CDKN2B

CDKN2B
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	1D9S
Identifiers
Aliases	CDKN2B, CDK4I, INK4B, MTS2, P15, TP15, p15INK4b, cyclin-dependent kinase inhibitor 2B, cyclin dependent kinase inhibitor 2B
External IDs	OMIM: 600431; MGI: 104737; HomoloGene: 55859; GeneCards: CDKN2B; OMA:CDKN2B - orthologs
Gene location (Human)
Chr.	Chromosome 9 (human)
End	22,009,305 bp
Gene location (Mouse)
Chr.	Chromosome 4 (mouse)
End	89,229,276 bp
RNA expression pattern
	Top expressed in
	Top expressed in
	More reference expression data
	More reference expression data
Gene ontology
Molecular function
Cellular component
Biological process
	Sources:Amigo / QuickGO
Orthologs
	1030
	12579
	ENSG00000147883
	ENSMUSG00000073802
	P42772
	P55271
	NM_078487; NM_004936
	NM_007670
	NP_004927; NP_511042
	NP_031696
	Wikidata
View/Edit Human	View/Edit Mouse

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.^[5]^[6]

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.^[7]^[8]^[9] 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.^[6]

Interactions

CDKN2B tumor suppressor gene product p15 has been shown to interact with cyclin-dependent kinase 4.^[10]^[11]

References

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000147883 – Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000073802 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ Hannon GJ, Beach D (September 1994). "p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest". Nature. 371 (6494): 257–61. Bibcode:1994Natur.371..257H. doi:10.1038/371257a0. PMID 8078588. S2CID 4268054.
^ ^a ^b "Entrez Gene: CDKN2B cyclin-dependent kinase inhibitor 2B (p15, inhibits CDK4)".
^ Tu Q, Hao J, Zhou X, Yan L, Dai H, Sun B, et al. (January 2018). "CDKN2B deletion is essential for pancreatic cancer development instead of unmeaningful co-deletion due to juxtaposition to CDKN2A". Oncogene. 37 (1): 128–138. doi:10.1038/onc.2017.316. PMC 5759028. PMID 28892048.
^ Jafri M, Wake NC, Ascher DB, Pires DE, Gentle D, Morris MR, et al. (July 2015). "Germline Mutations in the CDKN2B Tumor Suppressor Gene Predispose to Renal Cell Carcinoma". Cancer Discovery. 5 (7): 723–9. doi:10.1158/2159-8290.CD-14-1096. PMID 25873077.
^ Yu W, Gius D, Onyango P, Muldoon-Jacobs K, Karp J, Feinberg AP, Cui H (January 2008). "Epigenetic silencing of tumour suppressor gene p15 by its antisense RNA". Nature. 451 (7175): 202–6. Bibcode:2008Natur.451..202Y. doi:10.1038/nature06468. PMC 2743558. PMID 18185590.
^ Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, et al. (October 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–8. Bibcode:2005Natur.437.1173R. doi:10.1038/nature04209. PMID 16189514. S2CID 4427026.
^ Stelzl U, Worm U, Lalowski M, Haenig C, Brembeck FH, Goehler H, et al. (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. hdl:11858/00-001M-0000-0010-8592-0. PMID 16169070. S2CID 8235923.

