Cyclin-dependent kinase 9 explained

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.^[1]

CDK9 is also known to associate with other proteins such as TRAF2, and be involved in differentiation of skeletal muscle.^[2]

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. ^[3]

Interactions

CDK9 has been shown to interact with:

• Androgen receptor,^[4]
• CDC34 and
• CCNK,^[5]
• CCNT1,^{[5] [6] [7] [8] [9] [10] [11] [12]}
• CCNT2,^[13]
• MYBL2,^[11]
• RELA,^[14]
• RB1,^[15]
• SKP1A.^[10]
• SUPT5H,^[12] and
• RNAP II.^[16]

Further reading

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

External links

• • Drosophila Cyclin dependent kinase 9 - The Interactive Fly

Notes and References

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