CDKN2B explained

Cyclin-dependent kinase 4 inhibitor B also known as multiple tumor suppressor 2 (MTS-2) or p15^INK4b is a protein that is encoded by the CDKN2B gene in humans.^{[1] [2]}

Function

This gene lies adjacent to the tumor suppressor gene CDKN2A in a region that is frequently mutated, deleted, or disregulated in a wide variety of cancer.^{[3] [4] [5]} 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 transcripts of this gene encode proteins that share the N-terminal sequence but completely differ in the C-terminus.

Interactions

CDKN2B tumor suppressor gene product p15 has been shown to interact with cyclin-dependent kinase 4.^{[6] [7]}

Further reading

• Hall M, Bates S, Peters G . 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 . October 1995 . 7478582 .
• Stone S, Dayananth P, Jiang P, Weaver-Feldhaus JM, Tavtigian SV, Cannon-Albright L, Kamb A . Genomic structure, expression and mutational analysis of the P15 (MTS2) gene . Oncogene . 11 . 5 . 987–91 . September 1995 . 7675459 .
• Okamoto A, Hussain SP, Hagiwara K, Spillare EA, Rusin MR, Demetrick DJ, Serrano M, Hannon GJ, Shiseki M, Zariwala M . 6 . Mutations in the p16INK4/MTS1/CDKN2, p15INK4B/MTS2, and p18 genes in primary and metastatic lung cancer . Cancer Research . 55 . 7 . 1448–51 . April 1995 . 7882351 .
• Jen J, Harper JW, Bigner SH, Bigner DD, Papadopoulos N, Markowitz S, Willson JK, Kinzler KW, Vogelstein B . 6 . Deletion of p16 and p15 genes in brain tumors . Cancer Research . 54 . 24 . 6353–8 . December 1994 . 7987828 .
• Guan KL, Jenkins CW, Li Y, Nichols MA, Wu X, O'Keefe CL, Matera AG, Xiong Y . 6 . Growth suppression by p18, a p16INK4/MTS1- and p14INK4B/MTS2-related CDK6 inhibitor, correlates with wild-type pRb function . Genes & Development . 8 . 24 . 2939–52 . December 1994 . 8001816 . 10.1101/gad.8.24.2939 . free .
• Kamb A, Gruis NA, Weaver-Feldhaus J, Liu Q, Harshman K, Tavtigian SV, Stockert E, Day RS, Johnson BE, Skolnick MH . 6 . A cell cycle regulator potentially involved in genesis of many tumor types . Science . 264 . 5157 . 436–40 . April 1994 . 8153634 . 10.1126/science.8153634 . 1994Sci...264..436K .
• Reynisdóttir I, Massagué J . The subcellular locations of p15(Ink4b) and p27(Kip1) coordinate their inhibitory interactions with cdk4 and cdk2 . Genes & Development . 11 . 4 . 492–503 . February 1997 . 9042862 . 10.1101/gad.11.4.492 . free .
• Sandhu C, Garbe J, Bhattacharya N, Daksis J, Pan CH, Yaswen P, Koh J, Slingerland JM, Stampfer MR . 6 . Transforming growth factor beta stabilizes p15INK4B protein, increases p15INK4B-cdk4 complexes, and inhibits cyclin D1-cdk4 association in human mammary epithelial cells . Molecular and Cellular Biology . 17 . 5 . 2458–67 . May 1997 . 9111314 . 232094 . 10.1128/MCB.17.5.2458 .
• Iavarone A, Massagué J . 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 . May 1997 . 9163429 . 10.1038/387417a0 . 1997Natur.387..417L . 1040022 .
• Tsubari M, Tiihonen E, Laiho M . Cloning and characterization of p10, an alternatively spliced form of p15 cyclin-dependent kinase inhibitor . Cancer Research . 57 . 14 . 2966–73 . July 1997 . 9230210 .
• Rich JN, Zhang M, Datto MB, Bigner DD, Wang XF . 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 . The Journal of Biological Chemistry . 274 . 49 . 35053–8 . December 1999 . 10574984 . 10.1074/jbc.274.49.35053 . free .
• Yuan C, Selby TL, Li J, Byeon IJ, Tsai MD . Tumor suppressor INK4: refinement of p16INK4A structure and determination of p15INK4B structure by comparative modeling and NMR data . Protein Science . 9 . 6 . 1120–8 . June 2000 . 10892805 . 2144649 . 10.1110/ps.9.6.1120 .
• Hartley JL, Temple GF, Brasch MA . DNA cloning using in vitro site-specific recombination . Genome Research . 10 . 11 . 1788–95 . November 2000 . 11076863 . 310948 . 10.1101/gr.143000 .
• Staller P, Peukert K, Kiermaier A, Seoane J, Lukas J, Karsunky H, Möröy T, Bartek J, Massagué J, Hänel F, Eilers M . 6 . Repression of p15INK4b expression by Myc through association with Miz-1 . Nature Cell Biology . 3 . 4 . 392–9 . April 2001 . 11283613 . 10.1038/35070076 . 12696178 .
• Book: Orlow I, Cordon-Cardo C . Gene Probes . Evaluation of alterations in the tumor suppressor genes INK4A and INK4B in human bladder tumors . Methods Mol. Biol. . 179 . 43–59 . 2002 . 11692873 . 10.1385/1-59259-238-4:043 . 1-59259-238-4 .
• Agiostratidou G, Derventzi A, Gonos ES . Over-expression of CDKIs p15INK4b, p16INK4a and p21CIP1/WAF1 genes mediate growth arrest in human osteosarcoma cell lines . In Vivo . 15 . 5 . 443–6 . 2002 . 11695244 .
• Simon M, Park TW, Köster G, Mahlberg R, Hackenbroch M, Boström J, Löning T, Schramm J . 6 . Alterations of INK4a(p16-p14ARF)/INK4b(p15) expression and telomerase activation in meningioma progression . Journal of Neuro-Oncology . 55 . 3 . 149–58 . December 2001 . 11859969 . 10.1023/A:1013863630293 . Hackenbroch . 19711721 .
• Scarisbrick JJ, Woolford AJ, Calonje E, Photiou A, Ferreira S, Orchard G, Russell-Jones R, Whittaker SJ . 6 . Frequent abnormalities of the p15 and p16 genes in mycosis fungoides and sezary syndrome . The Journal of Investigative Dermatology . 118 . 3 . 493–9 . March 2002 . 11874489 . 10.1046/j.0022-202x.2001.01682.x . free .
• Kudoh K, Ichikawa Y, Yoshida S, Hirai M, Kikuchi Y, Nagata I, Miwa M, Uchida K . 6 . Inactivation of p16/CDKN2 and p15/MTS2 is associated with prognosis and response to chemotherapy in ovarian cancer . International Journal of Cancer . 99 . 4 . 579–82 . June 2002 . 11992549 . 10.1002/ijc.10331 . 81974 .
• Yang W, Zhang A, Han Y, Su X, Chen Y, Zhao W . Cyclin-Dependent Kinase Inhibitor 2b Controls Fibrosis and Functional Changes in Ischemia-Induced Heart Failure via the BMI1-p15-Rb Signalling Pathway . Canadian Journal of Cardiology . 37 . 4 . 655–664 . 2021 . 32428618 . 10.1016/j.cjca.2020.05.016 . 218756624 .

