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Gene Review

CCNT1  -  cyclin T1

Homo sapiens

Synonyms: CCNT, CYCT1, CycT1, Cyclin-T, Cyclin-T1, ...
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Disease relevance of CCNT1


High impact information on CCNT1

  • Cyclin T is a partner for CDK9, an RNAPII transcription elongation factor [5].
  • It binds CycT1 via an alanine-containing heptapeptide repeat and inhibits transcriptional elongation [6].
  • Interestingly, we find that the interaction between Tat and hCycT1 requires zinc as well as essential cysteine residues in both proteins [1].
  • Alanine-scanning mutagenesis of the hCycT1 TRM identified residues that are critical for the interaction with Tat and others that are required specifically for binding of the complex to TAR RNA [1].
  • By binding to the same surface in the cyclin T1, which together with CDK9 forms the positive transcription elongation factor b (P-TEFb) complex, Tat inhibits CIITA [7].

Chemical compound and disease context of CCNT1

  • The interaction between HIV-1 Tat and human cyclin T1 requires zinc and a critical cysteine residue that is not conserved in the murine CycT1 protein [1].
  • We identified granulin as a cyclin T1-interacting protein that represses expression from the HIV-1 promoter in transfected cells [8].
  • Our results suggest that Cdk9/Cyclin T1 complex may be required for neuron differentiation induced by retinoic acid, because the expression level of the complex varies during differentiation, but no significant changes were observed in its expression in the astrocytoma cell line [9].
  • Finally, a reciprocal exchange of the valine for the leucine at position 29 in human and equine cyclins T1, respectively, renders the human cyclin T1 active and the equine cyclin T1 inactive for Tat transactivation from EIAV [10].

Biological context of CCNT1


Anatomical context of CCNT1

  • Functional assays in HeLa cells showed that this cyclin T-binding domain (TBD) is required for the binding of Hexim1 to P-TEFb and inhibition of transcriptional activity in vivo [15].
  • Induction of TAK (cyclin T1/P-TEFb) in purified resting CD4(+) T lymphocytes by combination of cytokines [16].
  • These specific expression patterns are only partially justified by some well-known specialized functions of cyclin T1 in certain cell types, such as its involvement in peripheral blood lymphocytes and monocyte differentiation [12].
  • The high expression level found in other tissues suggests new possible roles for cyclin T1 in cell types other than those of lymphoid tissue [12].
  • CycT1 mRNA and protein levels are induced in activated human peripheral blood lymphocytes and CycT1 protein levels are induced by a post-transcriptional mechanism when human U937 promonocytic cells are stimulated to differentiate into macrophage-like cells [17].

Associations of CCNT1 with chemical compounds


Physical interactions of CCNT1

  • 7SK small nuclear RNA binds to and inhibits the activity of CDK9/cyclin T complexes [20].
  • Previously, a histidine-rich stretch in CycT1 was found to bind the CTD of RNAPII and direct the transcriptional activity of this P-TEFb complex when tethered artificially to DNA [21].
  • The addition of recombinant cyclin T1 to the selections yielded a phage display system that mirrors all binding properties of the cyclin T1-Tat-TAR complex known from cell assays and biochemical studies [22].
  • Tat does so by competing with CIITA for binding to cyclin T1, a component of the transcriptional elongation complex PTEFb [23].

Enzymatic interactions of CCNT1

  • Both Cdk9 and cyclin T1 showed only limited colocalization with different phosphorylated forms of RNA polymerase II [24].
  • Here we report that CDK9 is ubiquitinated and degraded by the proteasome whereas cyclin T1 is stable [25].
  • Here we demonstrate that a Medicago CYCLINT (CYCT) protein is a specific interactor of Ms;CDKC;1 and the interaction between these two proteins gives rise to an active kinase complex that localizes to the nucleus and phosphorylates the carboxy-terminal YSPTSPS heptapeptide repeat domain (CTD) of the largest subunit of RNA polymerase II in vitro [26].

