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CDK9
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3BLH, 3BLQ, 3BLR, 3LQ5, 3MI9, 3MIA, 3MY1, 3TN8, 3TNH, 3TNI, 4BCF, 4BCG, 4BCH, 4BCI, 4BCJ, 4EC8, 4EC9, 4IMY, 4OGR, 4OR5
Identifiers
Aliases	CDK9, C-2k, CDC2L4, CTK1, PITALRE, TAK, cyclin-dependent kinase 9, cyclin dependent kinase 9
External IDs	OMIM: 603251; MGI: 1328368; HomoloGene: 55566; GeneCards: CDK9; OMA:CDK9 - orthologs
Gene location (Human) Chr. Chromosome 9 (human) Band 9q34.11 Start 127,785,679 bp End 127,790,792 bp
Gene location (Mouse) Chr. Chromosome 2 (mouse) Band 2|2 B Start 32,595,796 bp End 32,603,088 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right uterine tube left ovary right ovary sural nerve left uterine tube gastric mucosa right hemisphere of cerebellum anterior pituitary body of uterus canal of the cervix Top expressed in granulocyte stroma of bone marrow superior frontal gyrus thymus fetal liver hematopoietic progenitor cell tibiofemoral joint primary visual cortex dermis epiblast spleen More reference expression data BioGPS More reference expression data
Gene ontology Molecular function nucleotide binding transferase activity protein kinase activity 7SK snRNA binding transcription coactivator binding snRNA binding ATP binding RNA polymerase II core promoter sequence-specific DNA binding DNA binding transcription factor binding protein binding protein serine/threonine kinase activity chromatin binding kinase activity cyclin-dependent protein serine/threonine kinase activity RNA polymerase II CTD heptapeptide repeat kinase activity protein kinase binding cyclin binding RNA polymerase II cis-regulatory region sequence-specific DNA binding Cellular component cytoplasm nucleus membrane nucleoplasm transcription elongation factor complex cyclin/CDK positive transcription elongation factor complex PML body chromosome cytoplasmic ribonucleoprotein granule cyclin-dependent protein kinase holoenzyme complex Biological process positive regulation of cardiac muscle hypertrophy positive regulation of mRNA 3'-UTR binding regulation of muscle cell differentiation negative regulation of mRNA polyadenylation DNA repair cellular response to cytokine stimulus positive regulation of viral transcription replication fork processing protein phosphorylation regulation of histone modification regulation of mitotic cell cycle cellular response to DNA damage stimulus transcription initiation from RNA polymerase II promoter regulation of DNA repair regulation of transcription, DNA-templated cell population proliferation transcription by RNA polymerase II phosphorylation positive regulation of histone H2B ubiquitination positive regulation of transcription by RNA polymerase II transcription, DNA-templated snRNA transcription by RNA polymerase II transcription elongation from RNA polymerase II promoter phosphorylation of RNA polymerase II C-terminal domain positive regulation of transcription elongation from RNA polymerase II promoter Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 1025 107951 Ensembl ENSG00000136807 ENSMUSG00000009555 UniProt P50750 Q99J95 RefSeq (mRNA) NM_001261 NM_130860 RefSeq (protein) NP_001252 NP_001252.1 NP_570930 Location (UCSC) Chr 9: 127.79 – 127.79 Mb Chr 2: 32.6 – 32.6 Mb PubMed search
Wikidata
View/Edit Human View/Edit Mouse

Cyclin-dependent kinase 9 or CDK9 is a cyclin-dependent kinase associated with P-TEFb.

Function

The protein encoded by this gene is a member of the cyclin-dependent kinase (CDK) family. CDK family members are highly similar to the gene products of S. cerevisiae cdc28, and S. pombe cdc2, and known as important cell cycle regulators. This kinase was found to be a component of the multiprotein complex TAK/P-TEFb, which is an elongation factor for RNA polymerase II-directed transcription and functions by phosphorylating the C-terminal domain of the largest subunit of RNA polymerase II. This protein forms a complex with and is regulated by its regulatory subunit cyclin T or cyclin K. HIV-1 Tat protein was found to interact with this protein and cyclin T, which suggested a possible involvement of this protein in AIDS.

CDK9 is also known to associate with other proteins such as TRAF2, and be involved in differentiation of skeletal muscle.

Inhibitors

Based on molecular docking results, Ligands-3, 5, 14, and 16 were screened among 17 different Pyrrolone-fused benzosuberene compounds as potent and specific inhibitors without any cross-reactivity against different CDK isoforms. Analysis of MD simulations and MM-PBSA studies, revealed the binding energy profiles of all the selected complexes. Selected ligands performed better than the experimental drug candidate (Roscovitine). Ligands-5 and 16 show specificity for CDK9. These ligands are expected to possess lower risk of side effects due to their natural origin.

