Cyclin-dependent kinase 2

CDK2
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCDK2, cyclin-dependent kinase 2, A630093N05Rik, CDKN2, p33(CDK2), cyclin dependent kinase 2
External IDsMGI: 104772 HomoloGene: 74409 GeneCards: CDK2
Gene location (Human)
Chr.Chromosome 12 (human)[1]
Band12q13.2Start55,966,769 bp[1]
End55,972,784 bp[1]
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez

1017

12566

Ensembl

ENSG00000123374

ENSMUSG00000025358

UniProt

P24941

P97377

RefSeq (mRNA)

NM_001290230
NM_001798
NM_052827

NM_016756
NM_183417

RefSeq (protein)

NP_001277159
NP_001789
NP_439892

NP_058036
NP_904326

Location (UCSC)Chr 12: 55.97 – 55.97 MbChr 10: 128.7 – 128.71 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Cyclin-dependent kinase 2, also known as cell division protein kinase 2, is an enzyme that in humans is encoded by the CDK2 gene.[5][6]

Function

The protein encoded by this gene is a member of the cyclin-dependent kinase family of Ser/Thr protein kinases. This protein kinase is highly similar to the gene products of S. cerevisiae cdc28, and S. pombe cdc2, also known as Cdk1 in humans. It is a catalytic subunit of the cyclin-dependent kinase complex, whose activity is restricted to the G1-S phase of the cell cycle, and is essential for the G1/S transition. This protein associates with and is regulated by the regulatory subunits of the complex including cyclin E or A. Cyclin E binds G1 phase Cdk2, which is required for the transition from G1 to S phase while binding with Cyclin A is required to progress through the S phase. Its activity is also regulated by phosphorylation. Two alternatively spliced variants and multiple transcription initiation sites of this gene have been reported.[6]

The role of this protein in G1-S transition has been recently questioned as cells lacking Cdk2 are reported to have no problem during this transition.[7]

Inhibitors

Known CDK inhibitors are p21Cip1 (CDKN1A) and p27Kip1 (CDKN1B).[8]

Drugs that inhibit Cdk2 and arrest the cell cycle, such as GW8510 and the experimental cancer drug seliciclib, may reduce the sensitivity of the epithelium to many cell cycle-active antitumor agents and, therefore, represent a strategy for prevention of chemotherapy-induced alopecia.[9]

Rosmarinic acid methyl ester is a plant-derived Cdk2 inhibitor, which was shown to suppress proliferation of vascular smooth muscle cells and to reduce neointima formation in mouse restenosis model.[10]

See also the PDB gallery below showing interactions with many inhibitors (inc Purvalanol B)

Gene regulation

In melanocytic cell types, expression of the CDK2 gene is regulated by the Microphthalmia-associated transcription factor.[11][12]

Interactions

Cyclin-dependent kinase 2 has been shown to interact with:

