protein, is downstream in the Nkx2-5 homeobox gene pathway | journal = Development | volume = 124 | issue = 4 | pages = 793–804 | date = Feb 1997 | pmid = 9043061 }}</ref><ref>{{cite journal | vauthors = Kuo H, Chen J, Ruiz-Lozano P, Zou Y, Nemer M, Chien KR | title = Control of segmental expression of the cardiac-restricted ankyrin repeat protein gene by distinct regulatory pathways in murine cardiogenesis | journal = Development | volume = 126 | issue = 19 | pages = 4223–34 | date = Oct 1999 | pmid = 10477291 }}</ref><ref>{{cite journal | vauthors = Takimoto E, Mizuno T, Terasaki F, Shimoyama M, Honda H, Shiojima I, Hiroi Y, Oka T, Hayashi D, Hirai H, Kudoh S, Toko H, Kawamura K, Nagai R, Yazaki Y, Komuro I | title = Up-regulation of natriuretic peptides in the ventricle of Csx/Nkx2-5 transgenic mice | journal = Biochemical and Biophysical Research Communications | volume = 270 | issue = 3 | pages = 1074–9 | date = Apr 2000 | pmid = 10772952 | doi = 10.1006/bbrc.2000.2561 }}</ref> and whose mRNA levels are exquisitely sensitive to Doxorubicin, mediated through a hydrogen peroxide/ERK/p38MAP kinase-dependent<ref>{{cite journal | vauthors = Jeyaseelan R, Poizat C, Baker RK, Abdishoo S, Isterabadi LB, Lyons GE, Kedes L | title = A novel cardiac-restricted target for doxorubicin. CARP, a nuclear modulator of gene expression in cardiac progenitor cells and cardiomyocytes | journal = The Journal of Biological Chemistry | volume = 272 | issue = 36 | pages = 22800–8 | date = Sep 1997 | pmid = 9278441 | doi=10.1074/jbc.272.36.22800}}</ref><ref>{{cite journal | vauthors = Aihara Y, Kurabayashi M, Tanaka T, Takeda SI, Tomaru K, Sekiguchi KI, Ohyama Y, Nagai R | title = Doxorubicin represses CARP gene transcription through the generation of oxidative stress in neonatal rat cardiac myocytes: possible role of serine/threonine kinase-dependent pathways | journal = Journal of Molecular and Cellular Cardiology | volume = 32 | issue = 8 | pages = 1401–14 | date = Aug 2000 | pmid = 10900167 | doi = 10.1006/jmcc.2000.1173 }}</ref> as well as M-CAT ''cis-element''-dependent<ref>{{cite journal | vauthors = Aihara Y, Kurabayashi M, Saito Y, Ohyama Y, Tanaka T, Takeda S, Tomaru K, Sekiguchi K, Arai M, Nakamura T, Nagai R | title = Cardiac ankyrin repeat protein is a novel marker of cardiac hypertrophy: role of M-CAT element within the promoter | journal = Hypertension | volume = 36 | issue = 1 | pages = 48–53 | date = Jul 2000 | pmid = 10904011 | doi=10.1161/01.hyp.36.1.48}}</ref> mechanism. Subsequent studies showed that CARP expression in [[cardiomyocytes]] is regulated by [[adrenergic receptor|alpha-adrenergic signaling]], in part via the transcription factor GATA4.<ref>{{cite journal | vauthors = Maeda T, Sepulveda J, Chen HH, Stewart AF | title = Alpha(1)-adrenergic activation of the cardiac ankyrin repeat protein gene in cardiac myocytes | journal = Gene | volume = 297 | issue = 1–2 | pages = 1–9 | date = Sep 2002 | pmid = 12384280 | doi=10.1016/s0378-1119(02)00924-1}}</ref><ref>{{cite journal | vauthors = Zhong L, Chiusa M, Cadar AG, Lin A, Samaras S, Davidson JM, Lim CC | title = Targeted inhibition of ANKRD1 disrupts sarcomeric ERK-GATA4 signal transduction and abrogates phenylephrine-induced cardiomyocyte hypertrophy | journal = Cardiovascular Research | volume = 106 | issue = 2 | pages = 261–71 | date = May 2015 | pmid = 25770146 | doi = 10.1093/cvr/cvv108 | pmc=4481572}}</ref> An additional study showed that [[adrenergic receptor|beta-adrenergic signaling]] via [[protein kinase A]] and [[CAMK|CaM kinase]] induces the expression of CARP, and that CARP may have a negative effect on [[contractility|contractile function]].<ref>{{cite journal | vauthors = Zolk O, Marx M, Jäckel E, El-Armouche A, Eschenhagen T | title = Beta-adrenergic stimulation induces cardiac ankyrin repeat protein expression: involvement of protein kinase A and calmodulin-dependent kinase | journal = Cardiovascular Research | volume = 59 | issue = 3 | pages = 563–72 | date = Sep 2003 | pmid = 14499857 | doi=10.1016/s0008-6363(03)00476-0}}</ref> CARP has also been identified as a transcriptional co-activator of tumor suppressor protein p53 for stimulating gene expression in muscle; p53 was found to be an upstream effector of CARP via upregulation of the proximal ANKRD1 promoter.<ref name="Kojic S p53">{{cite journal | vauthors = Kojic S, Nestorovic A, Rakicevic L, Belgrano A, Stankovic M, Divac A, Faulkner G | title = A novel role for cardiac ankyrin repeat protein Ankrd1/CARP as a co-activator of the p53 tumor suppressor protein | journal = Archives of Biochemistry and Biophysics | volume = 502 | issue = 1 | pages = 60–7 | date = Oct 2010 | pmid = 20599664 | doi = 10.1016/j.abb.2010.06.029 }}</ref> Interestingly, CARP protein has a relatively short half-life being longer in [[cardiomyocytes]] than [[endothelial cells]]; and CARP is degraded by the 26S proteasome via a PEST degron.<ref>{{cite journal | vauthors = Samaras SE, Chen B, Koch SR, Sawyer DB, Lim CC, Davidson JM | title = 26S proteasome regulation of Ankrd1/CARP in adult rat ventricular myocytes and human microvascular endothelial cells | journal = Biochemical and Biophysical Research Communications | volume = 425 | issue = 4 | pages = 830–5 | date = Sep 2012 | pmid = 22892129 | doi = 10.1016/j.bbrc.2012.07.162 | pmc=3460693}}</ref><ref>{{cite journal | vauthors = Badi I, Cinquetti R, Frascoli M, Parolini C, Chiesa G, Taramelli R, Acquati F | title = Intracellular ANKRD1 protein levels are regulated by 26S proteasome-mediated degradation | journal = FEBS Letters | volume = 583 | issue = 15 | pages = 2486–92 | date = Aug 2009 | pmid = 19589340 | doi = 10.1016/j.febslet.2009.07.001 }}</ref>
CARP was originally identified as a YB-1-associating, cardiac-restricted transcription co-repressor in the homeobox NKX2-5 pathway that is involved in [[ventricle (heart)|cardiac ventricular]] chamber specification, maturation and morphogenesis,<ref name="ReferenceB">{{cite journal | vauthors = Zou Y, Evans S, Chen J, Kuo HC, Harvey RP, Chien KR | title = CARP, a cardiac ankyrin repeat protein, is downstream in the Nkx2-5 homeobox gene pathway | journal = Development | volume = 124 | issue = 4 | pages = 793–804 | date = Feb 1997 | pmid = 9043061 }}</ref><ref>{{cite journal | vauthors = Kuo H, Chen J, Ruiz-Lozano P, Zou Y, Nemer M, Chien KR | title = Control of segmental expression of the cardiac-restricted ankyrin repeat protein gene by distinct regulatory pathways in murine cardiogenesis | journal = Development | volume = 126 | issue = 19 | pages = 4223–34 | date = Oct 1999 | pmid = 10477291 }}</ref><ref>{{cite journal | vauthors = Takimoto E, Mizuno T, Terasaki F, Shimoyama M, Honda H, Shiojima I, Hiroi Y, Oka T, Hayashi D, Hirai H, Kudoh S, Toko H, Kawamura K, Nagai R, Yazaki Y, Komuro I | title = Up-regulation of natriuretic peptides in the ventricle of Csx/Nkx2-5 transgenic mice | journal = Biochemical and Biophysical Research Communications | volume = 270 | issue = 3 | pages = 1074–9 | date = Apr 2000 | pmid = 10772952 | doi = 10.1006/bbrc.2000.2561 }}</ref> and whose mRNA levels are exquisitely sensitive to Doxorubicin, mediated through a hydrogen peroxide/ERK/p38MAP kinase-dependent<ref>{{cite journal | vauthors = Jeyaseelan R, Poizat C, Baker RK, Abdishoo S, Isterabadi LB, Lyons GE, Kedes L | title = A novel cardiac-restricted target for doxorubicin. CARP, a nuclear modulator of gene expression in cardiac progenitor cells and cardiomyocytes | journal = The Journal of Biological Chemistry | volume = 272 | issue = 36 | pages = 22800–8 | date = Sep 1997 | pmid = 9278441 | doi=10.1074/jbc.272.36.22800}}</ref><ref>{{cite journal | vauthors = Aihara Y, Kurabayashi M, Tanaka T, Takeda SI, Tomaru K, Sekiguchi KI, Ohyama Y, Nagai R | title = Doxorubicin represses CARP gene transcription through the generation of oxidative stress in neonatal rat cardiac myocytes: possible role of serine/threonine kinase-dependent pathways | journal = Journal of Molecular and Cellular Cardiology | volume = 32 | issue = 8 | pages = 1401–14 | date = Aug 2000 | pmid = 10900167 | doi = 10.1006/jmcc.2000.1173 }}</ref> as well as M-CAT ''cis-element''-dependent<ref>{{cite journal | vauthors = Aihara Y, Kurabayashi M, Saito Y, Ohyama Y, Tanaka T, Takeda S, Tomaru K, Sekiguchi K, Arai M, Nakamura T, Nagai R | title = Cardiac ankyrin repeat protein is a novel marker of cardiac hypertrophy: role of M-CAT element within the promoter | journal = Hypertension | volume = 36 | issue = 1 | pages = 48–53 | date = Jul 2000 | pmid = 10904011 | doi=10.1161/01.hyp.36.1.48}}</ref> mechanism. Subsequent studies showed that CARP expression in [[cardiomyocytes]] is regulated by [[adrenergic receptor|alpha-adrenergic signaling]], in part via the transcription factor GATA4.<ref>{{cite journal | vauthors = Maeda T, Sepulveda J, Chen HH, Stewart AF | title = Alpha(1)-adrenergic activation of the cardiac ankyrin repeat protein gene in cardiac myocytes | journal = Gene | volume = 297 | issue = 1–2 | pages = 1–9 | date = Sep 2002 | pmid = 12384280 | doi=10.1016/s0378-1119(02)00924-1}}</ref><ref>{{cite journal | vauthors = Zhong L, Chiusa M, Cadar AG, Lin A, Samaras S, Davidson JM, Lim CC | title = Targeted inhibition of ANKRD1 disrupts sarcomeric ERK-GATA4 signal transduction and abrogates phenylephrine-induced cardiomyocyte hypertrophy | journal = Cardiovascular Research | volume = 106 | issue = 2 | pages = 261–71 | date = May 2015 | pmid = 25770146 | doi = 10.1093/cvr/cvv108 | pmc=4481572}}</ref> An additional study showed that [[adrenergic receptor|beta-adrenergic signaling]] via [[protein kinase A]] and [[CAMK|CaM kinase]] induces the expression of CARP, and that CARP may have a negative effect on [[contractility|contractile function]].<ref>{{cite journal | vauthors = Zolk O, Marx M, Jäckel E, El-Armouche A, Eschenhagen T | title = Beta-adrenergic stimulation induces cardiac ankyrin repeat protein expression: involvement of protein kinase A and calmodulin-dependent kinase | journal = Cardiovascular Research | volume = 59 | issue = 3 | pages = 563–72 | date = Sep 2003 | pmid = 14499857 | doi=10.1016/s0008-6363(03)00476-0}}</ref> CARP has also been identified as a transcriptional co-activator of tumor suppressor protein p53 for stimulating gene expression in muscle; p53 was found to be an upstream effector of CARP via upregulation of the proximal ANKRD1 promoter.<ref name="Kojic S p53">{{cite journal | vauthors = Kojic S, Nestorovic A, Rakicevic L, Belgrano A, Stankovic M, Divac A, Faulkner G | title = A novel role for cardiac ankyrin repeat protein Ankrd1/CARP as a co-activator of the p53 tumor suppressor protein | journal = Archives of Biochemistry and Biophysics | volume = 502 | issue = 1 | pages = 60–7 | date = Oct 2010 | pmid = 20599664 | doi = 10.1016/j.abb.2010.06.029 }}</ref> CARP has a relatively short half-life being longer in [[cardiomyocytes]] than [[endothelial cells]]; and CARP is degraded by the 26S proteasome via a PEST degron.<ref>{{cite journal | vauthors = Samaras SE, Chen B, Koch SR, Sawyer DB, Lim CC, Davidson JM | title = 26S proteasome regulation of Ankrd1/CARP in adult rat ventricular myocytes and human microvascular endothelial cells | journal = Biochemical and Biophysical Research Communications | volume = 425 | issue = 4 | pages = 830–5 | date = Sep 2012 | pmid = 22892129 | doi = 10.1016/j.bbrc.2012.07.162 | pmc=3460693}}</ref><ref>{{cite journal | vauthors = Badi I, Cinquetti R, Frascoli M, Parolini C, Chiesa G, Taramelli R, Acquati F | title = Intracellular ANKRD1 protein levels are regulated by 26S proteasome-mediated degradation | journal = FEBS Letters | volume = 583 | issue = 15 | pages = 2486–92 | date = Aug 2009 | pmid = 19589340 | doi = 10.1016/j.febslet.2009.07.001 }}</ref>


