Parathyroid hormone-related protein: Difference between revisions

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{{Infobox gene}}
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| update_page = yes
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| update_protein_box = yes
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
{{GNF_Protein_box
| image = PBB_Protein_PTHLH_image.jpg
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 1bzg.
| PDB =
| Name = Parathyroid hormone-like hormone
| HGNCid = 9607
| Symbol = PTHLH
| AltSymbols =; PLP; HHM; MGC14611; PTHR; PTHRP
| OMIM = 168470
| ECnumber = 
| Homologene = 2113
| MGIid = 97800
| GeneAtlas_image1 = PBB_GE_PTHLH_206300_s_at_tn.png
| GeneAtlas_image2 = PBB_GE_PTHLH_211756_at_tn.png
| Function = {{GNF_GO|id=GO:0005179 |text = hormone activity}} {{GNF_GO|id=GO:0005509 |text = calcium ion binding}}
| Component = {{GNF_GO|id=GO:0005576 |text = extracellular region}} {{GNF_GO|id=GO:0005615 |text = extracellular space}} {{GNF_GO|id=GO:0005634 |text = nucleus}} {{GNF_GO|id=GO:0005737 |text = cytoplasm}}
| Process = {{GNF_GO|id=GO:0001501 |text = skeletal development}} {{GNF_GO|id=GO:0002076 |text = osteoblast development}} {{GNF_GO|id=GO:0007189 |text = G-protein signaling, adenylate cyclase activating pathway}} {{GNF_GO|id=GO:0007267 |text = cell-cell signaling}} {{GNF_GO|id=GO:0007565 |text = female pregnancy}} {{GNF_GO|id=GO:0007595 |text = lactation}} {{GNF_GO|id=GO:0008284 |text = positive regulation of cell proliferation}} {{GNF_GO|id=GO:0008285 |text = negative regulation of cell proliferation}} {{GNF_GO|id=GO:0008544 |text = epidermis development}} {{GNF_GO|id=GO:0030855 |text = epithelial cell differentiation}} {{GNF_GO|id=GO:0043129 |text = surfactant homeostasis}} {{GNF_GO|id=GO:0046058 |text = cAMP metabolic process}} {{GNF_GO|id=GO:0048286 |text = alveolus development}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 5744
    | Hs_Ensembl = ENSG00000087494
    | Hs_RefseqProtein = NP_002811
    | Hs_RefseqmRNA = NM_002820
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 12
    | Hs_GenLoc_start = 28006092
    | Hs_GenLoc_end = 28015124
    | Hs_Uniprot = P12272
    | Mm_EntrezGene = 19227
    | Mm_Ensembl = ENSMUSG00000048776
    | Mm_RefseqmRNA = NM_008970
    | Mm_RefseqProtein = NP_032996
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 6
    | Mm_GenLoc_start = 147214106
    | Mm_GenLoc_end = 147220540
    | Mm_Uniprot = Q540C1
  }}
}}
{{SI}}
{{CMG}}


==Overview==
'''Parathyroid hormone-related protein''' (or '''PTHrP''') is a [[protein]] member of the [[parathyroid hormone family]]. It is occasionally secreted by [[cancer]] cells ([[breast cancer]], certain types of [[lung cancer]] including [[squamous cell lung carcinoma]]). However, it also has normal functions.
'''Parathyroid hormone-related protein''' (or '''PTHrP''') is a [[protein]] member of the [[parathyroid hormone]] family. It is occasionally secreted by [[cancer]] cells ([[breast cancer]], certain types of [[lung cancer]] including [[squamous cell carcinoma]]). However, it also has normal functions.


==Functions==
== Function ==
PTHrP acts as an [[endocrine system | endocrine]], [[autocrine signalling | autocrine]]/[[paracrine signalling | paracrine]], and [[intracrine]] hormone. It regulates [[endochondral]] bone development and [[epithelial-mesenchymal transition|epithelial-mesenchymal interaction]]s during the formation of the mammary glands and teeth. It aids in normal mammary gland development and lactation, possibly by regulating the mobilization and transfer of calcium to the milk, as well as placental transfer of calcium.