Overview of signal transduction pathways involved in apoptosis.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000123374 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000025358 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:".
  4. ↑ "Mouse PubMed Reference:".
  5. ↑ Tsai LH, Harlow E, Meyerson M (September 1991). "Isolation of the human cdk2 gene that encodes the cyclin A- and adenovirus E1A-associated p33 kinase". Nature. 353 (6340): 174–7. doi:10.1038/353174a0. PMID 1653904.
  6. 1 2 "Entrez Gene: CDK2 cyclin-dependent kinase 2".
  7. ↑ Berthet C, Aleem E, Coppola V, Tessarollo L, Kaldis P (October 2003). "Cdk2 knockout mice are viable". Curr. Biol. 13 (20): 1775–85. doi:10.1016/j.cub.2003.09.024. PMID 14561402.
  8. ↑ Levkau B, Koyama H, Raines EW, Clurman BE, Herren B, Orth K, Roberts JM, Ross R (March 1998). "Cleavage of p21Cip1/Waf1 and p27Kip1 mediates apoptosis in endothelial cells through activation of Cdk2: role of a caspase cascade". Mol. Cell. 1 (4): 553–63. doi:10.1016/S1097-2765(00)80055-6. PMID 9660939.
  9. ↑ Davis ST, Benson BG, Bramson HN, Chapman DE, Dickerson SH, Dold KM, Eberwein DJ, Edelstein M, Frye SV, Gampe Jr RT, Griffin RJ, Harris PA, Hassell AM, Holmes WD, Hunter RN, Knick VB, Lackey K, Lovejoy B, Luzzio MJ, Murray D, Parker P, Rocque WJ, Shewchuk L, Veal JM, Walker DH, Kuyper LF (January 2001). "Prevention of chemotherapy-induced alopecia in rats by CDK inhibitors". Science. 291 (5501): 134–7. doi:10.1126/science.291.5501.134. PMID 11141566.
  10. ↑ Liu R, Heiss EH, Waltenberger B, Blažević T, Schachner D, Jiang B, Krystof V, Liu W, Schwaiger S, Peña-Rodríguez LM, Breuss JM, Stuppner H, Dirsch VM, Atanasov AG (April 2018). "Constituents of Mediterranean Spices Counteracting Vascular Smooth Muscle Cell Proliferation: Identification and Characterization of Rosmarinic Acid Methyl Ester as a Novel Inhibitor". Molecular Nutrition & Food Research. 62 (7): e1700860. doi:10.1002/mnfr.201700860. PMID 29405576.
  11. ↑ Du J, Widlund HR, Horstmann MA, Ramaswamy S, Ross K, Huber WE, Nishimura EK, Golub TR, Fisher DE (2004). "Critical role of CDK2 for melanoma growth linked to its melanocyte-specific transcriptional regulation by MITF". Cancer Cell. 6 (6): 565–76. doi:10.1016/j.ccr.2004.10.014. PMID 15607961.
  12. ↑ Hoek KS, Schlegel NC, Eichhoff OM, Widmer DS, Praetorius C, Einarsson SO, Valgeirsdottir S, Bergsteinsdottir K, Schepsky A, Dummer R, Steingrimsson E (2008). "Novel MITF targets identified using a two-step DNA microarray strategy". Pigment Cell Melanoma Res. 21 (6): 665–76. doi:10.1111/j.1755-148X.2008.00505.x. PMID 19067971.
  13. ↑ Chen Y, Farmer AA, Chen CF, Jones DC, Chen PL, Lee WH (July 1996). "BRCA1 is a 220-kDa nuclear phosphoprotein that is expressed and phosphorylated in a cell cycle-dependent manner". Cancer Res. 56 (14): 3168–72. PMID 8764100.
  14. ↑ Ruffner H, Jiang W, Craig AG, Hunter T, Verma IM (July 1999). "BRCA1 is phosphorylated at serine 1497 in vivo at a cyclin-dependent kinase 2 phosphorylation site". Mol. Cell. Biol. 19 (7): 4843–54. PMC 84283. PMID 10373534.
  15. ↑ Wang H, Shao N, Ding QM, Cui J, Reddy ES, Rao VN (July 1997). "BRCA1 proteins are transported to the nucleus in the absence of serum and splice variants BRCA1a, BRCA1b are tyrosine phosphoproteins that associate with E2F, cyclins and cyclin dependent kinases". Oncogene. 15 (2): 143–57. doi:10.1038/sj.onc.1201252. PMID 9244350.
  16. ↑ Shintani S, Ohyama H, Zhang X, McBride J, Matsuo K, Tsuji T, Hu MG, Hu G, Kohno Y, Lerman M, Todd R, Wong DT (September 2000). "p12(DOC-1) is a novel cyclin-dependent kinase 2-associated protein". Mol. Cell. Biol. 20 (17): 6300–7. doi:10.1128/MCB.20.17.6300-6307.2000. PMC 86104. PMID 10938106.
