* 143055

CYCLIN T1; CCNT1


Alternative titles; symbols

CYCLIN T; CCNT
CYCLIN C-RELATED PROTEIN
CDK9-ASSOCIATED C-TYPE CYCLIN


HGNC Approved Gene Symbol: CCNT1

Cytogenetic location: 12q13.11-q13.12     Genomic coordinates (GRCh38): 12:48,688,458-48,716,707 (from NCBI)


TEXT

Cloning and Expression

The human immunodeficiency virus (HIV)-1 Tat protein regulates transcription elongation through binding to the viral TAR (cis-acting transactivation response element) RNA stem-loop structure. Wei et al. (1998) isolated an 87-kD cyclin C (CCNC; 123838)-related protein, designated cyclin T, that interacted specifically with the transactivation domain of the HIV-1 Tat protein. The predicted 726-amino acid cyclin T protein contains a cyclin homology region, a putative coiled-coil motif, a histidine-rich motif, and a carboxy-terminal PEST sequence. It is most closely related to the essential S. pombe C-type cyclin Pch1. Northern blot analysis revealed that the major cyclin-T transcript of 8 kb was widely expressed in human tissues. A larger, 9.5-kb transcript was detected in blood, and a shorter mRNA species of 3.0 kb was detected exclusively in testis.


Gene Function

The amount of transcription and virus production of HIV-1 is controlled by trans-acting regulatory genes encoded in the viral genome and by agents known to activate T cells. Cellular factors are involved in mediating the response to both the trans-activating genes and T-cell activators. By the study of hybrid cell clones derived from the fusion of human and Chinese hamster ovary cells, Hart et al. (1989) showed that human chromosome 12 and the HIV Tat gene are necessary for high levels of viral gene expression. Similar findings were reported by Newstein et al. (1990), who found that the much lower level of expression of the HIV-1 Tat protein in rodent cells was reversed in stable rodent-human hybrid cells containing only human chromosome 12.

The HIV-1 Tat protein regulates transcription elongation through binding to the viral TAR (cis-acting transactivation response element) RNA stem-loop structure. Wei et al. (1998) noted that addition of Tat to nuclear extracts induces binding of the CDK9-containing P-TEFb complex, an RNA polymerase II transcription elongation factor, to TAR RNA. Moreover, the nuclear Tat/P-TEFb complexes do not associate with loop-mutant TAR RNA, indicating that interaction of Tat with P-TEFb might alter its RNA-binding specificity. Wei et al. (1998) identified cyclin T as a partner for CDK9. Interaction of Tat with cyclin T strongly enhanced the affinity and specificity of the Tat:TAR RNA interaction and conferred a requirement for sequences in the loop of TAR that were not recognized by Tat alone. Moreover, overexpression of human cyclin T rescued Tat activity in nonpermissive rodent cells. Wei et al. (1998) proposed that Tat directs cyclin T-CDK9 to RNA polymerase II through cooperative binding to TAR RNA.

Peng et al. (1998) demonstrated that CDK9 forms complexes with either cyclin T1 or cyclin T2 (603862) in HeLa cell nuclear extracts. Approximately 80% of CDK9 is complexed with cyclin T1. Each CDK9/cyclin T complex is an active positive transcription elongation factor b (P-TEFb; see also 603251) molecule that can phosphorylate the C-terminal domain of the largest subunit of RNA polymerase II (POLR2A; 180660) and facilitate the transition from abortive elongation into productive elongation.

Yang et al. (2001) identified 7SK snRNA (606515) as a specific P-TEFb-associated factor. 7SK inhibits general and HIV-1 Tat-specific transcriptional activities of P-TEFb in vivo and in vitro by inhibiting the kinase activity of CDK9 and preventing recruitment of P-TEFb to the HIV-1 promoter. 7SK is efficiently dissociated from P-TEFb (the CDK9/cyclin T1 heterodimer) by treatment of cells with ultraviolet irradiation and actinomycin D. As these 2 agents have been shown to enhance significantly HIV-1 transcription and phosphorylation of Pol-II, Yang et al. (2001) concluded that their data provide a mechanistic explanation for this stimulatory effect. Yang et al. (2001) further suggested that the 7SK/P-TEFb interaction may serve as a principal control point for the induction of cellular and HIV-1 viral gene expression during stress-related responses. The study demonstrated the involvement of an snRNA in controlling the activity of CDK/cyclin kinase.

