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Gene Review

CDK9  -  cyclin-dependent kinase 9

Homo sapiens

Synonyms: C-2K, C-2k, CDC2L4, CTK1, Cell division cycle 2-like protein kinase 4, ...
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Disease relevance of CDK9

  • The human positive transcription elongation factor P-TEFb, consisting of a CDK9/cyclin T1 heterodimer, functions as both a general and an HIV-1 Tat-specific transcription factor [1].
  • CDK9 autophosphorylation regulates high-affinity binding of the human immunodeficiency virus type 1 tat-P-TEFb complex to TAR RNA [2].
  • Disruption of TNF-alpha signaling using CDK9 inhibitors could serve as a potential therapeutic strategy against tumor invasion and metastasis [3].
  • In this report, we demonstrate that CDK9, which is the kinase component of the positive transcription elongation factor b (P-TEFb) complex, can activate viral transcription when tethered to the heterologous Rev response element RNA via the regulator of expression of virion proteins (Rev) [4].
  • In culture, dominant-negative Cdk9 blocked ET-1-induced hypertrophy, whereas an anti-sense "knockdown" of 7SK snRNA provoked spontaneous cell growth [5].

High impact information on CDK9


Chemical compound and disease context of CDK9


Biological context of CDK9

  • CDK9 is required for the global maintenance of histone H2B monoubiquitination [12].
  • In the absence of CDK9, replication-dependent histone mRNAs are not properly 3' end processed, but instead become polyadenylated [12].
  • Tat-induced CTD phosphorylation by CDK9 is strongly inhibited by low concentrations of 5, 6-dichloro-1-beta-D-ribofuranosylbenzimidazole, an inhibitor of transcription elongation by RNAP II [9].
  • Taken together, these results demonstrate that CDK9 phosphorylation is required for high-affinity binding of Tat-P-TEFb to TAR RNA and that the state of P-TEFb phosphorylation may regulate Tat transactivation in vivo [2].
  • CDK9 is a CDC2-related kinase and the catalytic subunit of the positive-transcription elongation factor b and the Tat-activating kinase [13].
  • Similarly, the levels of CDK9 protein did not change as cells exited the cell cycle and differentiated along various lineages [13].
  • These studies suggest that the ability of Tat to increase transcriptional elongation may be due to its ability to modify the substrate specificity of the CDK9 complex [9].

Anatomical context of CDK9


Associations of CDK9 with chemical compounds

  • Analysis of preinitiation complexes formed in immunodepleted extracts suggests that CDK9 phosphorylates serine 2, while CDK7 phosphorylates serine 5 [9].
  • Chase experiments with the dephosphorylated elongation transcription complexes were performed in the presence of the CDK9 kinase inhibitor DRB (5,6-dichloro-1-beta-D-ribofuranosyl-benzimidazole) [18].
  • Moreover, the addition of the CDK9 inhibitor flavopiridol blocked Tax transactivation in vitro and in vivo [19].
  • We determined that CDK9 is actively exported from the nucleus, and that leptomycin B (LMB), a specific inhibitor of nuclear export, inhibits this process [20].
  • CONCLUSIONS: H-9-immobilized latex beads are useful for trapping CDK9 and a subset of kinases from crude cell extracts [21].

Physical interactions of CDK9

  • We found that Cdk9 interacts in vitro with the cytoplasmic region of gp130 and we succeded in reproducing this interaction in vivo [22].
  • To identify additional factors involved in P-TEFb function we performed a yeast two-hybrid screen using CDK9 as bait and found that cyclin K interacts with CDK9 in vivo [23].
  • Upregulation of cyclin T1/CDK9 complexes during T cell activation [24].
  • Cellular control of gene expression by T-type cyclin/CDK9 complexes [25].
  • In an effort to further dissect the mechanisms implicated in AR transactivation, we report here that AR interacts with PITALRE, a kinase subunit of positive elongation factor b (P-TEFb) [26].
  • CDK9 interacts with NPAT to control replication-dependent histone mRNA 3' end processing [27].

Enzymatic interactions of CDK9

  • CDK9 is able to hyperphosphorylate the carboxyl-terminal domain (CTD) of the large subunit of RNA polymerase during elongation [28].
  • Here we report that CDK9 is ubiquitinated and degraded by the proteasome whereas cyclin T1 is stable [29].
  • The efficiency to promote the dephosphorylation of both proteins matches their capacity to inhibit purified Cdk9 kinase, suggesting that Cdk9 is the major kinase phosphorylating hSpt5 and Rpb1 in vivo [30].
  • The peptidyl-prolyl isomerase Pin1 interacts with hSpt5 phosphorylated by Cdk9 [30].
  • In the current work, we found that PITALRE kinase activity phosphorylated pRb at sites similar to those phosphorylated by the CDC2 kinase, which itself is known to mimic, in vitro, the in vivo phosphorylation of pRb [31].
  • PPM1B only efficiently dephosphorylated Cdk9 Thr-186 in vitro when 7SK RNA was depleted from P-TEFb [32].