In animal models of disease and injury, CARP has been characterized to be a stress-inducible [[myofibril]]lar protein. CARP has been shown to play a role in [[skeletal muscle]] structure<ref>{{cite journal | vauthors = Barash IA, Bang ML, Mathew L, Greaser ML, Chen J, Lieber RL | title = Structural and regulatory roles of muscle ankyrin repeat protein family in skeletal muscle | journal = American Journal of Physiology. Cell Physiology | volume = 293 | issue = 1 | pages = C218-27 | date = Jul 2007 | pmid = 17392382 | doi = 10.1152/ajpcell.00055.2007 }}</ref> remodeling,<ref>{{cite journal | vauthors = Laure L, Suel L, Roudaut C, Bourg N, Ouali A, Bartoli M, Richard I, Danièle N | title = Cardiac ankyrin repeat protein is a marker of skeletal muscle pathological remodelling | journal = The FEBS Journal | volume = 276 | issue = 3 | pages = 669–84 | date = Feb 2009 | pmid = 19143834 | doi = 10.1111/j.1742-4658.2008.06814.x }}</ref> and repair, being expressed in [[skeletal muscle]] near myotendinous junctions,<ref>{{cite journal | vauthors = Baumeister A, Arber S, Caroni P | title = Accumulation of muscle ankyrin repeat protein transcript reveals local activation of primary myotube endcompartments during muscle morphogenesis | journal = The Journal of Cell Biology | volume = 139 | issue = 5 | pages = 1231–42 | date = Dec 1997 | pmid = 9382869 | doi=10.1083/jcb.139.5.1231 | pmc=2140219}}</ref> and in vascular smooth muscle cells, as a downstream target of TGF-beta/Smad sigmaling in response to balloon injury<ref>{{cite journal | vauthors = Kanai H, Tanaka T, Aihara Y, Takeda S, Kawabata M, Miyazono K, Nagai R, Kurabayashi M | title = Transforming growth factor-beta/Smads signaling induces transcription of the cell type-restricted ankyrin repeat protein CARP gene through CAGA motif in vascular smooth muscle cells | journal = Circulation Research | volume = 88 | issue = 1 | pages = 30–6 | date = Jan 2001 | pmid = 11139470 | doi=10.1161/01.res.88.1.30}}</ref> and atherosclerotic plaques.<ref>{{cite journal | vauthors = de Waard V, van Achterberg TA, Beauchamp NJ, Pannekoek H, de Vries CJ | title = Cardiac ankyrin repeat protein (CARP) expression in human and murine atherosclerotic lesions: activin induces CARP in smooth muscle cells | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 23 | issue = 1 | pages = 64–8 | date = Jan 2003 | pmid = 12524226 | doi=10.1161/01.atv.0000042218.13101.50}}</ref> Further studies have identified a role for CARP in initiation and regulation of [[arteriogenesis]].<ref>{{cite journal | vauthors = Boengler K, Pipp F, Fernandez B, Ziegelhoeffer T, Schaper W, Deindl E | title = Arteriogenesis is associated with an induction of the cardiac ankyrin repeat protein (carp) | journal = Cardiovascular Research | volume = 59 | issue = 3 | pages = 573–81 | date = Sep 2003 | pmid = 14499858 | doi=10.1016/s0008-6363(03)00511-x}}</ref><ref>{{cite journal | vauthors = Shi Y, Reitmaier B, Regenbogen J, Slowey RM, Opalenik SR, Wolf E, Goppelt A, Davidson JM | title = CARP, a cardiac ankyrin repeat protein, is up-regulated during wound healing and induces angiogenesis in experimental granulation tissue | journal = The American Journal of Pathology | volume = 166 | issue = 1 | pages = 303–12 | date = Jan 2005 | pmid = 15632022 | doi = 10.1016/S0002-9440(10)62254-7 | pmc=1602297}}</ref><ref>{{cite journal | vauthors = Samaras SE, Shi Y, Davidson JM | title = CARP: fishing for novel mechanisms of neovascularization | journal = The Journal of Investigative Dermatology. Symposium Proceedings | volume = 11 | issue = 1 | pages = 124–31 | date = Sep 2006 | pmid = 17069020 | doi=10.1038/sj.jidsymp.5650014}}</ref> Decreased expression of CARP in cardiac cells within the ischemic region was detected in a rat model of [[ischemic injury]], and was thought to be linked to the induction of GADD153, an [[apoptosis]]-related gene.<ref>{{cite journal | vauthors = Lee MJ, Kwak YK, You KR, Lee BH, Kim DG | title = Involvement of GADD153 and cardiac ankyrin repeat protein in cardiac ischemia-reperfusion injury | journal = Experimental & Molecular Medicine | volume = 41 | issue = 4 | pages = 243–52 | date = Apr 2009 | pmid = 19299913 | doi = 10.3858/emm.2009.41.4.027 | pmc=2679233}}</ref> In [[cardiomyocytes]] treated with [[doxorubicin]], a model of [[anthracycline]]-induced [[cardiomyopathy]], CARP [[mRNA]] and [[protein]] levels were depleted, [[myofilament]] [[gene transcription]] was attenuated and [[sarcomere]]s showed significant disarray.<ref>{{cite journal | vauthors = Chen B, Zhong L, Roush SF, Pentassuglia L, Peng X, Samaras S, Davidson JM, Sawyer DB, Lim CC | title = Disruption of a GATA4/Ankrd1 signaling axis in cardiomyocytes leads to sarcomere disarray: implications for anthracycline cardiomyopathy | journal = PLOS ONE | volume = 7 | issue = 4 | pages = e35743 | date = 2012 | pmid = 22532871 | doi = 10.1371/journal.pone.0035743 | pmc=3332030}}</ref>
In animal models of disease and injury, CARP has been characterized to be a stress-inducible [[myofibril]]lar protein. CARP has been shown to play a role in [[skeletal muscle]] structure<ref>{{cite journal | vauthors = Barash IA, Bang ML, Mathew L, Greaser ML, Chen J, Lieber RL | title = Structural and regulatory roles of muscle ankyrin repeat protein family in skeletal muscle | journal = American Journal of Physiology. Cell Physiology | volume = 293 | issue = 1 | pages = C218-27 | date = Jul 2007 | pmid = 17392382 | doi = 10.1152/ajpcell.00055.2007 }}</ref> remodeling,<ref>{{cite journal | vauthors = Laure L, Suel L, Roudaut C, Bourg N, Ouali A, Bartoli M, Richard I, Danièle N | title = Cardiac ankyrin repeat protein is a marker of skeletal muscle pathological remodelling | journal = The FEBS Journal | volume = 276 | issue = 3 | pages = 669–84 | date = Feb 2009 | pmid = 19143834 | doi = 10.1111/j.1742-4658.2008.06814.x }}</ref> and repair, being expressed in [[skeletal muscle]] near myotendinous junctions,<ref>{{cite journal | vauthors = Baumeister A, Arber S, Caroni P | title = Accumulation of muscle ankyrin repeat protein transcript reveals local activation of primary myotube endcompartments during muscle morphogenesis | journal = The Journal of Cell Biology | volume = 139 | issue = 5 | pages = 1231–42 | date = Dec 1997 | pmid = 9382869 | doi=10.1083/jcb.139.5.1231 | pmc=2140219}}</ref> and in vascular smooth muscle cells, as a downstream target of TGF-beta/Smad sigmaling in response to balloon injury<ref>{{cite journal | vauthors = Kanai H, Tanaka T, Aihara Y, Takeda S, Kawabata M, Miyazono K, Nagai R, Kurabayashi M | title = Transforming growth factor-beta/Smads signaling induces transcription of the cell type-restricted ankyrin repeat protein CARP gene through CAGA motif in vascular smooth muscle cells | journal = Circulation Research | volume = 88 | issue = 1 | pages = 30–6 | date = Jan 2001 | pmid = 11139470 | doi=10.1161/01.res.88.1.30}}</ref> and atherosclerotic plaques.<ref>{{cite journal | vauthors = de Waard V, van Achterberg TA, Beauchamp NJ, Pannekoek H, de Vries CJ | title = Cardiac ankyrin repeat protein (CARP) expression in human and murine atherosclerotic lesions: activin induces CARP in smooth muscle cells | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 23 | issue = 1 | pages = 64–8 | date = Jan 2003 | pmid = 12524226 | doi=10.1161/01.atv.0000042218.13101.50}}</ref> Further studies have identified a role for CARP in initiation and regulation of [[arteriogenesis]].<ref>{{cite journal | vauthors = Boengler K, Pipp F, Fernandez B, Ziegelhoeffer T, Schaper W, Deindl E | title = Arteriogenesis is associated with an induction of the cardiac ankyrin repeat protein (carp) | journal = Cardiovascular Research | volume = 59 | issue = 3 | pages = 573–81 | date = Sep 2003 | pmid = 14499858 | doi=10.1016/s0008-6363(03)00511-x}}</ref><ref>{{cite journal | vauthors = Shi Y, Reitmaier B, Regenbogen J, Slowey RM, Opalenik SR, Wolf E, Goppelt A, Davidson JM | title = CARP, a cardiac ankyrin repeat protein, is up-regulated during wound healing and induces angiogenesis in experimental granulation tissue | journal = The American Journal of Pathology | volume = 166 | issue = 1 | pages = 303–12 | date = Jan 2005 | pmid = 15632022 | doi = 10.1016/S0002-9440(10)62254-7 | pmc=1602297}}</ref><ref>{{cite journal | vauthors = Samaras SE, Shi Y, Davidson JM | title = CARP: fishing for novel mechanisms of neovascularization | journal = The Journal of Investigative Dermatology. Symposium Proceedings | volume = 11 | issue = 1 | pages = 124–31 | date = Sep 2006 | pmid = 17069020 | doi=10.1038/sj.jidsymp.5650014}}</ref> Decreased expression of CARP in cardiac cells within the ischemic region was detected in a rat model of [[ischemic injury]], and was thought to be linked to the induction of GADD153, an [[apoptosis]]-related gene.<ref>{{cite journal | vauthors = Lee MJ, Kwak YK, You KR, Lee BH, Kim DG | title = Involvement of GADD153 and cardiac ankyrin repeat protein in cardiac ischemia-reperfusion injury | journal = Experimental & Molecular Medicine | volume = 41 | issue = 4 | pages = 243–52 | date = Apr 2009 | pmid = 19299913 | doi = 10.3858/emm.2009.41.4.027 | pmc=2679233}}</ref> In [[cardiomyocytes]] treated with [[doxorubicin]], a model of [[anthracycline]]-induced [[cardiomyopathy]], CARP [[mRNA]] and [[protein]] levels were depleted, [[myofilament]] [[gene transcription]] was attenuated and [[sarcomere]]s showed significant disarray.<ref>{{cite journal | vauthors = Chen B, Zhong L, Roush SF, Pentassuglia L, Peng X, Samaras S, Davidson JM, Sawyer DB, Lim CC | title = Disruption of a GATA4/Ankrd1 signaling axis in cardiomyocytes leads to sarcomere disarray: implications for anthracycline cardiomyopathy | journal = PLOS ONE | volume = 7 | issue = 4 | pages = e35743 | date = 2012 | pmid = 22532871 | doi = 10.1371/journal.pone.0035743 | pmc=3332030}}</ref>
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== Clinical significance ==
== Clinical significance ==