Nguyen et al. (2001) independently showed that in human HeLa cells more than half of the P-TEFb is sequestered in larger complexes that also contain 7SK RNA. P-TEFb and 7SK associate in a specific and reversible manner. In contrast to the smaller P-TEFb complexes, which have a high kinase activity, the large 7SK/P-TEFb complexes show very weak kinase activity. Inhibition of cellular transcription by chemical agents or ultraviolet irradiation triggers complete disruption of the P-TEFb/7SK complex, and enhances CDK9 activity. Nguyen et al. (2001) concluded that transcription-dependent interaction of P-TEFb with 7SK may therefore contribute to an important feedback loop modulating the activity of RNA Pol II.

Fong and Zhou (2001) demonstrated that splicing factors function directly to promote transcriptional elongation. The spliceosomal U small nuclear ribonucleoproteins (snRNPs) interact with human transcription elongation factor TAT-SF1 (300346) and strongly stimulate polymerase elongation when directed to an intron-free HIV-1 template. Fong and Zhou (2001) suggested that this effect is likely to be mediated through the binding of TAT-SF1 to elongation factor P-TEFb. Inclusion of splicing signals in the nascent transcript further stimulates transcription, supporting the notion that the recruitment of U snRNPs near the elongating polymerase is important for transcription. Because the TAT-SF1--U snRNP complex also stimulates splicing in vitro, Fong and Zhou (2001) proposed that it may serve as a dual-function factor to couple transcription and splicing and to facilitate their reciprocal activation.

Jang et al. (2005) found that epitope-tagged mouse Brd4 (608749) interacted with cyclin T1 and CDK9 in P-TEFb complexes contained in HeLa cell nuclear extracts. The bromodomain of Brd4 was required for the interaction. Brd4 overexpression increased P-TEFb-dependent phosphorylation of the C-terminal domain of RNA polymerase II and stimulated transcription from a reporter plasmid driven by an HIV-1 promoter. Conversely, reduced Brd4 expression in mouse fibroblasts by small interfering RNA reduced RNA polymerase II C-terminal domain phosphorylation and transcription. Chromatin immunoprecipitation assays indicated that recruitment of P-TEFb to a promoter was dependent on Brd4 and was enhanced by increased chromatin acetylation.

About half of cellular P-TEFb exists in an inactive complex with 7SK and the HEXIM1 protein (607328). Yang et al. (2005) demonstrated that the remaining half associated with BRD4. In stress-induced HeLa cells, 7SK/HEXIM1-bound P-TEFb was converted into the BRD4-associated form. The association of P-TEFb with BRD4 was necessary to form the transcriptionally active P-TEFb, to recruit P-TEFb to a promoter, and to enable P-TEFb to contact the Mediator complex (see 602984). The P-TEFb recruitment function of BRD4 could be substituted by that of HIV-1 Tat, which recruited P-TEFb directly for activated HIV-1 transcription.


Biochemical Features

Crystal Structure

Tahirov et al. (2010) described the crystal structure of the HIV Tat-P-TEFb complex, which is composed of HIV-1 Tat, human CDK9 (603251), and human cyclin T1 (CCNT1). Tat adopts a structure complementary to the surface of P-TEFb and makes extensive contacts, mainly with the cyclin T1 subunit of P-TEFb, but also with the T-loop of the CDK9 subunit. The structure provides a plausible explanation for the tolerance of Tat to sequence variations at certain sites. Importantly, Tat induces significant conformational changes in P-TEFb.


