Cyclin-dependent kinase 4 inhibitor B also known as multiple tumor suppressor 2 (MTS-2) or p15INK4b is a protein that is encoded by the CDKN2Bgene in humans.[1][2]
This gene lies adjacent to the tumor suppressor gene CDKN2A in a region that is frequently mutated and deleted in a wide variety of tumors. This gene encodes a cyclin-dependent kinase inhibitor, also known as p15Ink4b protein, which forms a complex with CDK4 or CDK6, and prevents the activation of the CDK kinases by cyclin D, thus the encoded protein functions as a cell growth regulator that inhibits cell cycle G1 progression. The expression of this gene was found to be dramatically induced by TGF beta, which suggested its role in the TGF beta induced growth inhibition. Two alternatively spliced transcript variants of this gene, which encode distinct proteins, have been reported.[2]
↑Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M (October 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–8. doi:10.1038/nature04209. PMID16189514.
↑Stelzl U, Worm U, Lalowski M, Haenig C, Brembeck FH, Goehler H, Stroedicke M, Zenkner M, Schoenherr A, Koeppen S, Timm J, Mintzlaff S, Abraham C, Bock N, Kietzmann S, Goedde A, Toksöz E, Droege A, Krobitsch S, Korn B, Birchmeier W, Lehrach H, Wanker EE (September 2005). "A human protein-protein interaction network: a resource for annotating the proteome". Cell. 122 (6): 957–68. doi:10.1016/j.cell.2005.08.029. PMID16169070.
Further reading
Hall M, Bates S, Peters G (1995). "Evidence for different modes of action of cyclin-dependent kinase inhibitors: p15 and p16 bind to kinases, p21 and p27 bind to cyclins". Oncogene. 11 (8): 1581–8. PMID7478582.
Stone S, Dayananth P, Jiang P, Weaver-Feldhaus JM, Tavtigian SV, Cannon-Albright L, Kamb A (1995). "Genomic structure, expression and mutational analysis of the P15 (MTS2) gene". Oncogene. 11 (5): 987–91. PMID7675459.
Okamoto A, Hussain SP, Hagiwara K, Spillare EA, Rusin MR, Demetrick DJ, Serrano M, Hannon GJ, Shiseki M, Zariwala M (1995). "Mutations in the p16INK4/MTS1/CDKN2, p15INK4B/MTS2, and p18 genes in primary and metastatic lung cancer". Cancer Res. 55 (7): 1448–51. PMID7882351.
Jen J, Harper JW, Bigner SH, Bigner DD, Papadopoulos N, Markowitz S, Willson JK, Kinzler KW, Vogelstein B (1994). "Deletion of p16 and p15 genes in brain tumors". Cancer Res. 54 (24): 6353–8. PMID7987828.
Guan KL, Jenkins CW, Li Y, Nichols MA, Wu X, O'Keefe CL, Matera AG, Xiong Y (1994). "Growth suppression by p18, a p16INK4/MTS1- and p14INK4B/MTS2-related CDK6 inhibitor, correlates with wild-type pRb function". Genes Dev. 8 (24): 2939–52. doi:10.1101/gad.8.24.2939. PMID8001816.
Kamb A, Gruis NA, Weaver-Feldhaus J, Liu Q, Harshman K, Tavtigian SV, Stockert E, Day RS, Johnson BE, Skolnick MH (1994). "A cell cycle regulator potentially involved in genesis of many tumor types". Science. 264 (5157): 436–40. doi:10.1126/science.8153634. PMID8153634.
Reynisdóttir I, Massagué J (1997). "The subcellular locations of p15(Ink4b) and p27(Kip1) coordinate their inhibitory interactions with cdk4 and cdk2". Genes Dev. 11 (4): 492–503. doi:10.1101/gad.11.4.492. PMID9042862.
Iavarone A, Massagué J (1997). "Repression of the CDK activator Cdc25A and cell-cycle arrest by cytokine TGF-beta in cells lacking the CDK inhibitor p15". Nature. 387 (6631): 417–22. doi:10.1038/387417a0. PMID9163429.
Tsubari M, Tiihonen E, Laiho M (1997). "Cloning and characterization of p10, an alternatively spliced form of p15 cyclin-dependent kinase inhibitor". Cancer Res. 57 (14): 2966–73. PMID9230210.
Rich JN, Zhang M, Datto MB, Bigner DD, Wang XF (1999). "Transforming growth factor-beta-mediated p15(INK4B) induction and growth inhibition in astrocytes is SMAD3-dependent and a pathway prominently altered in human glioma cell lines". J. Biol. Chem. 274 (49): 35053–8. doi:10.1074/jbc.274.49.35053. PMID10574984.
Staller P, Peukert K, Kiermaier A, Seoane J, Lukas J, Karsunky H, Möröy T, Bartek J, Massagué J, Hänel F, Eilers M (2001). "Repression of p15INK4b expression by Myc through association with Miz-1". Nat. Cell Biol. 3 (4): 392–9. doi:10.1038/35070076. PMID11283613.
Orlow I, Cordon-Cardo C (2002). "Evaluation of alterations in the tumor suppressor genes INK4A and INK4B in human bladder tumors". Methods Mol. Biol. 179: 43–59. doi:10.1385/1-59259-238-4:043. PMID11692873.
Agiostratidou G, Derventzi A, Gonos ES (2002). "Over-expression of CDKIs p15INK4b, p16INK4a and p21CIP1/WAF1 genes mediate growth arrest in human osteosarcoma cell lines". In Vivo. 15 (5): 443–6. PMID11695244.
Simon M, Park TW, Köster G, Mahlberg R, Hackenbroch M, Boström J, Löning T, Schramm J (2001). "Alterations of INK4a(p16-p14ARF)/INK4b(p15) expression and telomerase activation in meningioma progression". J. Neurooncol. 55 (3): 149–58. doi:10.1023/A:1013863630293. PMID11859969.
Scarisbrick JJ, Woolford AJ, Calonje E, Photiou A, Ferreira S, Orchard G, Russell-Jones R, Whittaker SJ (2002). "Frequent abnormalities of the p15 and p16 genes in mycosis fungoides and sezary syndrome". J. Invest. Dermatol. 118 (3): 493–9. doi:10.1046/j.0022-202x.2001.01682.x. PMID11874489.
Kudoh K, Ichikawa Y, Yoshida S, Hirai M, Kikuchi Y, Nagata I, Miwa M, Uchida K (2002). "Inactivation of p16/CDKN2 and p15/MTS2 is associated with prognosis and response to chemotherapy in ovarian cancer". Int. J. Cancer. 99 (4): 579–82. doi:10.1002/ijc.10331. PMID11992549.