A wide spectrum of clinical features have been associated with ''ANKRD1''/CARP [[protein]]. Mutations in ''ANKRD1'' have been associated with [[dilated cardiomyopathy]], two of which result in altered binding with [[TLN1]] and [[FHL2]].<ref name="Moulik M 2009">{{cite journal | vauthors = Moulik M, Vatta M, Witt SH, Arola AM, Murphy RT, McKenna WJ, Boriek AM, Oka K, Labeit S, Bowles NE, Arimura T, Kimura A, Towbin JA | title = ANKRD1, the gene encoding cardiac ankyrin repeat protein, is a novel dilated cardiomyopathy gene | journal = Journal of the American College of Cardiology | volume = 54 | issue = 4 | pages = 325–33 | date = Jul 2009 | pmid = 19608030 | doi = 10.1016/j.jacc.2009.02.076 | pmc=2915893}}</ref><ref>{{cite journal | vauthors = Duboscq-Bidot L, Charron P, Ruppert V, Fauchier L, Richter A, Tavazzi L, Arbustini E, Wichter T, Maisch B, Komajda M, Isnard R, Villard E | title = Mutations in the ANKRD1 gene encoding CARP are responsible for human dilated cardiomyopathy | journal = European Heart Journal | volume = 30 | issue = 17 | pages = 2128–36 | date = Sep 2009 | pmid = 19525294 | doi = 10.1093/eurheartj/ehp225 }}</ref> Mutations in ''ANKRD1'' have also been associated with [[hypertrophic cardiomyopathy]], and have shown to increase binding of CARP to [[Titin]] and [[MYPN]].<ref>{{cite journal | vauthors = Arimura T, Bos JM, Sato A, Kubo T, Okamoto H, Nishi H, Harada H, Koga Y, Moulik M, Doi YL, Towbin JA, Ackerman MJ, Kimura A | title = Cardiac ankyrin repeat protein gene (ANKRD1) mutations in hypertrophic cardiomyopathy | journal = Journal of the American College of Cardiology | volume = 54 | issue = 4 | pages = 334–42 | date = Jul 2009 | pmid = 19608031 | doi = 10.1016/j.jacc.2008.12.082 }}</ref> Examination of the functional effects of CARP [[hypertrophic cardiomyopathy]] mutations in engineered heart tissue demonstrated that [[Threonine|Thr]]123[[Methionine|Met]] was a gain-of-function mutation exhibiting augmented contractile properties; whereas [[Proline|Pro]]52[[Alanine|Ala]] and [[Isoleucine|Ile]]280[[Valine|Val]] were unstable and failed to incorporate into [[sarcomeres]], an effect that was remedied upon proteasome inhibition via [[epoxomicin]].<ref>{{cite journal | vauthors = Crocini C, Arimura T, Reischmann S, Eder A, Braren I, Hansen A, Eschenhagen T, Kimura A, Carrier L | title = Impact of ANKRD1 mutations associated with hypertrophic cardiomyopathy on contraction parameters of engineered heart tissue | journal = Basic Research in Cardiology | volume = 108 | issue = 3 | pages = 349 | date = May 2013 | pmid = 23572067 | doi = 10.1007/s00395-013-0349-x }}</ref>
A wide spectrum of clinical features have been associated with ''ANKRD1''/CARP. Mutations in ''ANKRD1'' have been associated with [[dilated cardiomyopathy]], two of which result in altered binding with [[TLN1]] and [[FHL2]].<ref name="Moulik M 2009">{{cite journal | vauthors = Moulik M, Vatta M, Witt SH, Arola AM, Murphy RT, McKenna WJ, Boriek AM, Oka K, Labeit S, Bowles NE, Arimura T, Kimura A, Towbin JA | title = ANKRD1, the gene encoding cardiac ankyrin repeat protein, is a novel dilated cardiomyopathy gene | journal = Journal of the American College of Cardiology | volume = 54 | issue = 4 | pages = 325–33 | date = Jul 2009 | pmid = 19608030 | doi = 10.1016/j.jacc.2009.02.076 | pmc=2915893}}</ref><ref>{{cite journal | vauthors = Duboscq-Bidot L, Charron P, Ruppert V, Fauchier L, Richter A, Tavazzi L, Arbustini E, Wichter T, Maisch B, Komajda M, Isnard R, Villard E | title = Mutations in the ANKRD1 gene encoding CARP are responsible for human dilated cardiomyopathy | journal = European Heart Journal | volume = 30 | issue = 17 | pages = 2128–36 | date = Sep 2009 | pmid = 19525294 | doi = 10.1093/eurheartj/ehp225 }}</ref> Mutations in ''ANKRD1'' have also been associated with [[hypertrophic cardiomyopathy]], and have shown to increase binding of CARP to [[Titin]] and [[MYPN]].<ref>{{cite journal | vauthors = Arimura T, Bos JM, Sato A, Kubo T, Okamoto H, Nishi H, Harada H, Koga Y, Moulik M, Doi YL, Towbin JA, Ackerman MJ, Kimura A | title = Cardiac ankyrin repeat protein gene (ANKRD1) mutations in hypertrophic cardiomyopathy | journal = Journal of the American College of Cardiology | volume = 54 | issue = 4 | pages = 334–42 | date = Jul 2009 | pmid = 19608031 | doi = 10.1016/j.jacc.2008.12.082 }}</ref> Examination of the functional effects of CARP [[hypertrophic cardiomyopathy]] mutations in engineered heart tissue demonstrated that [[Threonine|Thr]]123[[Methionine|Met]] was a gain-of-function mutation exhibiting augmented contractile properties; whereas [[Proline|Pro]]52[[Alanine|Ala]] and [[Isoleucine|Ile]]280[[Valine|Val]] were unstable and failed to incorporate into [[sarcomeres]], an effect that was remedied upon proteasome inhibition via [[epoxomicin]].<ref>{{cite journal | vauthors = Crocini C, Arimura T, Reischmann S, Eder A, Braren I, Hansen A, Eschenhagen T, Kimura A, Carrier L | title = Impact of ANKRD1 mutations associated with hypertrophic cardiomyopathy on contraction parameters of engineered heart tissue | journal = Basic Research in Cardiology | volume = 108 | issue = 3 | pages = 349 | date = May 2013 | pmid = 23572067 | doi = 10.1007/s00395-013-0349-x }}</ref>