Mapping

By homology to a mapped EST, Wei et al. (1998) mapped the cyclin T gene to chromosome 12.


REFERENCES

  1. Fong, Y. W., Zhou, Q. Stimulatory effect of splicing factors on transcriptional elongation. Nature 414: 929-933, 2001. [PubMed: 11780068, related citations] [Full Text]

  2. Hart, C. E., Ou, C.-Y., Galphin, J. C., Moore, J., Bacheler, L. T., Wasmuth, J. J., Petteway, S. R., Jr., Schochetman, G. Human chromosome 12 is required for elevated HIV-1 expression in human-hamster hybrid cells. Science 246: 488-491, 1989. [PubMed: 2683071, related citations] [Full Text]

  3. Jang, M. K., Mochizuki, K., Zhou, M., Jeong, H.-S., Brady, J. N., Ozato, K. The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA polymerase II-dependent transcription. Molec. Cell 19: 523-534, 2005. [PubMed: 16109376, related citations] [Full Text]

  4. Newstein, M., Stanbridge, E. J., Casey, G., Shank, P. R. Human chromosome 12 encodes a species-specific factor which increases human immunodeficiency virus type 1 tat-mediated trans activation in rodent cells. J. Virol. 64: 4565-4567, 1990. [PubMed: 2200890, related citations] [Full Text]

  5. Nguyen, V. T., Kiss, T., Michels, A. A., Bensaude, O. 7SK small nuclear RNA binds to and inhibits the activity of CDK9/cyclin T complexes. Nature 414: 322-325, 2001. [PubMed: 11713533, related citations] [Full Text]

  6. Peng, J., Zhu, Y., Milton, J. T., Price, D. H. Identification of multiple cyclin subunits of human P-TEFb. Genes Dev. 12: 755-762, 1998. [PubMed: 9499409, images, related citations] [Full Text]

  7. Tahirov, T. H., Babayeva, N. D., Varzavand, K., Cooper, J. J., Sedore, S. C., Price, D. H. Crystal structure of HIV-1 Tat complexed with human P-TEFb. Nature 465: 747-751, 2010. [PubMed: 20535204, images, related citations] [Full Text]

  8. Wei, P., Garber, M. E., Fang, S.-M., Fischer, W. H., Jones, K. A. A novel CDK9-associated C-type cyclin interacts directly with HIV-1 Tat and mediates its high-affinity, loop-specific binding to TAR RNA. Cell 92: 451-462, 1998. [PubMed: 9491887, related citations] [Full Text]

  9. Yang, Z., Yik, J. H. N., Chen, R., He, N., Jang, M. K., Ozato, K., Zhou, Q. Recruitment of P-TEFb for stimulation of transcriptional elongation by the bromodomain protein Brd4. Molec. Cell 19: 535-545, 2005. [PubMed: 16109377, related citations] [Full Text]

  10. Yang, Z., Zhu, Q., Luo, K., Zhou, Q. The 7SK small nuclear RNA inhibits the CDK9/cyclin T1 kinase to control transcription. Nature 414: 317-322, 2001. [PubMed: 11713532, related citations] [Full Text]


Ada Hamosh - updated : 8/20/2010
Matthew B. Gross - updated : 2/20/2009
Creation Date:
Victor A. McKusick : 11/16/1989
carol : 08/02/2019
carol : 08/05/2016
alopez : 08/30/2010
alopez : 8/30/2010
terry : 8/20/2010
carol : 6/3/2009
mgross : 2/20/2009
mgross : 2/20/2009
mgross : 2/20/2009
dkim : 12/2/1998
carol : 1/14/1993
supermim : 3/16/1992
carol : 3/20/1991
supermim : 3/20/1990
carol : 11/16/1989

* 143055

CYCLIN T1; CCNT1


Alternative titles; symbols

CYCLIN T; CCNT
CYCLIN C-RELATED PROTEIN
CDK9-ASSOCIATED C-TYPE CYCLIN


HGNC Approved Gene Symbol: CCNT1

Cytogenetic location: 12q13.11-q13.12     Genomic coordinates (GRCh38): 12:48,688,458-48,716,707 (from NCBI)