Regulatory relationships of CCNT1


Other interactions of CCNT1

  • A homology model of human cyclin T1 generated using the cyclin K structure as a template reveals that the two proteins have similar structures, as expected from their high level of sequence identity [28].
  • The active form of the positive transcription elongation factor b (P-TEFb) consists of cyclin T and the kinase Cdk9 [15].
  • Deletion mutants at the C-terminal region of cyclin T1 are negative for FRET with PML and fail to localize to nuclear bodies [13].
  • Cyclin T1 but not cyclin T2a is induced by a post-transcriptional mechanism in PAMP-activated monocyte-derived macrophages [29].
  • The positive transcriptional elongation factor b (P-TEFb), consisting of CDK9 and cyclin T, stimulates transcription by phosphorylating RNA polymerase II [30].

Analytical, diagnostic and therapeutic context of CCNT1


  1. The interaction between HIV-1 Tat and human cyclin T1 requires zinc and a critical cysteine residue that is not conserved in the murine CycT1 protein. Garber, M.E., Wei, P., KewalRamani, V.N., Mayall, T.P., Herrmann, C.H., Rice, A.P., Littman, D.R., Jones, K.A. Genes Dev. (1998) [Pubmed]
  2. MAQ1 and 7SK RNA interact with CDK9/cyclin T complexes in a transcription-dependent manner. Michels, A.A., Nguyen, V.T., Fraldi, A., Labas, V., Edwards, M., Bonnet, F., Lania, L., Bensaude, O. Mol. Cell. Biol. (2003) [Pubmed]
  3. CD4-specific transgenic expression of human cyclin T1 markedly increases human immunodeficiency virus type 1 (HIV-1) production by CD4+ T lymphocytes and myeloid cells in mice transgenic for a provirus encoding a monocyte-tropic HIV-1 isolate. Sun, J., Soos, T., Kewalramani, V.N., Osiecki, K., Zheng, J.H., Falkin, L., Santambrogio, L., Littman, D.R., Goldstein, H. J. Virol. (2006) [Pubmed]
  4. Transient induction of cyclin T1 during human macrophage differentiation regulates human immunodeficiency virus type 1 Tat transactivation function. Liou, L.Y., Herrmann, C.H., Rice, A.P. J. Virol. (2002) [Pubmed]
  5. 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]
  6. A model of repression: CTD analogs and PIE-1 inhibit transcriptional elongation by P-TEFb. Zhang, F., Barboric, M., Blackwell, T.K., Peterlin, B.M. Genes Dev. (2003) [Pubmed]
  7. 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]
  8. The growth factor granulin interacts with cyclin T1 and modulates P-TEFb-dependent transcription. Hoque, M., Young, T.M., Lee, C.G., Serrero, G., Mathews, M.B., Pe'ery, T. Mol. Cell. Biol. (2003) [Pubmed]
  9. 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]
  10. Interactions between equine cyclin T1, Tat, and TAR are disrupted by a leucine-to-valine substitution found in human cyclin T1. Taube, R., Fujinaga, K., Irwin, D., Wimmer, J., Geyer, M., Peterlin, B.M. J. Virol. (2000) [Pubmed]
  11. Functional inactivation of Cdk9 through oligomerization chain reaction. Napolitano, G., Mazzocco, A., Fraldi, A., Majello, B., Lania, L. Oncogene (2003) [Pubmed]
  12. Pattern of expression of cyclin T1 in human tissues. De Luca, A., Russo, P., Severino, A., Baldi, A., Battista, T., Cavallotti, I., De Luca, L., Baldi, F., Giordano, A., Paggi, M.G. J. Histochem. Cytochem. (2001) [Pubmed]
  13. Recruitment of human cyclin T1 to nuclear bodies through direct interaction with the PML protein. Marcello, A., Ferrari, A., Pellegrini, V., Pegoraro, G., Lusic, M., Beltram, F., Giacca, M. EMBO J. (2003) [Pubmed]