A missense mutation in ''ANKRD1'' was shown to be associated with the congenital heart defect, [[Anomalous pulmonary venous connection]].<ref>{{cite journal | vauthors = Cinquetti R, Badi I, Campione M, Bortoletto E, Chiesa G, Parolini C, Camesasca C, Russo A, Taramelli R, Acquati F | title = Transcriptional deregulation and a missense mutation define ANKRD1 as a candidate gene for total anomalous pulmonary venous return | journal = Human Mutation | volume = 29 | issue = 4 | pages = 468–74 | date = Apr 2008 | pmid = 18273862 | doi = 10.1002/humu.20711 }}</ref> CARP has been found as a sensitive and specific biomarker for the differential diagnosis of [[rhabdomyosarcoma]].<ref>{{cite journal | vauthors = Ishiguro N, Motoi T, Araki N, Ito H, Moriyama M, Yoshida H | title = Expression of cardiac ankyrin repeat protein, CARP, in malignant tumors: diagnostic use of CARP protein immunostaining in rhabdomyosarcoma | journal = Human Pathology | volume = 39 | issue = 11 | pages = 1673–9 | date = Nov 2008 | pmid = 18656235 | doi = 10.1016/j.humpath.2008.04.009 }}</ref> Interestingly, ''ANKRD1'' [[mRNA]] levels correlate with patient platinum sensitivity, thus ANKRD1 associates with platinum-based [[chemotherapy]] treatment outcome in [[Surface epithelial-stromal tumor|ovarian adenocarcinoma]] patients.<ref>{{cite journal | vauthors = Scurr LL, Guminski AD, Chiew YE, Balleine RL, Sharma R, Lei Y, Pryor K, Wain GV, Brand A, Byth K, Kennedy C, Rizos H, Harnett PR, deFazio A | title = Ankyrin repeat domain 1, ANKRD1, a novel determinant of cisplatin sensitivity expressed in ovarian cancer | journal = Clinical Cancer Research | volume = 14 | issue = 21 | pages = 6924–32 | date = Nov 2008 | pmid = 18980987 | doi = 10.1158/1078-0432.CCR-07-5189 }}</ref>
A missense mutation in ''ANKRD1'' was shown to be associated with the congenital heart defect, [[Anomalous pulmonary venous connection]].<ref>{{cite journal | vauthors = Cinquetti R, Badi I, Campione M, Bortoletto E, Chiesa G, Parolini C, Camesasca C, Russo A, Taramelli R, Acquati F | title = Transcriptional deregulation and a missense mutation define ANKRD1 as a candidate gene for total anomalous pulmonary venous return | journal = Human Mutation | volume = 29 | issue = 4 | pages = 468–74 | date = Apr 2008 | pmid = 18273862 | doi = 10.1002/humu.20711 }}</ref> CARP has been found as a sensitive and specific biomarker for the differential diagnosis of [[rhabdomyosarcoma]].<ref>{{cite journal | vauthors = Ishiguro N, Motoi T, Araki N, Ito H, Moriyama M, Yoshida H | title = Expression of cardiac ankyrin repeat protein, CARP, in malignant tumors: diagnostic use of CARP protein immunostaining in rhabdomyosarcoma | journal = Human Pathology | volume = 39 | issue = 11 | pages = 1673–9 | date = Nov 2008 | pmid = 18656235 | doi = 10.1016/j.humpath.2008.04.009 }}</ref> ''ANKRD1'' [[mRNA]] levels correlate with patient platinum sensitivity, thus ANKRD1 associates with platinum-based [[chemotherapy]] treatment outcome in [[Surface epithelial-stromal tumor|ovarian adenocarcinoma]] patients.<ref>{{cite journal | vauthors = Scurr LL, Guminski AD, Chiew YE, Balleine RL, Sharma R, Lei Y, Pryor K, Wain GV, Brand A, Byth K, Kennedy C, Rizos H, Harnett PR, deFazio A | title = Ankyrin repeat domain 1, ANKRD1, a novel determinant of cisplatin sensitivity expressed in ovarian cancer | journal = Clinical Cancer Research | volume = 14 | issue = 21 | pages = 6924–32 | date = Nov 2008 | pmid = 18980987 | doi = 10.1158/1078-0432.CCR-07-5189 }}</ref>