Interactions

CDK9 has been shown to interact with:

• Androgen receptor,
• CDC34 and
• CCNK,
• CCNT1,
• CCNT2,
• MYBL2,
• RELA,
• RB1,
• SKP1A.
• SUPT5H, and
• RNAP II.

References

1. ^ GRCh38: Ensembl release 89: ENSG00000136807 – Ensembl, May 2017
2. ^ GRCm38: Ensembl release 89: ENSMUSG00000009555 – 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.
5. "Entrez Gene: CDK9 cyclin-dependent kinase 9 (CDC2-related kinase)".
6. MacLachlan TK, Sang N, De Luca A, Puri PL, Levrero M, Giordano A (1998). "Binding of CDK9 to TRAF2". J. Cell. Biochem. 71 (4): 467–78. doi:10.1002/(SICI)1097-4644(19981215)71:4<467::AID-JCB2>3.0.CO;2-G. PMID 9827693. S2CID 25858837.
7. Singh R, Bhardwaj VK, Das P, Purohit R (November 2019). "Natural analogues inhibiting selective cyclin-dependent kinase protein isoforms: a computational perspective". Journal of Biomolecular Structure and Dynamics. 38 (17): 5126–5135. doi:10.1080/07391102.2019.1696709. PMID 3176087. S2CID 208276454.
8. Lee DK, Duan HO, Chang C (March 2001). "Androgen receptor interacts with the positive elongation factor P-TEFb and enhances the efficiency of transcriptional elongation". J. Biol. Chem. 276 (13): 9978–84. doi:10.1074/jbc.M002285200. PMID 11266437.
9. ^ Kiernan RE, Emiliani S, Nakayama K, Castro A, Labbé JC, Lorca T, Nakayama Ki K, Benkirane M (December 2001). "Interaction between cyclin T1 and SCF(SKP2) targets CDK9 for ubiquitination and degradation by the proteasome". Mol. Cell. Biol. 21 (23): 7956–70. doi:10.1128/MCB.21.23.7956-7970.2001. PMC 99964. PMID 11689688.
10. ^ Fu TJ, Peng J, Lee G, Price DH, Flores O (December 1999). "Cyclin K functions as a CDK9 regulatory subunit and participates in RNA polymerase II transcription". J. Biol. Chem. 274 (49): 34527–30. doi:10.1074/jbc.274.49.34527. PMID 10574912.
11. ^ Peng J, Zhu Y, Milton JT, Price DH (March 1998). "Identification of multiple cyclin subunits of human P-TEFb". Genes Dev. 12 (5): 755–62. doi:10.1101/gad.12.5.755. PMC 316581. PMID 9499409.
12. Cabart P, Chew HK, Murphy S (July 2004). "BRCA1 cooperates with NUFIP and P-TEFb to activate transcription by RNA polymerase II". Oncogene. 23 (31): 5316–29. doi:10.1038/sj.onc.1207684. PMID 15107825.
13. Young TM, Wang Q, Pe'ery T, Mathews MB (September 2003). "The human I-mfa domain-containing protein, HIC, interacts with cyclin T1 and modulates P-TEFb-dependent transcription". Mol. Cell. Biol. 23 (18): 6373–84. doi:10.1128/MCB.23.18.6373-6384.2003. PMC 193714. PMID 12944466.
14. Michels AA, Nguyen VT, Fraldi A, Labas V, Edwards M, Bonnet F, Lania L, Bensaude O (July 2003). "MAQ1 and 7SK RNA interact with CDK9/cyclin T complexes in a transcription-dependent manner". Mol. Cell. Biol. 23 (14): 4859–69. doi:10.1128/MCB.23.14.4859-4869.2003. PMC 162212. PMID 12832472.
15. Hoque M, Young TM, Lee CG, Serrero G, Mathews MB, Pe'ery T (March 2003). "The growth factor granulin interacts with cyclin T1 and modulates P-TEFb-dependent transcription". Mol. Cell. Biol. 23 (5): 1688–702. doi:10.1128/MCB.23.5.1688-1702.2003. PMC 151712. PMID 12588988.
16. ^ De Falco G, Bagella L, Claudio PP, De Luca A, Fu Y, Calabretta B, Sala A, Giordano A (January 2000). "Physical interaction between CDK9 and B-Myb results in suppression of B-Myb gene autoregulation". Oncogene. 19 (3): 373–9. doi:10.1038/sj.onc.1203305. PMID 10656684.
17. ^ Garber ME, Mayall TP, Suess EM, Meisenhelder J, Thompson NE, Jones KA (September 2000). "CDK9 autophosphorylation regulates high-affinity binding of the human immunodeficiency virus type 1 tat-P-TEFb complex to TAR RNA". Mol. Cell. Biol. 20 (18): 6958–69. doi:10.1128/MCB.20.18.6958-6969.2000. PMC 88771. PMID 10958691.
18. Amini S, Clavo A, Nadraga Y, Giordano A, Khalili K, Sawaya BE (August 2002). "Interplay between cdk9 and NF-kappaB factors determines the level of HIV-1 gene transcription in astrocytic cells". Oncogene. 21 (37): 5797–803. doi:10.1038/sj.onc.1205754. PMID 12173051.
19. Simone C, Bagella L, Bellan C, Giordano A (June 2002). "Physical interaction between pRb and cdk9/cyclinT2 complex". Oncogene. 21 (26): 4158–65. doi:10.1038/sj.onc.1205511. PMID 12037672.
20. Kim YK, Bourgeois CF, Isel C, Churcher MJ, Karn J (July 2002). "Phosphorylation of the RNA Polymerase II Carboxyl-Terminal Domain by CDK9 Is Directly Responsible for Human Immunodeficiency Virus Type 1 Tat-Activated Transcriptional Elongation". Mol Cell Biol. 22 (13): 4622–4637. doi:10.1128/MCB.22.13.4622-4637.2002. PMC 133925. PMID 12052871.