  17. 1 2 Connor MK, Kotchetkov R, Cariou S, Resch A, Lupetti R, Beniston RG, Melchior F, Hengst L, Slingerland JM (January 2003). "CRM1/Ran-mediated nuclear export of p27(Kip1) involves a nuclear export signal and links p27 export and proteolysis". Mol. Biol. Cell. 14 (1): 201–13. doi:10.1091/mbc.E02-06-0319. PMC 140238. PMID 12529437.
  18. 1 2 Rosner M, Hengstschläger M (November 2004). "Tuberin binds p27 and negatively regulates its interaction with the SCF component Skp2". J. Biol. Chem. 279 (47): 48707–15. doi:10.1074/jbc.M405528200. PMID 15355997.
  19. ↑ Youn CK, Cho HJ, Kim SH, Kim HB, Kim MH, Chang IY, Lee JS, Chung MH, Hahm KS, You HJ (February 2005). "Bcl-2 expression suppresses mismatch repair activity through inhibition of E2F transcriptional activity". Nat. Cell Biol. 7 (2): 137–47. doi:10.1038/ncb1215. PMID 15619620.
  20. ↑ Porter LA, Kong-Beltran M, Donoghue DJ (September 2003). "Spy1 interacts with p27Kip1 to allow G1/S progression". Mol. Biol. Cell. 14 (9): 3664–74. doi:10.1091/mbc.E02-12-0820. PMC 196558. PMID 12972555.
  21. 1 2 Law BK, Chytil A, Dumont N, Hamilton EG, Waltner-Law ME, Aakre ME, Covington C, Moses HL (December 2002). "Rapamycin potentiates transforming growth factor beta-induced growth arrest in nontransformed, oncogene-transformed, and human cancer cells". Mol. Cell. Biol. 22 (23): 8184–98. doi:10.1128/mcb.22.23.8184-8198.2002. PMC 134072. PMID 12417722.
  22. ↑ Yeh CT, Lu SC, Chao CH, Chao ML (May 2003). "Abolishment of the interaction between cyclin-dependent kinase 2 and Cdk-associated protein phosphatase by a truncated KAP mutant". Biochem. Biophys. Res. Commun. 305 (2): 311–4. doi:10.1016/s0006-291x(03)00757-5. PMID 12745075.
  23. ↑ Hannon GJ, Casso D, Beach D (March 1994). "KAP: a dual specificity phosphatase that interacts with cyclin-dependent kinases". Proc. Natl. Acad. Sci. U.S.A. 91 (5): 1731–5. doi:10.1073/pnas.91.5.1731. PMC 43237. PMID 8127873.
  24. 1 2 Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ (November 1993). "The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases". Cell. 75 (4): 805–16. doi:10.1016/0092-8674(93)90499-g. PMID 8242751.
  25. ↑ Wang H, Iakova P, Wilde M, Welm A, Goode T, Roesler WJ, Timchenko NA (October 2001). "C/EBPalpha arrests cell proliferation through direct inhibition of Cdk2 and Cdk4". Mol. Cell. 8 (4): 817–28. doi:10.1016/s1097-2765(01)00366-5. PMID 11684017.
  26. ↑ Sweeney C, Murphy M, Kubelka M, Ravnik SE, Hawkins CF, Wolgemuth DJ, Carrington M (January 1996). "A distinct cyclin A is expressed in germ cells in the mouse". Development. 122 (1): 53–64. PMID 8565853.
  27. ↑ Yang R, Morosetti R, Koeffler HP (March 1997). "Characterization of a second human cyclin A that is highly expressed in testis and in several leukemic cell lines". Cancer Res. 57 (5): 913–20. PMID 9041194.
  28. ↑ Müller-Tidow C, Wang W, Idos GE, Diederichs S, Yang R, Readhead C, Berdel WE, Serve H, Saville M, Watson R, Koeffler HP (April 2001). "Cyclin A1 directly interacts with B-myb and cyclin A1/cdk2 phosphorylate B-myb at functionally important serine and threonine residues: tissue-specific regulation of B-myb function". Blood. 97 (7): 2091–7. doi:10.1182/blood.v97.7.2091. PMID 11264176.
  29. ↑ Brown NR, Noble ME, Endicott JA, Johnson LN (November 1999). "The structural basis for specificity of substrate and recruitment peptides for cyclin-dependent kinases". Nat. Cell Biol. 1 (7): 438–43. doi:10.1038/15674. PMID 10559988.
  30. 1 2 3 Shanahan F, Seghezzi W, Parry D, Mahony D, Lees E (February 1999). "Cyclin E associates with BAF155 and BRG1, components of the mammalian SWI-SNF complex, and alters the ability of BRG1 to induce growth arrest". Mol. Cell. Biol. 19 (2): 1460–9. doi:10.1128/mcb.19.2.1460. PMC 116074. PMID 9891079.