CARP [[protein]] and [[mRNA]] expression has been shown to be upregulated in left [[ventricle (heart)|ventricle]]s of [[heart failure]] patients.<ref>{{cite journal | vauthors = Bogomolovas J, Brohm K, Čelutkienė J, Balčiūnaitė G, Bironaitė D, Bukelskienė V, Daunoravičus D, Witt CC, Fielitz J, Grabauskienė V, Labeit S | title = Induction of ankrd1 in dilated cardiomyopathy correlates with the heart failure progression | journal = BioMed Research International | volume = 2015 | pages = 273936 | date = 2015 | pmid = 25961010 | doi = 10.1155/2015/273936 | pmc=4415747}}</ref><ref>{{cite journal | vauthors = Wei YJ, Cui CJ, Huang YX, Zhang XL, Zhang H, Hu SS | title = Upregulated expression of cardiac ankyrin repeat protein in human failing hearts due to arrhythmogenic right ventricular cardiomyopathy | journal = European Journal of Heart Failure | volume = 11 | issue = 6 | pages = 559–66 | date = Jun 2009 | pmid = 19359327 | doi = 10.1093/eurjhf/hfp049 }}</ref><ref>{{cite journal | vauthors = Nagueh SF, Shah G, Wu Y, Torre-Amione G, King NM, Lahmers S, Witt CC, Becker K, Labeit S, Granzier HL | title = Altered titin expression, myocardial stiffness, and left ventricular function in patients with dilated cardiomyopathy | journal = Circulation | volume = 110 | issue = 2 | pages = 155–62 | date = Jul 2004 | pmid = 15238456 | doi = 10.1161/01.CIR.0000135591.37759.AF }}</ref><ref>{{cite journal | vauthors = Zolk O, Frohme M, Maurer A, Kluxen FW, Hentsch B, Zubakov D, Hoheisel JD, Zucker IH, Pepe S, Eschenhagen T | title = Cardiac ankyrin repeat protein, a negative regulator of cardiac gene expression, is augmented in human heart failure | journal = Biochemical and Biophysical Research Communications | volume = 293 | issue = 5 | pages = 1377–82 | date = May 2002 | pmid = 12054667 | doi = 10.1016/S0006-291X(02)00387-X }}</ref> Studies in patients with [[amyotrophic lateral sclerosis]],<ref>{{cite journal | vauthors = Nakamura K, Nakada C, Takeuchi K, Osaki M, Shomori K, Kato S, Ohama E, Sato K, Fukayama M, Mori S, Ito H, Moriyama M | title = Altered expression of cardiac ankyrin repeat protein and its homologue, ankyrin repeat protein with PEST and proline-rich region, in atrophic muscles in amyotrophic lateral sclerosis | journal = Pathobiology | volume = 70 | issue = 4 | pages = 197–203 | date = Apr 2003 | pmid = 12679596 | doi =  10.1159/000069329}}</ref> [[spinal muscular atrophy]], and [[congenital myopathy]],<ref>{{cite journal | vauthors = Nakada C, Oka A, Nonaka I, Sato K, Mori S, Ito H, Moriyama M | title = Cardiac ankyrin repeat protein is preferentially induced in atrophic myofibers of congenital myopathy and spinal muscular atrophy | journal = Pathology International | volume = 53 | issue = 10 | pages = 653–8 | date = Oct 2003 | pmid = 14516314 | doi=10.1046/j.1440-1827.2003.01541.x}}</ref> also found altered expression of CARP in [[skeletal muscle]] fibers. Another study in [[congenital muscular dystrophy]] and [[Duchenne muscular dystrophy]] patients showed elevated expression of CARP.<ref>{{cite journal | vauthors = Nakada C, Tsukamoto Y, Oka A, Nonaka I, Takeda S, Sato K, Mori S, Ito H, Moriyama M | title = Cardiac-restricted ankyrin-repeated protein is differentially induced in duchenne and congenital muscular dystrophy | journal = Laboratory Investigation | volume = 83 | issue = 5 | pages = 711–9 | date = May 2003 | pmid = 12746480 | doi=10.1097/01.lab.0000067484.35298.1a}}</ref> CARP expression is also elevated in patients with [[lupus nephritis]], and associates with [[proteinuria]] severity, suggesting that it may have biomarker potential.<ref>{{cite journal | vauthors = Matsuura K, Uesugi N, Hijiya N, Uchida T, Moriyama M | title = Upregulated expression of cardiac ankyrin-repeated protein in renal podocytes is associated with proteinuria severity in lupus nephritis | journal = Human Pathology | volume = 38 | issue = 3 | pages = 410–9 | date = Mar 2007 | pmid = 17239933 | doi = 10.1016/j.humpath.2006.09.006 }}</ref>
CARP and [[mRNA]] expression has been shown to be upregulated in left [[ventricle (heart)|ventricle]]s of [[heart failure]] patients.<ref>{{cite journal | vauthors = Bogomolovas J, Brohm K, Čelutkienė J, Balčiūnaitė G, Bironaitė D, Bukelskienė V, Daunoravičus D, Witt CC, Fielitz J, Grabauskienė V, Labeit S | title = Induction of ankrd1 in dilated cardiomyopathy correlates with the heart failure progression | journal = BioMed Research International | volume = 2015 | pages = 273936 | date = 2015 | pmid = 25961010 | doi = 10.1155/2015/273936 | pmc=4415747}}</ref><ref>{{cite journal | vauthors = Wei YJ, Cui CJ, Huang YX, Zhang XL, Zhang H, Hu SS | title = Upregulated expression of cardiac ankyrin repeat protein in human failing hearts due to arrhythmogenic right ventricular cardiomyopathy | journal = European Journal of Heart Failure | volume = 11 | issue = 6 | pages = 559–66 | date = Jun 2009 | pmid = 19359327 | doi = 10.1093/eurjhf/hfp049 }}</ref><ref>{{cite journal | vauthors = Nagueh SF, Shah G, Wu Y, Torre-Amione G, King NM, Lahmers S, Witt CC, Becker K, Labeit S, Granzier HL | title = Altered titin expression, myocardial stiffness, and left ventricular function in patients with dilated cardiomyopathy | journal = Circulation | volume = 110 | issue = 2 | pages = 155–62 | date = Jul 2004 | pmid = 15238456 | doi = 10.1161/01.CIR.0000135591.37759.AF }}</ref><ref>{{cite journal | vauthors = Zolk O, Frohme M, Maurer A, Kluxen FW, Hentsch B, Zubakov D, Hoheisel JD, Zucker IH, Pepe S, Eschenhagen T | title = Cardiac ankyrin repeat protein, a negative regulator of cardiac gene expression, is augmented in human heart failure | journal = Biochemical and Biophysical Research Communications | volume = 293 | issue = 5 | pages = 1377–82 | date = May 2002 | pmid = 12054667 | doi = 10.1016/S0006-291X(02)00387-X }}</ref> Studies in patients with [[amyotrophic lateral sclerosis]],<ref>{{cite journal | vauthors = Nakamura K, Nakada C, Takeuchi K, Osaki M, Shomori K, Kato S, Ohama E, Sato K, Fukayama M, Mori S, Ito H, Moriyama M | title = Altered expression of cardiac ankyrin repeat protein and its homologue, ankyrin repeat protein with PEST and proline-rich region, in atrophic muscles in amyotrophic lateral sclerosis | journal = Pathobiology | volume = 70 | issue = 4 | pages = 197–203 | date = Apr 2003 | pmid = 12679596 | doi =  10.1159/000069329}}</ref> [[spinal muscular atrophy]], and [[congenital myopathy]],<ref>{{cite journal | vauthors = Nakada C, Oka A, Nonaka I, Sato K, Mori S, Ito H, Moriyama M | title = Cardiac ankyrin repeat protein is preferentially induced in atrophic myofibers of congenital myopathy and spinal muscular atrophy | journal = Pathology International | volume = 53 | issue = 10 | pages = 653–8 | date = Oct 2003 | pmid = 14516314 | doi=10.1046/j.1440-1827.2003.01541.x}}</ref> also found altered expression of CARP in [[skeletal muscle]] fibers. Another study in [[congenital muscular dystrophy]] and [[Duchenne muscular dystrophy]] patients showed elevated expression of CARP.<ref>{{cite journal | vauthors = Nakada C, Tsukamoto Y, Oka A, Nonaka I, Takeda S, Sato K, Mori S, Ito H, Moriyama M | title = Cardiac-restricted ankyrin-repeated protein is differentially induced in duchenne and congenital muscular dystrophy | journal = Laboratory Investigation | volume = 83 | issue = 5 | pages = 711–9 | date = May 2003 | pmid = 12746480 | doi=10.1097/01.lab.0000067484.35298.1a}}</ref> CARP expression is also elevated in patients with [[lupus nephritis]], and associates with [[proteinuria]] severity, suggesting that it may have biomarker potential.<ref>{{cite journal | vauthors = Matsuura K, Uesugi N, Hijiya N, Uchida T, Moriyama M | title = Upregulated expression of cardiac ankyrin-repeated protein in renal podocytes is associated with proteinuria severity in lupus nephritis | journal = Human Pathology | volume = 38 | issue = 3 | pages = 410–9 | date = Mar 2007 | pmid = 17239933 | doi = 10.1016/j.humpath.2006.09.006 }}</ref>


== Interactions ==
== Interactions ==

Latest revision as of 00:26, 29 July 2018

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CARP, also known as Cardiac adriamycin-responsive protein or Cardiac ankyrin repeat protein is a protein that in humans is encoded by the ANKRD1 gene.[1][2] CARP is highly expressed in cardiac and skeletal muscle, and is a transcription factor involved in development and under conditions of stress. CARP has been implicated in several diseases, including dilated cardiomyopathy, hypertrophic cardiomyopathy, and several skeletal muscle myopathies.