PTHrP is related in function to the "normal" parathyroid hormone. When a [[tumor]] secretes PTHrP, this can lead to [[hypercalcemia]]. As this is sometimes the first sign of the [[malignancy]], [[hypercalcemia]] caused by PTHrP is considered a [[paraneoplastic phenomenon]].
PTHrP acts as an [[endocrine system|endocrine]], [[autocrine signalling|autocrine]], [[paracrine signalling|paracrine]], and [[intracrine]] hormone. It regulates [[endochondral]] bone development by maintaining the endochondral growth plate at a constant width. It also regulates [[epithelial-mesenchymal transition|epithelial-mesenchymal interaction]]s during the formation of the mammary glands.  


PTHrP shares the same [[N-terminal]] end as parathyroid hormone and therefore it can bind to the same receptor, the Type I PTH receptor ([[Parathyroid hormone receptor 1|PTHR1]]). PTHR1 is responsible for most cases of humoral hypercalcemia of malignancy.
=== Tooth eruption ===


==Genetics==
PTHrP is critical in  intraosseous phase of tooth eruption where it acts as a signalling molecule to stimulate local bone resorption. Without PTHrP, the bony crypt surrounding the tooth follicle will not resorb, and therefore the tooth will not erupt. In the context of tooth eruption, PTHrP is secreted by the cells of the Reduced Enamel Epithelium.
Four [[alternative splicing|alternatively spliced]] transcript variants encoding two distinct [[isoform]]s have been observed. There is also evidence for alternative translation initiation from non-AUG (CUG and GUG) start sites, in-frame and downstream of the initiator AUG codon, to give rise to nuclear forms of this hormone.<ref>{{cite web | title = Entrez Gene: PTHLH parathyroid hormone-like hormone| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5744| accessdate = }}</ref>


==History==
=== Mammary glands ===
The protein was first isolated in [[1988]] by Broadus ''et al''. Miao ''et al'' showed that disruption of the ''PTHrP'' gene in mice caused a lethal phenotype and distinct bone abnormalities, suggesting that PTHrP has a physiological function.


==References==
It aids in normal mammary gland development.<ref name="pmid17301089">{{cite journal | vauthors = Hens JR, Dann P, Zhang JP, Harris S, Robinson GW, Wysolmerski J | title = BMP4 and PTHrP interact to stimulate ductal outgrowth during embryonic mammary development and to inhibit hair follicle induction | journal = Development | volume = 134 | issue = 6 | pages = 1221–30 | date = March 2007 | pmid = 17301089 | doi = 10.1242/dev.000182 }}</ref><ref name="pmid16168142">{{cite journal | vauthors = Hens JR, Wysolmerski JJ | title = Key stages of mammary gland development: molecular mechanisms involved in the formation of the embryonic mammary gland | journal = Breast Cancer Research | volume = 7 | issue = 5 | pages = 220–4 | year = 2005 | pmid = 16168142 | pmc = 1242158 | doi = 10.1186/bcr1306 }}</ref> It is necessary for maintenance of the mammary bud. Loss of PTHrP or its receptor causes the mammary bud cell fate to change back into epidermis. In lactation, it may regulate in conjunction with the calcium sensing receptor the mobilization and transfer of calcium to the milk, as well as placental transfer of calcium.
{{reflist|2}}


==Further reading==
=== Humoral hypercalcemia of malignancy ===
{{refbegin | 2}}
 
* Broadus AE, Mangin M, Ikeda K, Insogna KL, Weir EC, Burtis WJ, Stewart AF. Humoral hypercalcemia of cancer. Identification of a novel parathyroid hormone-like peptide. ''[[N Engl J Med]]'' 1988;319:556-63. PMID 3043221.
PTHrP is related in function to the "normal" parathyroid hormone. When a [[tumor]] secretes PTHrP, this can lead to [[hypercalcemia]].<ref name="pmid3043221">{{cite journal | vauthors = Broadus AE, Mangin M, Ikeda K, Insogna KL, Weir EC, Burtis WJ, Stewart AF | title = Humoral hypercalcemia of cancer. Identification of a novel parathyroid hormone-like peptide | journal = The New England Journal of Medicine | volume = 319 | issue = 9 | pages = 556–63 | date = September 1988 | pmid = 3043221 | doi = 10.1056/NEJM198809013190906 }}</ref> As this is sometimes the first sign of the [[malignancy]], [[hypercalcemia]] caused by PTHrP is considered a [[paraneoplastic phenomenon]]. PTHR1 is responsible for most cases of humoral hypercalcemia of malignancy.
* Miao D, Li J, Xue Y, Su H, Karaplis AC, Goltzman D. Parathyroid hormone-related peptide is required for increased trabecular bone volume in parathyroid hormone-null mice. Endocrinology 2004;145:3554-62. PMID 15090463.
 