Hall M, Bates S, Peters G (October 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. PMID 7478582.
Stone S, Dayananth P, Jiang P, Weaver-Feldhaus JM, Tavtigian SV, Cannon-Albright L, Kamb A (September 1995). "Genomic structure, expression and mutational analysis of the P15 (MTS2) gene". Oncogene. 11 (5): 987–91. PMID 7675459.
Okamoto A, Hussain SP, Hagiwara K, Spillare EA, Rusin MR, Demetrick DJ, et al. (April 1995). "Mutations in the p16INK4/MTS1/CDKN2, p15INK4B/MTS2, and p18 genes in primary and metastatic lung cancer". Cancer Research. 55 (7): 1448–51. PMID 7882351.
Jen J, Harper JW, Bigner SH, Bigner DD, Papadopoulos N, Markowitz S, et al. (December 1994). "Deletion of p16 and p15 genes in brain tumors". Cancer Research. 54 (24): 6353–8. PMID 7987828.
Guan KL, Jenkins CW, Li Y, Nichols MA, Wu X, O'Keefe CL, et al. (December 1994). "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. doi:10.1101/gad.8.24.2939. PMID 8001816.
Kamb A, Gruis NA, Weaver-Feldhaus J, Liu Q, Harshman K, Tavtigian SV, et al. (April 1994). "A cell cycle regulator potentially involved in genesis of many tumor types". Science. 264 (5157): 436–40. Bibcode:1994Sci...264..436K. doi:10.1126/science.8153634. PMID 8153634.
Reynisdóttir I, Massagué J (February 1997). "The subcellular locations of p15(Ink4b) and p27(Kip1) coordinate their inhibitory interactions with cdk4 and cdk2". Genes & Development. 11 (4): 492–503. doi:10.1101/gad.11.4.492. PMID 9042862.
Sandhu C, Garbe J, Bhattacharya N, Daksis J, Pan CH, Yaswen P, et al. (May 1997). "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. doi:10.1128/MCB.17.5.2458. PMC 232094. PMID 9111314.
Iavarone A, Massagué J (May 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. Bibcode:1997Natur.387..417L. doi:10.1038/387417a0. PMID 9163429. S2CID 1040022.
Tsubari M, Tiihonen E, Laiho M (July 1997). "Cloning and characterization of p10, an alternatively spliced form of p15 cyclin-dependent kinase inhibitor". Cancer Research. 57 (14): 2966–73. PMID 9230210.
Rich JN, Zhang M, Datto MB, Bigner DD, Wang XF (December 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". The Journal of Biological Chemistry. 274 (49): 35053–8. doi:10.1074/jbc.274.49.35053. PMID 10574984.
Yuan C, Selby TL, Li J, Byeon IJ, Tsai MD (June 2000). "Tumor suppressor INK4: refinement of p16INK4A structure and determination of p15INK4B structure by comparative modeling and NMR data". Protein Science. 9 (6): 1120–8. doi:10.1110/ps.9.6.1120. PMC 2144649. PMID 10892805.
Hartley JL, Temple GF, Brasch MA (November 2000). "DNA cloning using in vitro site-specific recombination". Genome Research. 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948. PMID 11076863.
Staller P, Peukert K, Kiermaier A, Seoane J, Lukas J, Karsunky H, et al. (April 2001). "Repression of p15INK4b expression by Myc through association with Miz-1". Nature Cell Biology. 3 (4): 392–9. doi:10.1038/35070076. PMID 11283613. S2CID 12696178.
Orlow I, Cordon-Cardo C (2002). "Evaluation of alterations in the tumor suppressor genes INK4A and INK4B in human bladder tumors". Gene Probes. Methods Mol. Biol. Vol. 179. pp. 43–59. doi:10.1385/1-59259-238-4:043. ISBN 1-59259-238-4. PMID 11692873.
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. PMID 11695244.
Simon M, Park TW, Köster G, Mahlberg R, Hackenbroch M, Boström J, et al. (December 2001). "Alterations of INK4a(p16-p14ARF)/INK4b(p15) expression and telomerase activation in meningioma progression". Journal of Neuro-Oncology. 55 (3): 149–58. doi:10.1023/A:1013863630293. PMID 11859969. S2CID 19711721.
Scarisbrick JJ, Woolford AJ, Calonje E, Photiou A, Ferreira S, Orchard G, et al. (March 2002). "Frequent abnormalities of the p15 and p16 genes in mycosis fungoides and sezary syndrome". The Journal of Investigative Dermatology. 118 (3): 493–9. doi:10.1046/j.0022-202x.2001.01682.x. PMID 11874489.
Kudoh K, Ichikawa Y, Yoshida S, Hirai M, Kikuchi Y, Nagata I, et al. (June 2002). "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. doi:10.1002/ijc.10331. PMID 11992549. S2CID 81974.
Yang W, Zhang A, Han Y, Su X, Chen Y, Zhao W (2021). "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. doi:10.1016/j.cjca.2020.05.016. PMID 32428618. S2CID 218756624.

External links

CDKN2B human gene location in the UCSC Genome Browser.
CDKN2B human gene details in the UCSC Genome Browser.

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000147883 – Ensembl, May 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000073802 – Ensembl, May 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[pmid8078588-5] Hannon GJ, Beach D (September 1994). "p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest". Nature. 371 (6494): 257–61. Bibcode:1994Natur.371..257H. doi:10.1038/371257a0. PMID 8078588. S2CID 4268054.

[entrez-6] "Entrez Gene: CDKN2B cyclin-dependent kinase inhibitor 2B (p15, inhibits CDK4)".

[7] Tu Q, Hao J, Zhou X, Yan L, Dai H, Sun B, et al. (January 2018). "CDKN2B deletion is essential for pancreatic cancer development instead of unmeaningful co-deletion due to juxtaposition to CDKN2A". Oncogene. 37 (1): 128–138. doi:10.1038/onc.2017.316. PMC 5759028. PMID 28892048.

[8] Jafri M, Wake NC, Ascher DB, Pires DE, Gentle D, Morris MR, et al. (July 2015). "Germline Mutations in the CDKN2B Tumor Suppressor Gene Predispose to Renal Cell Carcinoma". Cancer Discovery. 5 (7): 723–9. doi:10.1158/2159-8290.CD-14-1096. PMID 25873077.

[9] Yu W, Gius D, Onyango P, Muldoon-Jacobs K, Karp J, Feinberg AP, Cui H (January 2008). "Epigenetic silencing of tumour suppressor gene p15 by its antisense RNA". Nature. 451 (7175): 202–6. Bibcode:2008Natur.451..202Y. doi:10.1038/nature06468. PMC 2743558. PMID 18185590.

[pmid16189514-10] Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, et al. (October 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–8. Bibcode:2005Natur.437.1173R. doi:10.1038/nature04209. PMID 16189514. S2CID 4427026.

[pmid16169070-11] Stelzl U, Worm U, Lalowski M, Haenig C, Brembeck FH, Goehler H, et al. (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. hdl:11858/00-001M-0000-0010-8592-0. PMID 16169070. S2CID 8235923.

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