TEXT

Cloning and Expression

The human immunodeficiency virus (HIV)-1 Tat protein regulates transcription elongation through binding to the viral TAR (cis-acting transactivation response element) RNA stem-loop structure. Wei et al. (1998) isolated an 87-kD cyclin C (CCNC; 123838)-related protein, designated cyclin T, that interacted specifically with the transactivation domain of the HIV-1 Tat protein. The predicted 726-amino acid cyclin T protein contains a cyclin homology region, a putative coiled-coil motif, a histidine-rich motif, and a carboxy-terminal PEST sequence. It is most closely related to the essential S. pombe C-type cyclin Pch1. Northern blot analysis revealed that the major cyclin-T transcript of 8 kb was widely expressed in human tissues. A larger, 9.5-kb transcript was detected in blood, and a shorter mRNA species of 3.0 kb was detected exclusively in testis.


Gene Function

The amount of transcription and virus production of HIV-1 is controlled by trans-acting regulatory genes encoded in the viral genome and by agents known to activate T cells. Cellular factors are involved in mediating the response to both the trans-activating genes and T-cell activators. By the study of hybrid cell clones derived from the fusion of human and Chinese hamster ovary cells, Hart et al. (1989) showed that human chromosome 12 and the HIV Tat gene are necessary for high levels of viral gene expression. Similar findings were reported by Newstein et al. (1990), who found that the much lower level of expression of the HIV-1 Tat protein in rodent cells was reversed in stable rodent-human hybrid cells containing only human chromosome 12.

The HIV-1 Tat protein regulates transcription elongation through binding to the viral TAR (cis-acting transactivation response element) RNA stem-loop structure. Wei et al. (1998) noted that addition of Tat to nuclear extracts induces binding of the CDK9-containing P-TEFb complex, an RNA polymerase II transcription elongation factor, to TAR RNA. Moreover, the nuclear Tat/P-TEFb complexes do not associate with loop-mutant TAR RNA, indicating that interaction of Tat with P-TEFb might alter its RNA-binding specificity. Wei et al. (1998) identified cyclin T as a partner for CDK9. Interaction of Tat with cyclin T strongly enhanced the affinity and specificity of the Tat:TAR RNA interaction and conferred a requirement for sequences in the loop of TAR that were not recognized by Tat alone. Moreover, overexpression of human cyclin T rescued Tat activity in nonpermissive rodent cells. Wei et al. (1998) proposed that Tat directs cyclin T-CDK9 to RNA polymerase II through cooperative binding to TAR RNA.

Peng et al. (1998) demonstrated that CDK9 forms complexes with either cyclin T1 or cyclin T2 (603862) in HeLa cell nuclear extracts. Approximately 80% of CDK9 is complexed with cyclin T1. Each CDK9/cyclin T complex is an active positive transcription elongation factor b (P-TEFb; see also 603251) molecule that can phosphorylate the C-terminal domain of the largest subunit of RNA polymerase II (POLR2A; 180660) and facilitate the transition from abortive elongation into productive elongation.

Yang et al. (2001) identified 7SK snRNA (606515) as a specific P-TEFb-associated factor. 7SK inhibits general and HIV-1 Tat-specific transcriptional activities of P-TEFb in vivo and in vitro by inhibiting the kinase activity of CDK9 and preventing recruitment of P-TEFb to the HIV-1 promoter. 7SK is efficiently dissociated from P-TEFb (the CDK9/cyclin T1 heterodimer) by treatment of cells with ultraviolet irradiation and actinomycin D. As these 2 agents have been shown to enhance significantly HIV-1 transcription and phosphorylation of Pol-II, Yang et al. (2001) concluded that their data provide a mechanistic explanation for this stimulatory effect. Yang et al. (2001) further suggested that the 7SK/P-TEFb interaction may serve as a principal control point for the induction of cellular and HIV-1 viral gene expression during stress-related responses. The study demonstrated the involvement of an snRNA in controlling the activity of CDK/cyclin kinase.