{{PBB_Further_reading
PTHrP shares the same [[N-terminal]] end as parathyroid hormone and therefore it can bind to the same receptor, the Type I PTH receptor ([[Parathyroid hormone receptor 1|PTHR1]]). PTHrP can simulate most of the actions of PTH including increases in bone resorption and distal tubular calcium reabsorption, and inhibition of proximal tubular phosphate transport.
| citations =
 
*{{cite journal  | author=Casey ML, MacDonald PC |title=The endothelin-parathyroid hormone-related protein vasoactive peptide system in human endometrium: modulation by transforming growth factor-beta. |journal=Hum. Reprod. |volume=11 Suppl 2 |issue= |pages= 62-82 |year= 1997 |pmid= 8982748 |doi=  }}
However, PTHrP is less likely than PTH to stimulate 1,25-dihydroxyvitamin D production. Therefore, PTHrP does not increase intestinal calcium absorption.
*{{cite journal  | author=Lam MH, Thomas RJ, Martin TJ, ''et al.'' |title=Nuclear and nucleolar localization of parathyroid hormone-related protein. |journal=Immunol. Cell Biol. |volume=78 |issue= 4 |pages= 395-402 |year= 2000 |pmid= 10947864 |doi=   | doi=10.1046/j.1440-1711.2000.00919.x}}
 
*{{cite journal  | author=Fiaschi-Taesch NM, Stewart AF |title=Minireview: parathyroid hormone-related protein as an intracrine factor--trafficking mechanisms and functional consequences. |journal=Endocrinology |volume=144 |issue= 2 |pages= 407-11 |year= 2003 |pmid= 12538599 |doi=    | doi=10.1210/en.2002-220818}}
== Genetics ==
*{{cite journal | author=Jans DA, Thomas RJ, Gillespie MT |title=Parathyroid hormone-related protein (PTHrP): a nucleocytoplasmic shuttling protein with distinct paracrine and intracrine roles. |journal=Vitam. Horm. |volume=66 |issue= |pages= 345-84 |year= 2003 |pmid= 12852260 |doi= }}
 
*{{cite journal | author=Maioli E, Fortino V, Pacini A |title=Parathyroid hormone-related protein in preeclampsia: a linkage between maternal and fetal failures. |journal=Biol. Reprod. |volume=71 |issue= 6 |pages= 1779-84 |year= 2005 |pmid= 15286039 |doi= 10.1095/biolreprod.104.030932 }}
Four [[alternative splicing|alternatively spliced]] transcript variants encoding two distinct [[isoform]]s have been observed. There is also evidence for alternative translation initiation from non-AUG (CUG and GUG) start sites, in-frame and downstream of the initiator AUG codon, to give rise to nuclear forms of this hormone.<ref>{{cite web | title = Entrez Gene: PTHLH parathyroid hormone-like hormone| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5744| accessdate = }}</ref>
*{{cite journal  | author=Fenton AJ, Kemp BE, Kent GN, ''et al.'' |title=A carboxyl-terminal peptide from the parathyroid hormone-related protein inhibits bone resorption by osteoclasts. |journal=Endocrinology |volume=129 |issue= 4 |pages= 1762-8 |year= 1991 |pmid= 1915066 |doi= }}
 
*{{cite journal  | author=Fenton AJ, Kemp BE, Hammonds RG, ''et al.'' |title=A potent inhibitor of osteoclastic bone resorption within a highly conserved pentapeptide region of parathyroid hormone-related protein; PTHrP[107-111] |journal=Endocrinology |volume=129 |issue= 6 |pages= 3424-6 |year= 1991 |pmid= 1954916 |doi=  }}
== Discovery ==
*{{cite journal | author=Moniz C, Burton PB, Malik AN, ''et al.'' |title=Parathyroid hormone-related peptide in normal human fetal development. |journal=J. Mol. Endocrinol. |volume=5 |issue= 3 |pages= 259-66 |year= 1991 |pmid= 2288637 |doi= }}
 