Structure

Human CARP is a 36.2kDa protein composed of 319 amino acids.,[3] though in cardiomyocytes, CARP can exist as multiple alternatively spliced forms.[4] CARP contains five tandem ankyrin repeats. Studies have shown that CARP can homodimerize.[5] Studies have also shown that CARP is N-terminally, post-translationally cleaved by calpain-3 in skeletal muscle, suggesting alternate bioactive forms of CARP exist.[6] CARP has been localized to nuclei and Z-discs in animal and human myocytes, and at intercalated discs in human cells.[7]

Function

CARP was originally identified as a YB-1-associating, cardiac-restricted transcription co-repressor in the homeobox NKX2-5 pathway that is involved in cardiac ventricular chamber specification, maturation and morphogenesis,[8][9][10] and whose mRNA levels are exquisitely sensitive to Doxorubicin, mediated through a hydrogen peroxide/ERK/p38MAP kinase-dependent[11][12] as well as M-CAT cis-element-dependent[13] mechanism. Subsequent studies showed that CARP expression in cardiomyocytes is regulated by alpha-adrenergic signaling, in part via the transcription factor GATA4.[14][15] An additional study showed that beta-adrenergic signaling via protein kinase A and CaM kinase induces the expression of CARP, and that CARP may have a negative effect on contractile function.[16] CARP has also been identified as a transcriptional co-activator of tumor suppressor protein p53 for stimulating gene expression in muscle; p53 was found to be an upstream effector of CARP via upregulation of the proximal ANKRD1 promoter.[17] CARP has a relatively short half-life being longer in cardiomyocytes than endothelial cells; and CARP is degraded by the 26S proteasome via a PEST degron.[18][19]

In animal models of disease and injury, CARP has been characterized to be a stress-inducible myofibrillar protein. CARP has been shown to play a role in skeletal muscle structure[20] remodeling,[21] and repair, being expressed in skeletal muscle near myotendinous junctions,[22] and in vascular smooth muscle cells, as a downstream target of TGF-beta/Smad sigmaling in response to balloon injury[23] and atherosclerotic plaques.[24] Further studies have identified a role for CARP in initiation and regulation of arteriogenesis.[25][26][27] Decreased expression of CARP in cardiac cells within the ischemic region was detected in a rat model of ischemic injury, and was thought to be linked to the induction of GADD153, an apoptosis-related gene.[28] In cardiomyocytes treated with doxorubicin, a model of anthracycline-induced cardiomyopathy, CARP mRNA and protein levels were depleted, myofilament gene transcription was attenuated and sarcomeres showed significant disarray.[29]

In a transgenic mouse model of cardiac-specific overexpression of CARP, mice exhibited normal physiology at baseline, but were protected against pathological cardiac hypertrophy induced via pressure-overload or isoproterenol, which could be attributed to the downregulation of the ERK1/2, MEK and TGFbeta-1 pathways.[30] Another study demonstrated that adenoviral overexpression of CARP in cardiomyocytes enhances cardiac hypertrophy induced by Angiotensin II or pressure-overload[31] and promotoes cardiomyocyte apoptosis via p53 activation and mitochondrial dysfunction.[32] However, transgenic knockout models of either CARP alone or CARP in combination with the other muscle ankyrin repeat proteins (MARPs), ANKRD2 and ANKRD23 demonstrated a lack of cardiac phenotype; mice displayed normal cardiac function at baseline and in response to pressure overload-induced cardiac hypertrophy, suggesting that these proteins are not essential.[33]

Interactions between CARP and the sarcomeric proteins myopalladin and titin suggest that it may also be involved in the myofibrillar stretch-sensor system. Passive stretch in fetal cardiomyocytes induced differential CARP distribution at nuclei and I-band titin N2A regions.[34] In a mouse model of muscular dystrophy with myositis (mdm) caused by a small deletion in titin, CARP mRNA expression was shown to be 30-fold elevated in skeletal muscle tissue.[35]

Clinical significance

A wide spectrum of clinical features have been associated with ANKRD1/CARP. Mutations in ANKRD1 have been associated with dilated cardiomyopathy, two of which result in altered binding with TLN1 and FHL2.[36][37] Mutations in ANKRD1 have also been associated with hypertrophic cardiomyopathy, and have shown to increase binding of CARP to Titin and MYPN.[38] Examination of the functional effects of CARP hypertrophic cardiomyopathy mutations in engineered heart tissue demonstrated that Thr123Met was a gain-of-function mutation exhibiting augmented contractile properties; whereas Pro52Ala and Ile280Val were unstable and failed to incorporate into sarcomeres, an effect that was remedied upon proteasome inhibition via epoxomicin.[39]

A missense mutation in ANKRD1 was shown to be associated with the congenital heart defect, Anomalous pulmonary venous connection.[40] CARP has been found as a sensitive and specific biomarker for the differential diagnosis of rhabdomyosarcoma.[41] ANKRD1 mRNA levels correlate with patient platinum sensitivity, thus ANKRD1 associates with platinum-based chemotherapy treatment outcome in ovarian adenocarcinoma patients.[42]

CARP and mRNA expression has been shown to be upregulated in left ventricles of heart failure patients.[43][44][45][46] Studies in patients with amyotrophic lateral sclerosis,[47] spinal muscular atrophy, and congenital myopathy,[48] also found altered expression of CARP in skeletal muscle fibers. Another study in congenital muscular dystrophy and Duchenne muscular dystrophy patients showed elevated expression of CARP.[49] CARP expression is also elevated in patients with lupus nephritis, and associates with proteinuria severity, suggesting that it may have biomarker potential.[50]

Interactions

ANKRD1 has been shown to interact with:

