Biology:Cyclin-dependent kinase 9
 Generic protein structure example |
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[5] and
- CCNK,[6]
- CCNT1,[6][7][8][9][10][11][5][12][13]
- CCNT2,[7]
- MYBL2,[12]
- RELA,[14]
- RB1,[15]
- SKP1A.[5]
- SUPT5H,[13] and
- RNAP II.[16]
References
- ↑ "Entrez Gene: CDK9 cyclin-dependent kinase 9 (CDC2-related kinase)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1025.
- ↑ "Binding of CDK9 to TRAF2". J. Cell. Biochem. 71 (4): 467–78. 1998. doi:10.1002/(SICI)1097-4644(19981215)71:4<467::AID-JCB2>3.0.CO;2-G. PMID 9827693.
- ↑ "Natural analogues inhibiting selective cyclin-dependent kinase protein isoforms: a computational perspective". Journal of Biomolecular Structure and Dynamics 38 (17): 5126–5135. November 2019. doi:10.1080/07391102.2019.1696709. PMID 3176087.
- ↑ "Androgen receptor interacts with the positive elongation factor P-TEFb and enhances the efficiency of transcriptional elongation". J. Biol. Chem. 276 (13): 9978–84. March 2001. doi:10.1074/jbc.M002285200. PMID 11266437.
- ↑ 5.0 5.1 5.2 "Interaction between cyclin T1 and SCF(SKP2) targets CDK9 for ubiquitination and degradation by the proteasome". Mol. Cell. Biol. 21 (23): 7956–70. December 2001. doi:10.1128/MCB.21.23.7956-7970.2001. PMID 11689688.
- ↑ 6.0 6.1 "Cyclin K functions as a CDK9 regulatory subunit and participates in RNA polymerase II transcription". J. Biol. Chem. 274 (49): 34527–30. December 1999. doi:10.1074/jbc.274.49.34527. PMID 10574912.
- ↑ 7.0 7.1 "Identification of multiple cyclin subunits of human P-TEFb". Genes Dev. 12 (5): 755–62. March 1998. doi:10.1101/gad.12.5.755. PMID 9499409.
- ↑ "BRCA1 cooperates with NUFIP and P-TEFb to activate transcription by RNA polymerase II". Oncogene 23 (31): 5316–29. July 2004. doi:10.1038/sj.onc.1207684. PMID 15107825.
- ↑ "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. September 2003. doi:10.1128/MCB.23.18.6373-6384.2003. PMID 12944466.
- ↑ "MAQ1 and 7SK RNA interact with CDK9/cyclin T complexes in a transcription-dependent manner". Mol. Cell. Biol. 23 (14): 4859–69. July 2003. doi:10.1128/MCB.23.14.4859-4869.2003. PMID 12832472.
- ↑ "The growth factor granulin interacts with cyclin T1 and modulates P-TEFb-dependent transcription". Mol. Cell. Biol. 23 (5): 1688–702. March 2003. doi:10.1128/MCB.23.5.1688-1702.2003. PMID 12588988.
- ↑ 12.0 12.1 "Physical interaction between CDK9 and B-Myb results in suppression of B-Myb gene autoregulation". Oncogene 19 (3): 373–9. January 2000. doi:10.1038/sj.onc.1203305. PMID 10656684.
- ↑ 13.0 13.1 "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. September 2000. doi:10.1128/MCB.20.18.6958-6969.2000. PMID 10958691.
- ↑ "Interplay between cdk9 and NF-kappaB factors determines the level of HIV-1 gene transcription in astrocytic cells". Oncogene 21 (37): 5797–803. August 2002. doi:10.1038/sj.onc.1205754. PMID 12173051.
- ↑ "Physical interaction between pRb and cdk9/cyclinT2 complex". Oncogene 21 (26): 4158–65. June 2002. doi:10.1038/sj.onc.1205511. PMID 12037672.
- ↑ "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. July 2002. doi:10.1128/MCB.22.13.4622-4637.2002. 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.
- "Transcriptional control: Tat cofactors and transcriptional elongation.". Curr. Biol. 8 (13): R447–9. 1998. doi:10.1016/S0960-9822(98)70289-1. PMID 9651670.
- "Regulatory functions of Cdk9 and of cyclin T1 in HIV tat transactivation pathway gene expression.". J. Cell. Biochem. 75 (3): 357–68. 2000. doi:10.1002/(SICI)1097-4644(19991201)75:3<357::AID-JCB1>3.0.CO;2-K. PMID 10536359.
- "Multiple modes of transcriptional regulation by the HIV-1 Tat transactivator.". IUBMB Life 51 (3): 175–81. 2002. doi:10.1080/152165401753544241. PMID 11547919.
- "Multiple effects of HIV-1 trans-activator protein on the pathogenesis of HIV-1 infection.". Eur. J. Clin. Invest. 34 (1): 57–66. 2004. doi:10.1111/j.1365-2362.2004.01282.x. PMID 14984439.
- "Regulation of TAK/P-TEFb in CD4+ T lymphocytes and macrophages.". Curr. HIV Res. 1 (4): 395–404. 2004. doi:10.2174/1570162033485159. PMID 15049426.
- "Multiple actions of the human immunodeficiency virus type-1 Tat protein on microglial cell functions.". Neurochem. Res. 29 (5): 965–78. 2004. doi:10.1023/B:NERE.0000021241.90133.89. PMID 15139295.
- "HIV-1 infection and regulation of Tat function in macrophages.". Int. J. Biochem. Cell Biol. 36 (9): 1767–75. 2005. doi:10.1016/j.biocel.2004.02.018. PMID 15183343.
- "A review of HIV-1 Tat protein biological effects.". Cell Biochem. Funct. 23 (4): 223–7. 2005. doi:10.1002/cbf.1147. PMID 15473004.
- "HIV-1 TAR RNA: the target of molecular interactions between the virus and its host.". Curr. HIV Res. 3 (1): 61–71. 2005. doi:10.2174/1570162052772924. PMID 15638724.
- "HIV-1 tat protein and cell proliferation and survival: a brief review.". New Microbiol. 28 (2): 95–109. 2005. 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.
External links
- Cyclin-Dependent+Kinase+9 at the US 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.
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