*{{cite journal | author=Hammonds RG, McKay P, Winslow GA, ''et al.'' |title=Purification and characterization of recombinant human parathyroid hormone-related protein. |journal=J. Biol. Chem. |volume=264 |issue= 25 |pages= 14806-11 |year= 1989 |pmid= 2549037 |doi= }}
The protein was first isolated in 1987 by T.J. Martin's team at the University of Melbourne. Miao ''et al.'' showed that disruption of the ''PTHrP'' gene in mice caused a lethal phenotype and distinct bone abnormalities, suggesting that PTHrP has a physiological function.
*{{cite journal | author=Yasuda T, Banville D, Hendy GN, Goltzman D |title=Characterization of the human parathyroid hormone-like peptide gene. Functional and evolutionary aspects. |journal=J. Biol. Chem. |volume=264 |issue= 13 |pages= 7720-5 |year= 1989 |pmid= 2708388 |doi= }}
 
*{{cite journal | author=Suva LJ, Mather KA, Gillespie MT, ''et al.'' |title=Structure of the 5' flanking region of the gene encoding human parathyroid-hormone-related protein (PTHrP). |journal=Gene |volume=77 |issue= 1 |pages= 95-105 |year= 1989 |pmid= 2744490 |doi=    | doi=10.1016/0378-1119(89)90363-6}}
== Interactions ==
*{{cite journal | author=Mangin M, Webb AC, Dreyer BE, ''et al.'' |title=Identification of a cDNA encoding a parathyroid hormone-like peptide from a human tumor associated with humoral hypercalcemia of malignancy. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=85 |issue= 2 |pages= 597-601 |year= 1988 |pmid= 2829195 |doi=    | doi=10.1073/pnas.85.2.597}}
 
*{{cite journal | author=Moseley JM, Kubota M, Diefenbach-Jagger H, ''et al.'' |title=Parathyroid hormone-related protein purified from a human lung cancer cell line. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=84 |issue= 14 |pages= 5048-52 |year= 1987 |pmid= 2885845 |doi=    | doi=10.1073/pnas.84.14.5048}}
Parathyroid hormone-related protein has been shown to [[Protein-protein interaction|interact]] with [[KPNB1]]<ref name=pmid12504010>{{cite journal | vauthors = Cingolani G, Bednenko J, Gillespie MT, Gerace L | title = Molecular basis for the recognition of a nonclassical nuclear localization signal by importin beta | journal = Molecular Cell | volume = 10 | issue = 6 | pages = 1345–53 | date = December 2002 | pmid = 12504010 | doi = 10.1016/S1097-2765(02)00727-X }}</ref><ref name=pmid11401507>{{cite journal | vauthors = Lam MH, Hu W, Xiao CY, Gillespie MT, Jans DA | title = Molecular dissection of the importin beta1-recognized nuclear targeting signal of parathyroid hormone-related protein | journal = Biochemical and Biophysical Research Communications | volume = 282 | issue = 2 | pages = 629–34 | date = March 2001 | pmid = 11401507 | doi = 10.1006/bbrc.2001.4607 }}</ref> and [[Arrestin beta 1]].<ref name=pmid12220636>{{cite journal | vauthors = Conlan LA, Martin TJ, Gillespie MT | title = The COOH-terminus of parathyroid hormone-related protein (PTHrP) interacts with beta-arrestin 1B | journal = FEBS Letters | volume = 527 | issue = 1-3 | pages = 71–5 | date = September 2002 | pmid = 12220636 | doi = 10.1016/S0014-5793(02)03164-2 }}</ref>
*{{cite journal | author=Mangin M, Ikeda K, Dreyer BE, Broadus AE |title=Isolation and characterization of the human parathyroid hormone-like peptide gene. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=86 |issue= 7 |pages= 2408-12 |year= 1989 |pmid= 2928340 |doi=    | doi=10.1073/pnas.86.7.2408}}
 