References

  1. ↑ Chu W, Burns DK, Swerlick RA, Presky DH (June 1995). "Identification and characterization of a novel cytokine-inducible nuclear protein from human endothelial cells". J. Biol. Chem. 270 (17): 10236–45. doi:10.1074/jbc.270.17.10236. PMID 7730328.
  2. ↑ "Entrez Gene: ANKRD1 ankyrin repeat domain 1 (cardiac muscle)".
  3. ↑ "Protein sequence of human ANKRD1 (Uniprot ID: Q15327)". Cardiac Organellar Protein Atlas Knowledgebase. Retrieved 23 June 2015.
  4. ↑ Torrado M, Iglesias R, Nespereira B, Centeno A, López E, Mikhailov AT (Jul 2009). "Intron retention generates ANKRD1 splice variants that are co-regulated with the main transcript in normal and failing myocardium". Gene. 440 (1–2): 28–41. doi:10.1016/j.gene.2009.03.017. PMID 19341785.
  5. ↑ 5.0 5.1 Witt SH, Labeit D, Granzier H, Labeit S, Witt CC (2005). "Dimerization of the cardiac ankyrin protein CARP: implications for MARP titin-based signaling". Journal of Muscle Research and Cell Motility. 26 (6–8): 401–8. doi:10.1007/s10974-005-9022-9. PMID 16450059.
  6. ↑ Laure L, Danièle N, Suel L, Marchand S, Aubert S, Bourg N, Roudaut C, Duguez S, Bartoli M, Richard I (Oct 2010). "A new pathway encompassing calpain 3 and its newly identified substrate cardiac ankyrin repeat protein is involved in the regulation of the nuclear factor-κB pathway in skeletal muscle". The FEBS Journal. 277 (20): 4322–37. doi:10.1111/j.1742-4658.2010.07820.x. PMID 20860623.
  7. ↑ Jasnic-Savovic J, Nestorovic A, Savic S, Karasek S, Vitulo N, Valle G, Faulkner G, Radojkovic D, Kojic S (Jun 2015). "Profiling of skeletal muscle Ankrd2 protein in human cardiac tissue and neonatal rat cardiomyocytes". Histochemistry and Cell Biology. 143 (6): 583–97. doi:10.1007/s00418-015-1307-5. PMID 25585647.
  8. ↑ 8.0 8.1 Zou Y, Evans S, Chen J, Kuo HC, Harvey RP, Chien KR (Feb 1997). "CARP, a cardiac ankyrin repeat protein, is downstream in the Nkx2-5 homeobox gene pathway". Development. 124 (4): 793–804. PMID 9043061.
  9. ↑ Kuo H, Chen J, Ruiz-Lozano P, Zou Y, Nemer M, Chien KR (Oct 1999). "Control of segmental expression of the cardiac-restricted ankyrin repeat protein gene by distinct regulatory pathways in murine cardiogenesis". Development. 126 (19): 4223–34. PMID 10477291.
  10. ↑ Takimoto E, Mizuno T, Terasaki F, Shimoyama M, Honda H, Shiojima I, Hiroi Y, Oka T, Hayashi D, Hirai H, Kudoh S, Toko H, Kawamura K, Nagai R, Yazaki Y, Komuro I (Apr 2000). "Up-regulation of natriuretic peptides in the ventricle of Csx/Nkx2-5 transgenic mice". Biochemical and Biophysical Research Communications. 270 (3): 1074–9. doi:10.1006/bbrc.2000.2561. PMID 10772952.
  11. ↑ Jeyaseelan R, Poizat C, Baker RK, Abdishoo S, Isterabadi LB, Lyons GE, Kedes L (Sep 1997). "A novel cardiac-restricted target for doxorubicin. CARP, a nuclear modulator of gene expression in cardiac progenitor cells and cardiomyocytes". The Journal of Biological Chemistry. 272 (36): 22800–8. doi:10.1074/jbc.272.36.22800. PMID 9278441.
  12. ↑ Aihara Y, Kurabayashi M, Tanaka T, Takeda SI, Tomaru K, Sekiguchi KI, Ohyama Y, Nagai R (Aug 2000). "Doxorubicin represses CARP gene transcription through the generation of oxidative stress in neonatal rat cardiac myocytes: possible role of serine/threonine kinase-dependent pathways". Journal of Molecular and Cellular Cardiology. 32 (8): 1401–14. doi:10.1006/jmcc.2000.1173. PMID 10900167.
  13. ↑ Aihara Y, Kurabayashi M, Saito Y, Ohyama Y, Tanaka T, Takeda S, Tomaru K, Sekiguchi K, Arai M, Nakamura T, Nagai R (Jul 2000). "Cardiac ankyrin repeat protein is a novel marker of cardiac hypertrophy: role of M-CAT element within the promoter". Hypertension. 36 (1): 48–53. doi:10.1161/01.hyp.36.1.48. PMID 10904011.
  14. ↑ Maeda T, Sepulveda J, Chen HH, Stewart AF (Sep 2002). "Alpha(1)-adrenergic activation of the cardiac ankyrin repeat protein gene in cardiac myocytes". Gene. 297 (1–2): 1–9. doi:10.1016/s0378-1119(02)00924-1. PMID 12384280.
  15. ↑ Zhong L, Chiusa M, Cadar AG, Lin A, Samaras S, Davidson JM, Lim CC (May 2015). "Targeted inhibition of ANKRD1 disrupts sarcomeric ERK-GATA4 signal transduction and abrogates phenylephrine-induced cardiomyocyte hypertrophy". Cardiovascular Research. 106 (2): 261–71. doi:10.1093/cvr/cvv108. PMC 4481572. PMID 25770146.
  16. ↑ Zolk O, Marx M, Jäckel E, El-Armouche A, Eschenhagen T (Sep 2003). "Beta-adrenergic stimulation induces cardiac ankyrin repeat protein expression: involvement of protein kinase A and calmodulin-dependent kinase". Cardiovascular Research. 59 (3): 563–72. doi:10.1016/s0008-6363(03)00476-0. PMID 14499857.
  17. ↑ 17.0 17.1 Kojic S, Nestorovic A, Rakicevic L, Belgrano A, Stankovic M, Divac A, Faulkner G (Oct 2010). "A novel role for cardiac ankyrin repeat protein Ankrd1/CARP as a co-activator of the p53 tumor suppressor protein". Archives of Biochemistry and Biophysics. 502 (1): 60–7. doi:10.1016/j.abb.2010.06.029. PMID 20599664.
  18. ↑ Samaras SE, Chen B, Koch SR, Sawyer DB, Lim CC, Davidson JM (Sep 2012). "26S proteasome regulation of Ankrd1/CARP in adult rat ventricular myocytes and human microvascular endothelial cells". Biochemical and Biophysical Research Communications. 425 (4): 830–5. doi:10.1016/j.bbrc.2012.07.162. PMC 3460693. PMID 22892129.
  19. ↑ Badi I, Cinquetti R, Frascoli M, Parolini C, Chiesa G, Taramelli R, Acquati F (Aug 2009). "Intracellular ANKRD1 protein levels are regulated by 26S proteasome-mediated degradation". FEBS Letters. 583 (15): 2486–92. doi:10.1016/j.febslet.2009.07.001. PMID 19589340.
  20. ↑ Barash IA, Bang ML, Mathew L, Greaser ML, Chen J, Lieber RL (Jul 2007). "Structural and regulatory roles of muscle ankyrin repeat protein family in skeletal muscle". American Journal of Physiology. Cell Physiology. 293 (1): C218–27. doi:10.1152/ajpcell.00055.2007. PMID 17392382.
  21. ↑ Laure L, Suel L, Roudaut C, Bourg N, Ouali A, Bartoli M, Richard I, Danièle N (Feb 2009). "Cardiac ankyrin repeat protein is a marker of skeletal muscle pathological remodelling". The FEBS Journal. 276 (3): 669–84. doi:10.1111/j.1742-4658.2008.06814.x. PMID 19143834.
  22. ↑ Baumeister A, Arber S, Caroni P (Dec 1997). "Accumulation of muscle ankyrin repeat protein transcript reveals local activation of primary myotube endcompartments during muscle morphogenesis". The Journal of Cell Biology. 139 (5): 1231–42. doi:10.1083/jcb.139.5.1231. PMC 2140219. PMID 9382869.
  23. ↑ Kanai H, Tanaka T, Aihara Y, Takeda S, Kawabata M, Miyazono K, Nagai R, Kurabayashi M (Jan 2001). "Transforming growth factor-beta/Smads signaling induces transcription of the cell type-restricted ankyrin repeat protein CARP gene through CAGA motif in vascular smooth muscle cells". Circulation Research. 88 (1): 30–6. doi:10.1161/01.res.88.1.30. PMID 11139470.
  24. ↑ de Waard V, van Achterberg TA, Beauchamp NJ, Pannekoek H, de Vries CJ (Jan 2003). "Cardiac ankyrin repeat protein (CARP) expression in human and murine atherosclerotic lesions: activin induces CARP in smooth muscle cells". Arteriosclerosis, Thrombosis, and Vascular Biology. 23 (1): 64–8. doi:10.1161/01.atv.0000042218.13101.50. PMID 12524226.
  25. ↑ Boengler K, Pipp F, Fernandez B, Ziegelhoeffer T, Schaper W, Deindl E (Sep 2003). "Arteriogenesis is associated with an induction of the cardiac ankyrin repeat protein (carp)". Cardiovascular Research. 59 (3): 573–81. doi:10.1016/s0008-6363(03)00511-x. PMID 14499858.
  26. ↑ Shi Y, Reitmaier B, Regenbogen J, Slowey RM, Opalenik SR, Wolf E, Goppelt A, Davidson JM (Jan 2005). "CARP, a cardiac ankyrin repeat protein, is up-regulated during wound healing and induces angiogenesis in experimental granulation tissue". The American Journal of Pathology. 166 (1): 303–12. doi:10.1016/S0002-9440(10)62254-7. PMC 1602297. PMID 15632022.
  27. ↑ Samaras SE, Shi Y, Davidson JM (Sep 2006). "CARP: fishing for novel mechanisms of neovascularization". The Journal of Investigative Dermatology. Symposium Proceedings. 11 (1): 124–31. doi:10.1038/sj.jidsymp.5650014. PMID 17069020.
  28. ↑ Lee MJ, Kwak YK, You KR, Lee BH, Kim DG (Apr 2009). "Involvement of GADD153 and cardiac ankyrin repeat protein in cardiac ischemia-reperfusion injury". Experimental & Molecular Medicine. 41 (4): 243–52. doi:10.3858/emm.2009.41.4.027. PMC 2679233. PMID 19299913.