Regulatory relationships of CDK9


Other interactions of CDK9

  • We now report an in vitro reconstitution of 7SK-dependent HEXIM1 association to purified P-TEFb and subsequent CDK9 inhibition [37].
  • CDK9 is constitutively expressed throughout the cell cycle, and its steady-state expression is independent of SKP2 [13].
  • CDK8 and CDK9 complexes, bound to viral activators E1A and Tat, respectively, target only serine 5 for phosphorylation in the CTD peptides, and binding to the viral activators does not change the substrate preference of these kinases [38].
  • Our findings indicate that CDK9 mediates TNF-alpha-induced MMP-9 transcription [3].
  • We also observed that Cdk9 synergized with IL-6 in inducing the activation of an IL-6-responsive reporter plasmid [22].
  • We present evidence that CDK9 is regulated by N-CoR and its associated HDAC3 and that acetylation of CDK9 affects its ability to phosphorylate the CTD of pol II [39].

Analytical, diagnostic and therapeutic context of CDK9




  1. The 7SK small nuclear RNA inhibits the CDK9/cyclin T1 kinase to control transcription. Yang, Z., Zhu, Q., Luo, K., Zhou, Q. Nature (2001) [Pubmed]
  2. CDK9 autophosphorylation regulates high-affinity binding of the human immunodeficiency virus type 1 tat-P-TEFb complex to TAR RNA. Garber, M.E., Mayall, T.P., Suess, E.M., Meisenhelder, J., Thompson, N.E., Jones, K.A. Mol. Cell. Biol. (2000) [Pubmed]
  3. Cyclin-dependent kinase 9 is required for tumor necrosis factor-alpha-stimulated matrix metalloproteinase-9 expression in human lung adenocarcinoma cells. Shan, B., Zhuo, Y., Chin, D., Morris, C.A., Morris, G.F., Lasky, J.A. J. Biol. Chem. (2005) [Pubmed]
  4. The ability of positive transcription elongation factor B to transactivate human immunodeficiency virus transcription depends on a functional kinase domain, cyclin T1, and Tat. Fujinaga, K., Cujec, T.P., Peng, J., Garriga, J., Price, D.H., Graña, X., Peterlin, B.M. J. Virol. (1998) [Pubmed]
  5. Cyclins that don't cycle--cyclin T/cyclin-dependent kinase-9 determines cardiac muscle cell size. Sano, M., Schneider, M.D. Cell Cycle (2003) [Pubmed]
  6. A novel CDK9-associated C-type cyclin interacts directly with HIV-1 Tat and mediates its high-affinity, loop-specific binding to TAR RNA. Wei, P., Garber, M.E., Fang, S.M., Fischer, W.H., Jones, K.A. Cell (1998) [Pubmed]
  7. Activation and function of cyclin T-Cdk9 (positive transcription elongation factor-b) in cardiac muscle-cell hypertrophy. Sano, M., Abdellatif, M., Oh, H., Xie, M., Bagella, L., Giordano, A., Michael, L.H., DeMayo, F.J., Schneider, M.D. Nat. Med. (2002) [Pubmed]
  8. 7SK small nuclear RNA binds to and inhibits the activity of CDK9/cyclin T complexes. Nguyen, V.T., Kiss, T., Michels, A.A., Bensaude, O. Nature (2001) [Pubmed]
  9. Tat modifies the activity of CDK9 to phosphorylate serine 5 of the RNA polymerase II carboxyl-terminal domain during human immunodeficiency virus type 1 transcription. Zhou, M., Halanski, M.A., Radonovich, M.F., Kashanchi, F., Peng, J., Price, D.H., Brady, J.N. Mol. Cell. Biol. (2000) [Pubmed]
  10. Differential effects on HIV replication and T cell activation following direct inhibition of CDK9 or flavopiridol (FVP) treatment in primary peripheral blood lymphocytes. Salerno, D., Hasham, M., Marshall, R., Garriga, J., Tsygankov, A., Graña, X. Retrovirology (2006) [Pubmed]
  11. Cdk9 regulates neural differentiation and its expression correlates with the differentiation grade of neuroblastoma and PNET tumors. De Falco, G., Bellan, C., D'Amuri, A., Angeloni, G., Leucci, E., Giordano, A., Leoncini, L. Cancer Biol. Ther. (2005) [Pubmed]