*{{cite journal | author=Thiede MA, Strewler GJ, Nissenson RA, ''et al.'' |title=Human renal carcinoma expresses two messages encoding a parathyroid hormone-like peptide: evidence for the alternative splicing of a single-copy gene. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=85 |issue= 13 |pages= 4605-9 |year= 1988 |pmid= 3290897 |doi=   | doi=10.1073/pnas.85.13.4605}}
== See also ==
*{{cite journal | author=Suva LJ, Winslow GA, Wettenhall RE, ''et al.'' |title=A parathyroid hormone-related protein implicated in malignant hypercalcemia: cloning and expression. |journal=Science |volume=237 |issue= 4817 |pages= 893-6 |year= 1987 |pmid= 3616618 |doi=   | doi=10.1126/science.3616618}}
* Analogs used as pharmaceutical drugs
*{{cite journal | author=Campos RV, Zhang L, Drucker DJ |title=Differential expression of RNA transcripts encoding unique carboxy-terminal sequences of human parathyroid hormone-related peptide. |journal=Mol. Endocrinol. |volume=8 |issue= 12 |pages= 1656-66 |year= 1995 |pmid= 7708054 |doi= }}
** [[Teriparatide]]
*{{cite journal | author=Holick MF, Ray S, Chen TC, ''et al.'' |title=A parathyroid hormone antagonist stimulates epidermal proliferation and hair growth in mice. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=91 |issue= 17 |pages= 8014-6 |year= 1994 |pmid= 8058749 |doi=   | doi=10.1073/pnas.91.17.8014}}
** [[Abaloparatide]]
*{{cite journal | author=Seitz PK, Cooper KM, Ives KL, ''et al.'' |title=Parathyroid hormone-related peptide production and action in a myoepithelial cell line derived from normal human breast. |journal=Endocrinology |volume=133 |issue= 3 |pages= 1116-24 |year= 1993 |pmid= 8396010 |doi=    | doi=10.1210/en.133.3.1116}}
 
*{{cite journal  | author=Li H, Seitz PK, Selvanayagam P, ''et al.'' |title=Effect of endogenously produced parathyroid hormone-related peptide on growth of a human hepatoma cell line (Hep G2). |journal=Endocrinology |volume=137 |issue= 6 |pages= 2367-74 |year= 1996 |pmid= 8641188 |doi=    | doi=10.1210/en.137.6.2367}}
== References ==
}}
{{reflist|33em}}
 
== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = Miao D, Li J, Xue Y, Su H, Karaplis AC, Goltzman D | title = Parathyroid hormone-related peptide is required for increased trabecular bone volume in parathyroid hormone-null mice | journal = Endocrinology | volume = 145 | issue = 8 | pages = 3554–62 | date = August 2004 | pmid = 15090463 | doi = 10.1210/en.2003-1695 }}
* {{cite journal | vauthors = Casey ML, MacDonald PC | title = The endothelin-parathyroid hormone-related protein vasoactive peptide system in human endometrium: modulation by transforming growth factor-beta | journal = Human Reproduction | volume = 11 Suppl 2 | issue =  | pages = 62–82 | date = October 1996 | pmid = 8982748 | doi = 10.1093/humrep/11.suppl_2.62 }}
* {{cite journal | vauthors = Lam MH, Thomas RJ, Martin TJ, Gillespie MT, Jans DA | title = Nuclear and nucleolar localization of parathyroid hormone-related protein | journal = Immunology and Cell Biology | volume = 78 | issue = 4 | pages = 395–402 | date = August 2000 | pmid = 10947864 | doi = 10.1046/j.1440-1711.2000.00919.x }}
* {{cite journal | vauthors = Fiaschi-Taesch NM, Stewart AF | title = Minireview: parathyroid hormone-related protein as an intracrine factor--trafficking mechanisms and functional consequences | journal = Endocrinology | volume = 144 | issue = 2 | pages = 407–11 | date = February 2003 | pmid = 12538599 | doi = 10.1210/en.2002-220818 }}
* {{cite journal | vauthors = Jans DA, Thomas RJ, Gillespie MT | title = Parathyroid hormone-related protein (PTHrP): a nucleocytoplasmic shuttling protein with distinct paracrine and intracrine roles | journal = Vitamins and Hormones | volume = 66 | issue = | pages = 345–84 | year = 2003 | pmid = 12852260 | doi = 10.1016/S0083-6729(03)01010-0 | isbn = 978-0-12-709866-1 | series = Vitamins & Hormones }}
* {{cite journal | vauthors = Maioli E, Fortino V, Pacini A | title = Parathyroid hormone-related protein in preeclampsia: a linkage between maternal and fetal failures | journal = Biology of Reproduction | volume = 71 | issue = 6 | pages = 1779–84 | date = December 2004 | pmid = 15286039 | doi = 10.1095/biolreprod.104.030932 }}
* {{cite journal | vauthors = Fenton AJ, Kemp BE, Kent GN, Moseley JM, Zheng MH, Rowe DJ, Britto JM, Martin TJ, Nicholson GC | title = A carboxyl-terminal peptide from the parathyroid hormone-related protein inhibits bone resorption by osteoclasts | journal = Endocrinology | volume = 129 | issue = 4 | pages = 1762–8 | date = October 1991 | pmid = 1915066 | doi = 10.1210/endo-129-4-1762 }}
* {{cite journal | vauthors = Fenton AJ, Kemp BE, Hammonds RG, Mitchelhill K, Moseley JM, Martin TJ, Nicholson GC | title = A potent inhibitor of osteoclastic bone resorption within a highly conserved pentapeptide region of parathyroid hormone-related protein; PTHrP[107-111] | journal = Endocrinology | volume = 129 | issue = 6 | pages = 3424–6 | date = December 1991 | pmid = 1954916 | doi = 10.1210/endo-129-6-3424 }}
* {{cite journal | vauthors = Moniz C, Burton PB, Malik AN, Dixit M, Banga JP, Nicolaides K, Quirke P, Knight DE, McGregor AM | title = Parathyroid hormone-related peptide in normal human fetal development | journal = Journal of Molecular Endocrinology | volume = 5 | issue = 3 | pages = 259–66 | date = December 1990 | pmid = 2288637 | doi = 10.1677/jme.0.0050259 }}
* {{cite journal | vauthors = Hammonds RG, McKay P, Winslow GA, Diefenbach-Jagger H, Grill V, Glatz J, Rodda CP, Moseley JM, Wood WI, Martin TJ | title = Purification and characterization of recombinant human parathyroid hormone-related protein | journal = The Journal of Biological Chemistry | volume = 264 | issue = 25 | pages = 14806–11 | date = September 1989 | pmid = 2549037 | doi = }}
* {{cite journal | vauthors = Yasuda T, Banville D, Hendy GN, Goltzman D | title = Characterization of the human parathyroid hormone-like peptide gene. Functional and evolutionary aspects | journal = The Journal of Biological Chemistry | volume = 264 | issue = 13 | pages = 7720–5 | date = May 1989 | pmid = 2708388 | doi = }}