  31. 1 2 McKenzie PP, Danks MK, Kriwacki RW, Harris LC (July 2003). "P21Waf1/Cip1 dysfunction in neuroblastoma: a novel mechanism of attenuating G0-G1 cell cycle arrest". Cancer Res. 63 (13): 3840–4. PMID 12839982.
  32. ↑ Koff A, Giordano A, Desai D, Yamashita K, Harper JW, Elledge S, Nishimoto T, Morgan DO, Franza BR, Roberts JM (September 1992). "Formation and activation of a cyclin E-cdk2 complex during the G1 phase of the human cell cycle". Science. 257 (5077): 1689–94. doi:10.1126/science.1388288. PMID 1388288.
  33. ↑ Mayer C, Zhao J, Yuan X, Grummt I (February 2004). "mTOR-dependent activation of the transcription factor TIF-IA links rRNA synthesis to nutrient availability". Genes Dev. 18 (4): 423–34. doi:10.1101/gad.285504. PMC 359396. PMID 15004009.
  34. ↑ Boudrez A, Beullens M, Groenen P, Van Eynde A, Vulsteke V, Jagiello I, Murray M, Krainer AR, Stalmans W, Bollen M (August 2000). "NIPP1-mediated interaction of protein phosphatase-1 with CDC5L, a regulator of pre-mRNA splicing and mitotic entry". J. Biol. Chem. 275 (33): 25411–7. doi:10.1074/jbc.M001676200. PMID 10827081.
  35. ↑ Henneke G, Koundrioukoff S, Hübscher U (July 2003). "Phosphorylation of human Fen1 by cyclin-dependent kinase modulates its role in replication fork regulation". Oncogene. 22 (28): 4301–13. doi:10.1038/sj.onc.1206606. PMID 12853968.
  36. ↑ Méndez J, Zou-Yang XH, Kim SY, Hidaka M, Tansey WP, Stillman B (March 2002). "Human origin recognition complex large subunit is degraded by ubiquitin-mediated proteolysis after initiation of DNA replication". Mol. Cell. 9 (3): 481–91. doi:10.1016/s1097-2765(02)00467-7. PMID 11931757.
  37. 1 2 Yam CH, Ng RW, Siu WY, Lau AW, Poon RY (January 1999). "Regulation of cyclin A-Cdk2 by SCF component Skp1 and F-box protein Skp2". Mol. Cell. Biol. 19 (1): 635–45. doi:10.1128/mcb.19.1.635. PMC 83921. PMID 9858587.
  38. ↑ Ono T, Kitaura H, Ugai H, Murata T, Yokoyama KK, Iguchi-Ariga SM, Ariga H (October 2000). "TOK-1, a novel p21Cip1-binding protein that cooperatively enhances p21-dependent inhibitory activity toward CDK2 kinase". J. Biol. Chem. 275 (40): 31145–54. doi:10.1074/jbc.M003031200. PMID 10878006.
  39. 1 2 Cheng A, Kaldis P, Solomon MJ (November 2000). "Dephosphorylation of human cyclin-dependent kinases by protein phosphatase type 2C alpha and beta 2 isoforms". J. Biol. Chem. 275 (44): 34744–9. doi:10.1074/jbc.M006210200. PMID 10934208.
  40. ↑ Leng X, Noble M, Adams PD, Qin J, Harper JW (April 2002). "Reversal of growth suppression by p107 via direct phosphorylation by cyclin D1/cyclin-dependent kinase 4". Mol. Cell. Biol. 22 (7): 2242–54. doi:10.1128/mcb.22.7.2242-2254.2002. PMC 133692. PMID 11884610.
  41. ↑ Lacy S, Whyte P (May 1997). "Identification of a p130 domain mediating interactions with cyclin A/cdk 2 and cyclin E/cdk 2 complexes". Oncogene. 14 (20): 2395–406. doi:10.1038/sj.onc.1201085. PMID 9188854.
  42. ↑ Marti A, Wirbelauer C, Scheffner M, Krek W (May 1999). "Interaction between ubiquitin-protein ligase SCFSKP2 and E2F-1 underlies the regulation of E2F-1 degradation". Nat. Cell Biol. 1 (1): 14–9. doi:10.1038/8984. PMID 10559858.

Further reading

  • Kaldis P, Aleem E (2007). "Cell cycle sibling rivalry: Cdc2 vs. Cdk2". Cell Cycle. 4 (11): 1491–4. doi:10.4161/cc.4.11.2124. PMID 16258277.
  • Moore NL, Narayanan R, Weigel NL (2007). "Cyclin dependent kinase 2 and the regulation of human progesterone receptor activity". Steroids. 72 (2): 202–9. doi:10.1016/j.steroids.2006.11.025. PMC 1950255. PMID 17207508.
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