  12. CDK9 directs H2B monoubiquitination and controls replication-dependent histone mRNA 3'-end processing. Pirngruber, J., Shchebet, A., Schreiber, L., Shema, E., Minsky, N., Chapman, R.D., Eick, D., Aylon, Y., Oren, M., Johnsen, S.A. EMBO. Rep. (2009) [Pubmed]
  13. CDK9 is constitutively expressed throughout the cell cycle, and its steady-state expression is independent of SKP2. Garriga, J., Bhattacharya, S., Calbó, J., Marshall, R.M., Truongcao, M., Haines, D.S., Graña, X. Mol. Cell. Biol. (2003) [Pubmed]
  14. Cyclin T1 expression is regulated by multiple signaling pathways and mechanisms during activation of human peripheral blood lymphocytes. Marshall, R.M., Salerno, D., Garriga, J., Graña, X. J. Immunol. (2005) [Pubmed]
  15. Cyclin T: three forms for different roles in physiological and pathological functions. De Luca, A., De Falco, M., Baldi, A., Paggi, M.G. J. Cell. Physiol. (2003) [Pubmed]
  16. Regulation of TAK/P-TEFb in CD4+ T lymphocytes and macrophages. Rice, A.P., Herrmann, C.H. Current HIV research. (2003) [Pubmed]
  17. Induction of TAK (cyclin T1/P-TEFb) in purified resting CD4(+) T lymphocytes by combination of cytokines. Ghose, R., Liou, L.Y., Herrmann, C.H., Rice, A.P. J. Virol. (2001) [Pubmed]
  18. Phosphorylation of the RNA polymerase II carboxyl-terminal domain by CDK9 is directly responsible for human immunodeficiency virus type 1 Tat-activated transcriptional elongation. Kim, Y.K., Bourgeois, C.F., Isel, C., Churcher, M.J., Karn, J. Mol. Cell. Biol. (2002) [Pubmed]
  19. Tax Interacts with P-TEFb in a Novel Manner To Stimulate Human T-Lymphotropic Virus Type 1 Transcription. Zhou, M., Lu, H., Park, H., Wilson-Chiru, J., Linton, R., Brady, J.N. J. Virol. (2006) [Pubmed]
  20. CDK9 has the intrinsic property to shuttle between nucleus and cytoplasm, and enhanced expression of cyclin T1 promotes its nuclear localization. Napolitano, G., Licciardo, P., Carbone, R., Majello, B., Lania, L. J. Cell. Physiol. (2002) [Pubmed]
  21. Mechanism of H-8 inhibition of cyclin-dependent kinase 9: study using inhibitor-immobilized matrices. Shima, D., Yugami, M., Tatsuno, M., Wada, T., Yamaguchi, Y., Handa, H. Genes Cells (2003) [Pubmed]
  22. Cdk9, a member of the cdc2-like family of kinases, binds to gp130, the receptor of the IL-6 family of cytokines. Falco, G.D., Neri, L.M., Falco, M.D., Bellan, C., Yu, Z., Luca, A.D., Leoncini, L., Giordano, A. Oncogene (2002) [Pubmed]
  23. Cyclin K functions as a CDK9 regulatory subunit and participates in RNA polymerase II transcription. Fu, T.J., Peng, J., Lee, G., Price, D.H., Flores, O. J. Biol. Chem. (1999) [Pubmed]
  24. Upregulation of cyclin T1/CDK9 complexes during T cell activation. Garriga, J., Peng, J., Parreño, M., Price, D.H., Henderson, E.E., Graña, X. Oncogene (1998) [Pubmed]
  25. Cellular control of gene expression by T-type cyclin/CDK9 complexes. Garriga, J., Graña, X. Gene (2004) [Pubmed]
  26. Androgen receptor interacts with the positive elongation factor P-TEFb and enhances the efficiency of transcriptional elongation. Lee, D.K., Duan, H.O., Chang, C. J. Biol. Chem. (2001) [Pubmed]
  27. Induced G1 cell-cycle arrest controls replication-dependent histone mRNA 3' end processing through p21, NPAT and CDK9. Pirngruber, J., Johnsen, S.A. Oncogene. (2010) [Pubmed]
  28. Spt5 cooperates with human immunodeficiency virus type 1 Tat by preventing premature RNA release at terminator sequences. Bourgeois, C.F., Kim, Y.K., Churcher, M.J., West, M.J., Karn, J. Mol. Cell. Biol. (2002) [Pubmed]