Notes and References

1. Hannon GJ, Beach D . p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest . Nature . 371 . 6494 . 257–61 . September 1994 . 8078588 . 10.1038/371257a0 . 1994Natur.371..257H . 4268054 .
2. Web site: Entrez Gene: CDKN2B cyclin-dependent kinase inhibitor 2B (p15, inhibits CDK4).
3. Tu Q, Hao J, Zhou X, Yan L, Dai H, Sun B, Yang D, An S, Lv L, Jiao B, Chen C, Lai R, Shi P, Zhao X . 6 . CDKN2B deletion is essential for pancreatic cancer development instead of unmeaningful co-deletion due to juxtaposition to CDKN2A . Oncogene . 37 . 1 . 128–138 . January 2018 . 28892048 . 5759028 . 10.1038/onc.2017.316 .
4. Jafri M, Wake NC, Ascher DB, Pires DE, Gentle D, Morris MR, Rattenberry E, Simpson MA, Trembath RC, Weber A, Woodward ER, Donaldson A, Blundell TL, Latif F, Maher ER . 6 . Germline Mutations in the CDKN2B Tumor Suppressor Gene Predispose to Renal Cell Carcinoma . Cancer Discovery . 5 . 7 . 723–9 . July 2015 . 25873077 . 10.1158/2159-8290.CD-14-1096 . free .
5. Yu W, Gius D, Onyango P, Muldoon-Jacobs K, Karp J, Feinberg AP, Cui H . Epigenetic silencing of tumour suppressor gene p15 by its antisense RNA . Nature . 451 . 7175 . 202–6 . January 2008 . 18185590 . 2743558 . 10.1038/nature06468 . 2008Natur.451..202Y .
6. 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 . 6 . Towards a proteome-scale map of the human protein-protein interaction network . Nature . 437 . 7062 . 1173–8 . October 2005 . 16189514 . 10.1038/nature04209 . 2005Natur.437.1173R . 4427026 .
7. 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 . 6 . A human protein-protein interaction network: a resource for annotating the proteome . Cell . 122 . 6 . 957–68 . September 2005 . 16169070 . 10.1016/j.cell.2005.08.029 . free . 8235923 . 11858/00-001M-0000-0010-8592-0 .