  14. Optimized chimeras between kinase-inactive mutant Cdk9 and truncated cyclin T1 proteins efficiently inhibit Tat transactivation and human immunodeficiency virus gene expression. Fujinaga, K., Irwin, D., Geyer, M., Peterlin, B.M. J. Virol. (2002) [Pubmed]
  15. Identification of a cyclin T-binding domain in Hexim1 and biochemical analysis of its binding competition with HIV-1 Tat. Schulte, A., Czudnochowski, N., Barboric, M., Schönichen, A., Blazek, D., Peterlin, B.M., Geyer, M. J. Biol. Chem. (2005) [Pubmed]
  16. 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]
  17. Isolation and characterization of the human cyclin T1 promoter. Liu, H., Rice, A.P. Gene (2000) [Pubmed]
  18. The breast cell growth inhibitor, estrogen down regulated gene 1, modulates a novel functional interaction between estrogen receptor alpha and transcriptional elongation factor cyclin T1. Wittmann, B.M., Fujinaga, K., Deng, H., Ogba, N., Montano, M.M. Oncogene (2005) [Pubmed]
  19. Regulation of TAK/P-TEFb in CD4+ T lymphocytes and macrophages. Rice, A.P., Herrmann, C.H. Current HIV research. (2003) [Pubmed]
  20. 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]
  21. Transcriptional activity and substrate recognition of cyclin T2 from P-TEFb. Kurosu, T., Zhang, F., Peterlin, B.M. Gene (2004) [Pubmed]
  22. Binding of phage-displayed HIV-1 Tat to TAR RNA in the presence of cyclin T1. Jonas, G., Hoffmann, S., Willbold, D. J. Biomed. Sci. (2001) [Pubmed]
  23. Inhibition of class II trans-activator function by HIV-1 tat in mouse cells is independent of competition for binding to cyclin T1. Mudhasani, R., Fontes, J.D. Mol. Immunol. (2002) [Pubmed]
  24. The Cdk9 and cyclin T subunits of TAK/P-TEFb localize to splicing factor-rich nuclear speckle regions. Herrmann, C.H., Mancini, M.A. J. Cell. Sci. (2001) [Pubmed]
  25. 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]
  26. The Medicago CDKC;1-CYCLINT;1 kinase complex phosphorylates the carboxy-terminal domain of RNA polymerase II and promotes transcription. Fülöp, K., Pettkó-Szandtner, A., Magyar, Z., Miskolczi, P., Kondorosi, E., Dudits, D., Bakó, L. Plant J. (2005) [Pubmed]
  27. Interleukin-10 inhibits HIV-1 LTR-directed gene expression in human macrophages through the induction of cyclin T1 proteolysis. Wang, Y., Rice, A.P. Virology (2006) [Pubmed]
  28. Crystal Structure of Human Cyclin K, a Positive Regulator of Cyclin-dependent Kinase 9. Baek, K., Brown, R.S., Birrane, G., Ladias, J.A. J. Mol. Biol. (2007) [Pubmed]
  29. Cyclin T1 but not cyclin T2a is induced by a post-transcriptional mechanism in PAMP-activated monocyte-derived macrophages. Liou, L.Y., Haaland, R.E., Herrmann, C.H., Rice, A.P. J. Leukoc. Biol. (2006) [Pubmed]
  30. Inhibition of P-TEFb (CDK9/Cyclin T) kinase and RNA polymerase II transcription by the coordinated actions of HEXIM1 and 7SK snRNA. Yik, J.H., Chen, R., Nishimura, R., Jennings, J.L., Link, A.J., Zhou, Q. Mol. Cell (2003) [Pubmed]
  31. Increased association of 7SK snRNA with Tat cofactor P-TEFb following activation of peripheral blood lymphocytes. Haaland, R.E., Herrmann, C.H., Rice, A.P. AIDS (2003) [Pubmed]
  32. Evidence for conformational flexibility in the Tat-TAR recognition motif of cyclin T1. Das, C., Edgcomb, S.P., Peteranderl, R., Chen, L., Frankel, A.D. Virology (2004) [Pubmed]
  33. Induction of the HIV-1 Tat co-factor cyclin T1 during monocyte differentiation is required for the regulated expression of a large portion of cellular mRNAs. Yu, W., Wang, Y., Shaw, C.A., Qin, X.F., Rice, A.P. Retrovirology (2006) [Pubmed]
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