Further reading

• Jeang KT (1998). "Tat, Tat-associated kinase, and transcription". J. Biomed. Sci. 5 (1): 24–7. doi:10.1007/BF02253352. PMID 9570510.
• Yankulov K, Bentley D (1998). "Transcriptional control: Tat cofactors and transcriptional elongation". Curr. Biol. 8 (13): R447–9. Bibcode:1998CBio....8.R447Y. doi:10.1016/S0960-9822(98)70289-1. PMID 9651670. S2CID 15480646.
• Romano G, Kasten M, De Falco G, et al. (2000). "Regulatory functions of Cdk9 and of cyclin T1 in HIV tat transactivation pathway gene expression". J. Cell. Biochem. 75 (3): 357–68. doi:10.1002/(SICI)1097-4644(19991201)75:3<357::AID-JCB1>3.0.CO;2-K. PMID 10536359. S2CID 43685090.
• Marcello A, Zoppé M, Giacca M (2002). "Multiple modes of transcriptional regulation by the HIV-1 Tat transactivator". IUBMB Life. 51 (3): 175–81. doi:10.1080/152165401753544241. PMID 11547919. S2CID 10931640.
• Huigen MC, Kamp W, Nottet HS (2004). "Multiple effects of HIV-1 trans-activator protein on the pathogenesis of HIV-1 infection". Eur. J. Clin. Invest. 34 (1): 57–66. doi:10.1111/j.1365-2362.2004.01282.x. PMID 14984439. S2CID 29713968.
• Rice AP, Herrmann CH (2004). "Regulation of TAK/P-TEFb in CD4+ T lymphocytes and macrophages". Curr. HIV Res. 1 (4): 395–404. doi:10.2174/1570162033485159. PMID 15049426.
• Minghetti L, Visentin S, Patrizio M, et al. (2004). "Multiple actions of the human immunodeficiency virus type-1 Tat protein on microglial cell functions". Neurochem. Res. 29 (5): 965–78. doi:10.1023/B:NERE.0000021241.90133.89. PMID 15139295. S2CID 25323034.
• Liou LY, Herrmann CH, Rice AP (2005). "HIV-1 infection and regulation of Tat function in macrophages". Int. J. Biochem. Cell Biol. 36 (9): 1767–75. doi:10.1016/j.biocel.2004.02.018. PMID 15183343.
• Pugliese A, Vidotto V, Beltramo T, et al. (2005). "A review of HIV-1 Tat protein biological effects". Cell Biochem. Funct. 23 (4): 223–7. doi:10.1002/cbf.1147. PMID 15473004. S2CID 8408278.
• Bannwarth S, Gatignol A (2005). "HIV-1 TAR RNA: the target of molecular interactions between the virus and its host". Curr. HIV Res. 3 (1): 61–71. doi:10.2174/1570162052772924. PMID 15638724.
• Gibellini D, Vitone F, Schiavone P, Re MC (2005). "HIV-1 tat protein and cell proliferation and survival: a brief review". New Microbiol. 28 (2): 95–109. PMID 16035254.
• Peruzzi F (2006). "The multiple functions of HIV-1 Tat: proliferation versus apoptosis". Front. Biosci. 11: 708–17. doi:10.2741/1829. PMID 16146763.

See also

• Enitociclib

External links

• Cyclin-Dependent+Kinase+9 at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Drosophila Cyclin dependent kinase 9 - The Interactive Fly
• CDK9 human gene location in the UCSC Genome Browser.
• CDK9 human gene details in the UCSC Genome Browser.

• Biology

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• Genes on human chromosome 9
• Cell cycle
• Proteins
• EC 2.7.11
• EC 2.7 stubs