Nguyen et al. (2001) independently showed that in human HeLa cells more than half of the P-TEFb is sequestered in larger complexes that also contain 7SK RNA. P-TEFb and 7SK associate in a specific and reversible manner. In contrast to the smaller P-TEFb complexes, which have a high kinase activity, the large 7SK/P-TEFb complexes show very weak kinase activity. Inhibition of cellular transcription by chemical agents or ultraviolet irradiation triggers complete disruption of the P-TEFb/7SK complex, and enhances CDK9 activity. Nguyen et al. (2001) concluded that transcription-dependent interaction of P-TEFb with 7SK may therefore contribute to an important feedback loop modulating the activity of RNA Pol II.

Fong and Zhou (2001) demonstrated that splicing factors function directly to promote transcriptional elongation. The spliceosomal U small nuclear ribonucleoproteins (snRNPs) interact with human transcription elongation factor TAT-SF1 (300346) and strongly stimulate polymerase elongation when directed to an intron-free HIV-1 template. Fong and Zhou (2001) suggested that this effect is likely to be mediated through the binding of TAT-SF1 to elongation factor P-TEFb. Inclusion of splicing signals in the nascent transcript further stimulates transcription, supporting the notion that the recruitment of U snRNPs near the elongating polymerase is important for transcription. Because the TAT-SF1--U snRNP complex also stimulates splicing in vitro, Fong and Zhou (2001) proposed that it may serve as a dual-function factor to couple transcription and splicing and to facilitate their reciprocal activation.

Jang et al. (2005) found that epitope-tagged mouse Brd4 (608749) interacted with cyclin T1 and CDK9 in P-TEFb complexes contained in HeLa cell nuclear extracts. The bromodomain of Brd4 was required for the interaction. Brd4 overexpression increased P-TEFb-dependent phosphorylation of the C-terminal domain of RNA polymerase II and stimulated transcription from a reporter plasmid driven by an HIV-1 promoter. Conversely, reduced Brd4 expression in mouse fibroblasts by small interfering RNA reduced RNA polymerase II C-terminal domain phosphorylation and transcription. Chromatin immunoprecipitation assays indicated that recruitment of P-TEFb to a promoter was dependent on Brd4 and was enhanced by increased chromatin acetylation.

About half of cellular P-TEFb exists in an inactive complex with 7SK and the HEXIM1 protein (607328). Yang et al. (2005) demonstrated that the remaining half associated with BRD4. In stress-induced HeLa cells, 7SK/HEXIM1-bound P-TEFb was converted into the BRD4-associated form. The association of P-TEFb with BRD4 was necessary to form the transcriptionally active P-TEFb, to recruit P-TEFb to a promoter, and to enable P-TEFb to contact the Mediator complex (see 602984). The P-TEFb recruitment function of BRD4 could be substituted by that of HIV-1 Tat, which recruited P-TEFb directly for activated HIV-1 transcription.


Biochemical Features

Crystal Structure

Tahirov et al. (2010) described the crystal structure of the HIV Tat-P-TEFb complex, which is composed of HIV-1 Tat, human CDK9 (603251), and human cyclin T1 (CCNT1). Tat adopts a structure complementary to the surface of P-TEFb and makes extensive contacts, mainly with the cyclin T1 subunit of P-TEFb, but also with the T-loop of the CDK9 subunit. The structure provides a plausible explanation for the tolerance of Tat to sequence variations at certain sites. Importantly, Tat induces significant conformational changes in P-TEFb.


Mapping

By homology to a mapped EST, Wei et al. (1998) mapped the cyclin T gene to chromosome 12.