  29. ↑ Chen B, Zhong L, Roush SF, Pentassuglia L, Peng X, Samaras S, Davidson JM, Sawyer DB, Lim CC (2012). "Disruption of a GATA4/Ankrd1 signaling axis in cardiomyocytes leads to sarcomere disarray: implications for anthracycline cardiomyopathy". PLOS ONE. 7 (4): e35743. doi:10.1371/journal.pone.0035743. PMC 3332030. PMID 22532871.
  30. ↑ Song Y, Xu J, Li Y, Jia C, Ma X, Zhang L, Xie X, Zhang Y, Gao X, Zhang Y, Zhu D (2012). "Cardiac ankyrin repeat protein attenuates cardiac hypertrophy by inhibition of ERK1/2 and TGF-β signaling pathways". PLOS ONE. 7 (12): e50436. doi:10.1371/journal.pone.0050436. PMC 3515619. PMID 23227174.
  31. ↑ Chen C, Shen L, Cao S, Li X, Xuan W, Zhang J, Huang X, Bin J, Xu D, Li G, Kitakaze M, Liao Y (2014). "Cytosolic CARP promotes angiotensin II- or pressure overload-induced cardiomyocyte hypertrophy through calcineurin accumulation". PLOS ONE. 9 (8): e104040. doi:10.1371/journal.pone.0104040. PMC 4121294. PMID 25089522.
  32. ↑ Shen L, Chen C, Wei X, Li X, Luo G, Zhang J, Bin J, Huang X, Cao S, Li G, Liao Y (May 2015). "Overexpression of ankyrin repeat domain 1 enhances cardiomyocyte apoptosis by promoting p53 activation and mitochondrial dysfunction in rodents". Clinical Science. 128 (10): 665–78. doi:10.1042/CS20140586. PMID 25511237.
  33. ↑ Bang ML, Gu Y, Dalton ND, Peterson KL, Chien KR, Chen J (2014). "The muscle ankyrin repeat proteins CARP, Ankrd2, and DARP are not essential for normal cardiac development and function at basal conditions and in response to pressure overload". PLOS ONE. 9 (4): e93638. doi:10.1371/journal.pone.0093638. PMC 3988038. PMID 24736439.
  34. ↑ Miller MK, Bang ML, Witt CC, Labeit D, Trombitas C, Watanabe K, Granzier H, McElhinny AS, Gregorio CC, Labeit S (Nov 2003). "The muscle ankyrin repeat proteins: CARP, ankrd2/Arpp and DARP as a family of titin filament-based stress response molecules". Journal of Molecular Biology. 333 (5): 951–64. doi:10.1016/j.jmb.2003.09.012. PMID 14583192.
  35. ↑ Witt CC, Ono Y, Puschmann E, McNabb M, Wu Y, Gotthardt M, Witt SH, Haak M, Labeit D, Gregorio CC, Sorimachi H, Granzier H, Labeit S (Feb 2004). "Induction and myofibrillar targeting of CARP, and suppression of the Nkx2.5 pathway in the MDM mouse with impaired titin-based signaling". Journal of Molecular Biology. 336 (1): 145–54. doi:10.1016/j.jmb.2003.12.021. PMID 14741210.
  36. ↑ 36.0 36.1 36.2 Moulik M, Vatta M, Witt SH, Arola AM, Murphy RT, McKenna WJ, Boriek AM, Oka K, Labeit S, Bowles NE, Arimura T, Kimura A, Towbin JA (Jul 2009). "ANKRD1, the gene encoding cardiac ankyrin repeat protein, is a novel dilated cardiomyopathy gene". Journal of the American College of Cardiology. 54 (4): 325–33. doi:10.1016/j.jacc.2009.02.076. PMC 2915893. PMID 19608030.
  37. ↑ Duboscq-Bidot L, Charron P, Ruppert V, Fauchier L, Richter A, Tavazzi L, Arbustini E, Wichter T, Maisch B, Komajda M, Isnard R, Villard E (Sep 2009). "Mutations in the ANKRD1 gene encoding CARP are responsible for human dilated cardiomyopathy". European Heart Journal. 30 (17): 2128–36. doi:10.1093/eurheartj/ehp225. PMID 19525294.
  38. ↑ Arimura T, Bos JM, Sato A, Kubo T, Okamoto H, Nishi H, Harada H, Koga Y, Moulik M, Doi YL, Towbin JA, Ackerman MJ, Kimura A (Jul 2009). "Cardiac ankyrin repeat protein gene (ANKRD1) mutations in hypertrophic cardiomyopathy". Journal of the American College of Cardiology. 54 (4): 334–42. doi:10.1016/j.jacc.2008.12.082. PMID 19608031.
  39. ↑ Crocini C, Arimura T, Reischmann S, Eder A, Braren I, Hansen A, Eschenhagen T, Kimura A, Carrier L (May 2013). "Impact of ANKRD1 mutations associated with hypertrophic cardiomyopathy on contraction parameters of engineered heart tissue". Basic Research in Cardiology. 108 (3): 349. doi:10.1007/s00395-013-0349-x. PMID 23572067.
  40. ↑ Cinquetti R, Badi I, Campione M, Bortoletto E, Chiesa G, Parolini C, Camesasca C, Russo A, Taramelli R, Acquati F (Apr 2008). "Transcriptional deregulation and a missense mutation define ANKRD1 as a candidate gene for total anomalous pulmonary venous return". Human Mutation. 29 (4): 468–74. doi:10.1002/humu.20711. PMID 18273862.
  41. ↑ Ishiguro N, Motoi T, Araki N, Ito H, Moriyama M, Yoshida H (Nov 2008). "Expression of cardiac ankyrin repeat protein, CARP, in malignant tumors: diagnostic use of CARP protein immunostaining in rhabdomyosarcoma". Human Pathology. 39 (11): 1673–9. doi:10.1016/j.humpath.2008.04.009. PMID 18656235.
  42. ↑ Scurr LL, Guminski AD, Chiew YE, Balleine RL, Sharma R, Lei Y, Pryor K, Wain GV, Brand A, Byth K, Kennedy C, Rizos H, Harnett PR, deFazio A (Nov 2008). "Ankyrin repeat domain 1, ANKRD1, a novel determinant of cisplatin sensitivity expressed in ovarian cancer". Clinical Cancer Research. 14 (21): 6924–32. doi:10.1158/1078-0432.CCR-07-5189. PMID 18980987.
  43. ↑ Bogomolovas J, Brohm K, Čelutkienė J, Balčiūnaitė G, Bironaitė D, Bukelskienė V, Daunoravičus D, Witt CC, Fielitz J, Grabauskienė V, Labeit S (2015). "Induction of ankrd1 in dilated cardiomyopathy correlates with the heart failure progression". BioMed Research International. 2015: 273936. doi:10.1155/2015/273936. PMC 4415747. PMID 25961010.
  44. ↑ Wei YJ, Cui CJ, Huang YX, Zhang XL, Zhang H, Hu SS (Jun 2009). "Upregulated expression of cardiac ankyrin repeat protein in human failing hearts due to arrhythmogenic right ventricular cardiomyopathy". European Journal of Heart Failure. 11 (6): 559–66. doi:10.1093/eurjhf/hfp049. PMID 19359327.
  45. ↑ Nagueh SF, Shah G, Wu Y, Torre-Amione G, King NM, Lahmers S, Witt CC, Becker K, Labeit S, Granzier HL (Jul 2004). "Altered titin expression, myocardial stiffness, and left ventricular function in patients with dilated cardiomyopathy". Circulation. 110 (2): 155–62. doi:10.1161/01.CIR.0000135591.37759.AF. PMID 15238456.
  46. ↑ Zolk O, Frohme M, Maurer A, Kluxen FW, Hentsch B, Zubakov D, Hoheisel JD, Zucker IH, Pepe S, Eschenhagen T (May 2002). "Cardiac ankyrin repeat protein, a negative regulator of cardiac gene expression, is augmented in human heart failure". Biochemical and Biophysical Research Communications. 293 (5): 1377–82. doi:10.1016/S0006-291X(02)00387-X. PMID 12054667.
  47. ↑ Nakamura K, Nakada C, Takeuchi K, Osaki M, Shomori K, Kato S, Ohama E, Sato K, Fukayama M, Mori S, Ito H, Moriyama M (Apr 2003). "Altered expression of cardiac ankyrin repeat protein and its homologue, ankyrin repeat protein with PEST and proline-rich region, in atrophic muscles in amyotrophic lateral sclerosis". Pathobiology. 70 (4): 197–203. doi:10.1159/000069329. PMID 12679596.
  48. ↑ Nakada C, Oka A, Nonaka I, Sato K, Mori S, Ito H, Moriyama M (Oct 2003). "Cardiac ankyrin repeat protein is preferentially induced in atrophic myofibers of congenital myopathy and spinal muscular atrophy". Pathology International. 53 (10): 653–8. doi:10.1046/j.1440-1827.2003.01541.x. PMID 14516314.
  49. ↑ Nakada C, Tsukamoto Y, Oka A, Nonaka I, Takeda S, Sato K, Mori S, Ito H, Moriyama M (May 2003). "Cardiac-restricted ankyrin-repeated protein is differentially induced in duchenne and congenital muscular dystrophy". Laboratory Investigation. 83 (5): 711–9. doi:10.1097/01.lab.0000067484.35298.1a. PMID 12746480.
  50. ↑ Matsuura K, Uesugi N, Hijiya N, Uchida T, Moriyama M (Mar 2007). "Upregulated expression of cardiac ankyrin-repeated protein in renal podocytes is associated with proteinuria severity in lupus nephritis". Human Pathology. 38 (3): 410–9. doi:10.1016/j.humpath.2006.09.006. PMID 17239933.
  51. ↑ 51.0 51.1 Miller MK, Bang ML, Witt CC, Labeit D, Trombitas C, Watanabe K, Granzier H, McElhinny AS, Gregorio CC, Labeit S (November 2003). "The muscle ankyrin repeat proteins: CARP, ankrd2/Arpp and DARP as a family of titin filament-based stress response molecules". J. Mol. Biol. 333 (5): 951–64. doi:10.1016/j.jmb.2003.09.012. PMID 14583192.
  52. ↑ Bang ML, Mudry RE, McElhinny AS, Trombitás K, Geach AJ, Yamasaki R, Sorimachi H, Granzier H, Gregorio CC, Labeit S (April 2001). "Myopalladin, a novel 145-kilodalton sarcomeric protein with multiple roles in Z-disc and I-band protein assemblies". J. Cell Biol. 153 (2): 413–27. doi:10.1083/jcb.153.2.413. PMC 2169455. PMID 11309420.
  53. ↑ Torrado M, Nespereira B, López E, Centeno A, Castro-Beiras A, Mikhailov AT (Feb 2005). "ANKRD1 specifically binds CASQ2 in heart extracts and both proteins are co-enriched in piglet cardiac Purkinje cells". Journal of Molecular and Cellular Cardiology. 38 (2): 353–65. doi:10.1016/j.yjmcc.2004.11.034. PMID 15698842.

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