* {{cite journal | vauthors = Suva LJ, Mather KA, Gillespie MT, Webb GC, Ng KW, Winslow GA, Wood WI, Martin TJ, Hudson PJ | title = Structure of the 5' flanking region of the gene encoding human parathyroid-hormone-related protein (PTHrP) | journal = Gene | volume = 77 | issue = 1 | pages = 95–105 | date = April 1989 | pmid = 2744490 | doi = 10.1016/0378-1119(89)90363-6 }}
* {{cite journal | vauthors = Mangin M, Webb AC, Dreyer BE, Posillico JT, Ikeda K, Weir EC, Stewart AF, Bander NH, Milstone L, Barton DE | title = Identification of a cDNA encoding a parathyroid hormone-like peptide from a human tumor associated with humoral hypercalcemia of malignancy | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 85 | issue = 2 | pages = 597–601 | date = January 1988 | pmid = 2829195 | pmc = 279598 | doi = 10.1073/pnas.85.2.597 }}
* {{cite journal | vauthors = Moseley JM, Kubota M, Diefenbach-Jagger H, Wettenhall RE, Kemp BE, Suva LJ, Rodda CP, Ebeling PR, Hudson PJ, Zajac JD | title = Parathyroid hormone-related protein purified from a human lung cancer cell line | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 84 | issue = 14 | pages = 5048–52 | date = July 1987 | pmid = 2885845 | pmc = 305244 | doi = 10.1073/pnas.84.14.5048 }}
* {{cite journal | vauthors = Mangin M, Ikeda K, Dreyer BE, Broadus AE | title = Isolation and characterization of the human parathyroid hormone-like peptide gene | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 86 | issue = 7 | pages = 2408–12 | date = April 1989 | pmid = 2928340 | pmc = 286922 | doi = 10.1073/pnas.86.7.2408 }}
* {{cite journal | vauthors = Thiede MA, Strewler GJ, Nissenson RA, Rosenblatt M, Rodan GA | title = Human renal carcinoma expresses two messages encoding a parathyroid hormone-like peptide: evidence for the alternative splicing of a single-copy gene | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 85 | issue = 13 | pages = 4605–9 | date = July 1988 | pmid = 3290897 | pmc = 280483 | doi = 10.1073/pnas.85.13.4605 }}
* {{cite journal | vauthors = Suva LJ, Winslow GA, Wettenhall RE, Hammonds RG, Moseley JM, Diefenbach-Jagger H, Rodda CP, Kemp BE, Rodriguez H, Chen EY | title = A parathyroid hormone-related protein implicated in malignant hypercalcemia: cloning and expression | journal = Science | volume = 237 | issue = 4817 | pages = 893–6 | date = August 1987 | pmid = 3616618 | doi = 10.1126/science.3616618 }}
* {{cite journal | vauthors = Campos RV, Zhang L, Drucker DJ | title = Differential expression of RNA transcripts encoding unique carboxy-terminal sequences of human parathyroid hormone-related peptide | journal = Molecular Endocrinology | volume = 8 | issue = 12 | pages = 1656–66 | date = December 1994 | pmid = 7708054 | doi = 10.1210/me.8.12.1656 }}
* {{cite journal | vauthors = Holick MF, Ray S, Chen TC, Tian X, Persons KS | title = A parathyroid hormone antagonist stimulates epidermal proliferation and hair growth in mice | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 91 | issue = 17 | pages = 8014–6 | date = August 1994 | pmid = 8058749 | pmc = 44535 | doi = 10.1073/pnas.91.17.8014 }}
* {{cite journal | vauthors = Seitz PK, Cooper KM, Ives KL, Ishizuka J, Townsend CM, Rajaraman S, Cooper CW | title = Parathyroid hormone-related peptide production and action in a myoepithelial cell line derived from normal human breast | journal = Endocrinology | volume = 133 | issue = 3 | pages = 1116–24 | date = September 1993 | pmid = 8396010 | doi = 10.1210/en.133.3.1116 }}
* {{cite journal | vauthors = Li H, Seitz PK, Selvanayagam P, Rajaraman S, Cooper CW | title = Effect of endogenously produced parathyroid hormone-related peptide on growth of a human hepatoma cell line (Hep G2) | journal = Endocrinology | volume = 137 | issue = 6 | pages = 2367–74 | date = June 1996 | pmid = 8641188 | doi = 10.1210/en.137.6.2367 }}
{{refend}}
{{refend}}