  29. Interaction between cyclin T1 and SCF(SKP2) targets CDK9 for ubiquitination and degradation by the proteasome. Kiernan, R.E., Emiliani, S., Nakayama, K., Castro, A., Labbé, J.C., Lorca, T., Nakayama Ki, K., Benkirane, M. Mol. Cell. Biol. (2001) [Pubmed]
  30. The peptidyl-prolyl isomerase Pin1 interacts with hSpt5 phosphorylated by Cdk9. Lavoie, S.B., Albert, A.L., Handa, H., Vincent, M., Bensaude, O. J. Mol. Biol. (2001) [Pubmed]
  31. CDC2-related kinase PITALRE phosphorylates pRb exclusively on serine and is widely expressed in human tissues. De Luca, A., Esposito, V., Baldi, A., Claudio, P.P., Fu, Y., Caputi, M., Pisano, M.M., Baldi, F., Giordano, A. J. Cell. Physiol. (1997) [Pubmed]
  32. Phosphatase PPM1A regulates phosphorylation of Thr-186 in the Cdk9 T-loop. Wang, Y., Dow, E.C., Liang, Y.Y., Ramakrishnan, R., Liu, H., Sung, T.L., Lin, X., Rice, A.P. J. Biol. Chem. (2008) [Pubmed]
  33. Tat competes with CIITA for the binding to P-TEFb and blocks the expression of MHC class II genes in HIV infection. Kanazawa, S., Okamoto, T., Peterlin, B.M. Immunity (2000) [Pubmed]
  34. AZ703, an imidazo[1,2-a]pyridine inhibitor of cyclin-dependent kinases 1 and 2, induces E2F-1-dependent apoptosis enhanced by depletion of cyclin-dependent kinase 9. Cai, D., Byth, K.F., Shapiro, G.I. Cancer Res. (2006) [Pubmed]
  35. Cdk9 phosphorylates p53 on serine 392 independently of CKII. Claudio, P.P., Cui, J., Ghafouri, M., Mariano, C., White, M.K., Safak, M., Sheffield, J.B., Giordano, A., Khalili, K., Amini, S., Sawaya, B.E. J. Cell. Physiol. (2006) [Pubmed]
  36. HIV-1 Tat interaction with cyclin T1 represses mannose receptor and the bone morphogenetic protein receptor-2 transcription. Caldwell, R.L., Lane, K.B., Shepherd, V.L. Arch. Biochem. Biophys. (2006) [Pubmed]
  37. Binding of the 7SK snRNA turns the HEXIM1 protein into a P-TEFb (CDK9/cyclin T) inhibitor. Michels, A.A., Fraldi, A., Li, Q., Adamson, T.E., Bonnet, F., Nguyen, V.T., Sedore, S.C., Price, J.P., Price, D.H., Lania, L., Bensaude, O. EMBO J. (2004) [Pubmed]
  38. Three RNA polymerase II carboxyl-terminal domain kinases display distinct substrate preferences. Ramanathan, Y., Rajpara, S.M., Reza, S.M., Lees, E., Shuman, S., Mathews, M.B., Pe'ery, T. J. Biol. Chem. (2001) [Pubmed]
  39. Regulation of P-TEFb elongation complex activity by CDK9 acetylation. Fu, J., Yoon, H.G., Qin, J., Wong, J. Mol. Cell. Biol. (2007) [Pubmed]
  40. Direct evidence that HIV-1 Tat stimulates RNA polymerase II carboxyl-terminal domain hyperphosphorylation during transcriptional elongation. Isel, C., Karn, J. J. Mol. Biol. (1999) [Pubmed]
  41. CDK9/CYCLIN T1 expression during normal lymphoid differentiation and malignant transformation. Bellan, C., De Falco, G., Lazzi, S., Micheli, P., Vicidomini, S., Schürfeld, K., Amato, T., Palumbo, A., Bagella, L., Sabattini, E., Bartolommei, S., Hummel, M., Pileri, S., Tosi, P., Leoncini, L., Giordano, A. J. Pathol. (2004) [Pubmed]
  42. Genomic organization and characterization of promoter function of the human CDK9 gene. Liu, H., Rice, A.P. Gene (2000) [Pubmed]
  43. Expression, purification, and circular dichroism analysis of human CDK9. Leopoldino, A.M., Canduri, F., Cabral, H., Junqueira, M., de Marqui, A.B., Apponi, L.H., da Fonseca, I.O., Domont, G.B., Santos, D.S., Valentini, S., Bonilla-Rodriguez, G.O., Fossey, M.A., de Azevedo, W.F., Tajara, E.H. Protein Expr. Purif. (2006) [Pubmed]
  44. Cloning of murine CDK9/PITALRE and its tissue-specific expression in development. Bagella, L., MacLachlan, T.K., Buono, R.J., Pisano, M.M., Giordano, A., De Luca, A. J. Cell. Physiol. (1998) [Pubmed]
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