REFERENCES

  1. Fong, Y. W., Zhou, Q. Stimulatory effect of splicing factors on transcriptional elongation. Nature 414: 929-933, 2001. [PubMed: 11780068] [Full Text: https://doi.org/10.1038/414929a]

  2. Hart, C. E., Ou, C.-Y., Galphin, J. C., Moore, J., Bacheler, L. T., Wasmuth, J. J., Petteway, S. R., Jr., Schochetman, G. Human chromosome 12 is required for elevated HIV-1 expression in human-hamster hybrid cells. Science 246: 488-491, 1989. [PubMed: 2683071] [Full Text: https://doi.org/10.1126/science.2683071]

  3. Jang, M. K., Mochizuki, K., Zhou, M., Jeong, H.-S., Brady, J. N., Ozato, K. The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA polymerase II-dependent transcription. Molec. Cell 19: 523-534, 2005. [PubMed: 16109376] [Full Text: https://doi.org/10.1016/j.molcel.2005.06.027]

  4. Newstein, M., Stanbridge, E. J., Casey, G., Shank, P. R. Human chromosome 12 encodes a species-specific factor which increases human immunodeficiency virus type 1 tat-mediated trans activation in rodent cells. J. Virol. 64: 4565-4567, 1990. [PubMed: 2200890] [Full Text: https://doi.org/10.1128/JVI.64.9.4565-4567.1990]

  5. Nguyen, V. T., Kiss, T., Michels, A. A., Bensaude, O. 7SK small nuclear RNA binds to and inhibits the activity of CDK9/cyclin T complexes. Nature 414: 322-325, 2001. [PubMed: 11713533] [Full Text: https://doi.org/10.1038/35104581]

  6. Peng, J., Zhu, Y., Milton, J. T., Price, D. H. Identification of multiple cyclin subunits of human P-TEFb. Genes Dev. 12: 755-762, 1998. [PubMed: 9499409] [Full Text: https://doi.org/10.1101/gad.12.5.755]

  7. Tahirov, T. H., Babayeva, N. D., Varzavand, K., Cooper, J. J., Sedore, S. C., Price, D. H. Crystal structure of HIV-1 Tat complexed with human P-TEFb. Nature 465: 747-751, 2010. [PubMed: 20535204] [Full Text: https://doi.org/10.1038/nature09131]

  8. Wei, P., Garber, M. E., Fang, S.-M., Fischer, W. H., Jones, K. A. A novel CDK9-associated C-type cyclin interacts directly with HIV-1 Tat and mediates its high-affinity, loop-specific binding to TAR RNA. Cell 92: 451-462, 1998. [PubMed: 9491887] [Full Text: https://doi.org/10.1016/s0092-8674(00)80939-3]

  9. Yang, Z., Yik, J. H. N., Chen, R., He, N., Jang, M. K., Ozato, K., Zhou, Q. Recruitment of P-TEFb for stimulation of transcriptional elongation by the bromodomain protein Brd4. Molec. Cell 19: 535-545, 2005. [PubMed: 16109377] [Full Text: https://doi.org/10.1016/j.molcel.2005.06.029]

  10. Yang, Z., Zhu, Q., Luo, K., Zhou, Q. The 7SK small nuclear RNA inhibits the CDK9/cyclin T1 kinase to control transcription. Nature 414: 317-322, 2001. [PubMed: 11713532] [Full Text: https://doi.org/10.1038/35104575]


Contributors:
Ada Hamosh - updated : 8/20/2010
Matthew B. Gross - updated : 2/20/2009

Creation Date:
Victor A. McKusick : 11/16/1989

Edit History:
carol : 08/02/2019
carol : 08/05/2016
alopez : 08/30/2010
alopez : 8/30/2010
terry : 8/20/2010
carol : 6/3/2009
mgross : 2/20/2009
mgross : 2/20/2009
mgross : 2/20/2009
dkim : 12/2/1998
carol : 1/14/1993
supermim : 3/16/1992
carol : 3/20/1991
supermim : 3/20/1990
carol : 11/16/1989