{{NLM content}}
{{NLM content}}
{{PDB Gallery|geneid=5744}}
{{Intercellular signaling peptides and proteins}}
{{Signaling peptide/protein receptor modulators}}


[[Category:Oncology]]
[[Category:Oncology]]
[[Category:Oncology stub]]
[[Category:Parathyroid hormone receptor agonists]]
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Latest revision as of 05:18, 21 November 2017

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Parathyroid hormone-related protein (or PTHrP) is a protein member of the parathyroid hormone family. It is occasionally secreted by cancer cells (breast cancer, certain types of lung cancer including squamous cell lung carcinoma). However, it also has normal functions.

Function

PTHrP acts as an endocrine, autocrine, paracrine, and intracrine hormone. It regulates endochondral bone development by maintaining the endochondral growth plate at a constant width. It also regulates epithelial-mesenchymal interactions during the formation of the mammary glands.

Tooth eruption

PTHrP is critical in intraosseous phase of tooth eruption where it acts as a signalling molecule to stimulate local bone resorption. Without PTHrP, the bony crypt surrounding the tooth follicle will not resorb, and therefore the tooth will not erupt. In the context of tooth eruption, PTHrP is secreted by the cells of the Reduced Enamel Epithelium.

Mammary glands

It aids in normal mammary gland development.[1][2] It is necessary for maintenance of the mammary bud. Loss of PTHrP or its receptor causes the mammary bud cell fate to change back into epidermis. In lactation, it may regulate in conjunction with the calcium sensing receptor the mobilization and transfer of calcium to the milk, as well as placental transfer of calcium.

Humoral hypercalcemia of malignancy

PTHrP is related in function to the "normal" parathyroid hormone. When a tumor secretes PTHrP, this can lead to hypercalcemia.[3] As this is sometimes the first sign of the malignancy, hypercalcemia caused by PTHrP is considered a paraneoplastic phenomenon. PTHR1 is responsible for most cases of humoral hypercalcemia of malignancy.

PTHrP shares the same N-terminal end as parathyroid hormone and therefore it can bind to the same receptor, the Type I PTH receptor (PTHR1). PTHrP can simulate most of the actions of PTH including increases in bone resorption and distal tubular calcium reabsorption, and inhibition of proximal tubular phosphate transport.

However, PTHrP is less likely than PTH to stimulate 1,25-dihydroxyvitamin D production. Therefore, PTHrP does not increase intestinal calcium absorption.

Genetics

Four alternatively spliced transcript variants encoding two distinct isoforms have been observed. There is also evidence for alternative translation initiation from non-AUG (CUG and GUG) start sites, in-frame and downstream of the initiator AUG codon, to give rise to nuclear forms of this hormone.[4]

Discovery

The protein was first isolated in 1987 by T.J. Martin's team at the University of Melbourne. Miao et al. showed that disruption of the PTHrP gene in mice caused a lethal phenotype and distinct bone abnormalities, suggesting that PTHrP has a physiological function.

Interactions

Parathyroid hormone-related protein has been shown to interact with KPNB1[5][6] and Arrestin beta 1.[7]

See also

References

  1. ↑ Hens JR, Dann P, Zhang JP, Harris S, Robinson GW, Wysolmerski J (March 2007). "BMP4 and PTHrP interact to stimulate ductal outgrowth during embryonic mammary development and to inhibit hair follicle induction". Development. 134 (6): 1221–30. doi:10.1242/dev.000182. PMID 17301089.
  2. ↑ Hens JR, Wysolmerski JJ (2005). "Key stages of mammary gland development: molecular mechanisms involved in the formation of the embryonic mammary gland". Breast Cancer Research. 7 (5): 220–4. doi:10.1186/bcr1306. PMC 1242158. PMID 16168142.
  3. ↑ Broadus AE, Mangin M, Ikeda K, Insogna KL, Weir EC, Burtis WJ, Stewart AF (September 1988). "Humoral hypercalcemia of cancer. Identification of a novel parathyroid hormone-like peptide". The New England Journal of Medicine. 319 (9): 556–63. doi:10.1056/NEJM198809013190906. PMID 3043221.
  4. ↑ "Entrez Gene: PTHLH parathyroid hormone-like hormone".
  5. ↑ Cingolani G, Bednenko J, Gillespie MT, Gerace L (December 2002). "Molecular basis for the recognition of a nonclassical nuclear localization signal by importin beta". Molecular Cell. 10 (6): 1345–53. doi:10.1016/S1097-2765(02)00727-X. PMID 12504010.
  6. ↑ Lam MH, Hu W, Xiao CY, Gillespie MT, Jans DA (March 2001). "Molecular dissection of the importin beta1-recognized nuclear targeting signal of parathyroid hormone-related protein". Biochemical and Biophysical Research Communications. 282 (2): 629–34. doi:10.1006/bbrc.2001.4607. PMID 11401507.
  7. ↑ Conlan LA, Martin TJ, Gillespie MT (September 2002). "The COOH-terminus of parathyroid hormone-related protein (PTHrP) interacts with beta-arrestin 1B". FEBS Letters. 527 (1–3): 71–5. doi:10.1016/S0014-5793(02)03164-2. PMID 12220636.

Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.


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