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, Ping; Garber, Mitchell E.; Fang, Shimin; Fischer, Wolfgang; Jones, Katherine A.

doi:10.1016/s0092-8674(00)80939-3

Cited by 1,162 publications

(1,237 citation statements)

References 48 publications

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“…Cloning of the subunits of PTEFb has revealed that it is a cyclin/CDK pair (Peng et al, 1998a;Wei et al, 1998;Zhu et al, 1997). The small subunit of Drosophila P-TEFb was cloned using sequence information obtained from the puri®ed protein and was found to be the homolog of the human CDC2-related kinase PI-TALRE (GranÄ a et al, 1994a).…”

Section: Introductionmentioning

confidence: 99%

Upregulation of cyclin T1/CDK9 complexes during T cell activation

et al. 1998

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Cyclin T1 has been identi®ed recently as a regulatory subunit of CDK9 and as a component of the transcription elongation factor P-TEFb. Cyclin T1/CDK9 complexes phosphorylate the carboxy terminal domain (CTD) of RNA polymerase II (RNAP II) in vitro. Here we report that the levels of cyclin T1 are dramatically upregulated by two independent signaling pathways triggered respectively by PMA and PHA in primary human peripheral blood lymphocytes (PBLs). Activation of these two pathways in tandem is su cient for PBLs to enter and progress through the cell cycle. However, the expression of cyclin T1 is not growth and/or cell cycle regulated in other cell types, indicating that regulation of cyclin T1 expression is dependent on tissue-speci®c signaling pathways. Upregulation of cyclin T1 in stimulated PBLs results in induction of the CTD kinase activity of the cyclin T1/CDK9 complex, which in turn correlates directly with phosphorylation of RNAP II in vivo, linking for the ®rst time activation of the cyclin T1/ CDK9 pair with phosphorylation of RNAP II in vivo. In addition, we report here that endogenous CDK9 and cyclin T1 complexes associate with HIV-1 generated Tat in relevant cells and under physiological conditions (HIV-1 infected T cells). This, together with our results showing that HIV-1 replication in stimulated PBLs correlates with the levels of cyclin T1 protein and associated CTD kinase activity, suggests that the cyclin T1/CDK9 pair is one of the HIV-1 required host cellular cofactors generated during T cell activation.

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Section: Introductionmentioning

confidence: 99%

Upregulation of cyclin T1/CDK9 complexes during T cell activation

et al. 1998

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“…It di ers from other cdks because its expression is not cell cycle regulated and does not appear to be required during the cell cycle. In living cells, CDK9 is found associated with cyclins of the T class (T1, T2a and T2b) (Peng et al, 1998;Wei et al, 1998). CDK9 and cyclin T belong to the TAK complex, which is part of the basal transcription machinery (Yang et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

“…The TAK complex phosphorylates the Carboxyl Terminal Domain (CTD) of the RNA Polymerase II (RNA Pol II) converting the unphosphorylated, inactive pre-initiation complex into a phosphorylated and active form of the elongating complex (Dahmus, 1996). It was shown recently that CDK9 is actually the kinase of the complex responsible for RNA pol II activation (Wei et al, 1998). In addition, CDK9/Cyclin T binds the Tat proteins of the HIV virus, suggesting a possible role for this kinase in viral replication (Romano et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Physical interaction between CDK9 and B-Myb results in suppression of B-Myb gene autoregulation

et al. 2000

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B-Myb is a transcription factor belonging to the myb family, whose activity has been associated with augmented DNA synthesis and cell cycle progression. We showed recently that B-Myb autoregulates its own expression through promoter transactivation. We report in this study that CDK9, the cyclin T associated kinase, which phosphorylates and activates RNA-Polymerase II, suppresses B-Myb autoregulation through direct interaction with the carboxyl-terminus of the B-Myb protein. Downregulation of the transactivating ability of B-Myb is independent of the kinase activity of CDK9, because a kinase de®cient mutant (dn-CDK9) also represses B-myb gene autoregulation. Overexpression of CDK9 did not result in suppression of p53-dependent transactivation or inhibition of the basal activity of the promoters tested so far, demonstrating that CDK9 is a B-Myb-speci®c repressor. Rather, transfection of the dominant negative dn-CDK9 construct inhibited the basal activity of the reporter genes, con®rming an essential role for CDK9 in gene transcription. In addition, Cyclin T1 restores B-Myb transactivating activity when co-transfected along with CDK9, suggesting that the down-regulatory e ect observed on B-Myb is speci®cally due to CDK9 alone. Thus, our data suggest that CDK9 is involved in the negative regulation of activated transcription mediated by certain transcription factors, such as B-Myb. This may indicate the existence of a feedback loop, mediated by the di erent activities of CDK9, which links basal with activated transcription.

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“…Peng et al (1998b) and Wei et al (1998) showed that human P-TEFb contains multiple cyclin subunits: cyclin T1 and T2. Cyclin T contains an amino terminal box motif that is highly conserved from Drosophila to human.…”

Section: Cyclin T Cloning and Expressionmentioning

confidence: 99%

“…Removal of the CTD in early elongation complexes abolished P-TEFb function, suggesting that the CTD is the target for P-TEFb function (Marshall et al, 1996). P-TEFb is composed of at least two subunits: the catalytic subunit CDK9 and the regulatory subunit cyclin T (Yang et al, 1997;Zhu et al, 1997;Wei et al, 1998). Complexes containing CDK9 and cyclin T1-related proteins, cyclin T2a or cyclin T2b, are also active for P-TEFb activity (Peng et al, 1998b).…”

Section: Cyclin T and Its Physiological Functionmentioning

confidence: 99%

Cyclin T: Three forms for different roles in physiological and pathological functions

Luca¹,

Falco

Baldi³

et al. 2002

Journal Cellular Physiology

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Cyclins are members of family of proteins involved in the cell cycle regulation. They are regulatory subunits of complexes with proteins called cyclin-dependent kinases (CDKs). There are three forms of cyclin T: cyclin T1, cyclin T2a, and T2b. All cyclin T contain an N-terminal ''cyclin homology box,'' the most conserved region among different members of the cyclin family that serves to bind CDK9. In addition to the N-terminal cyclin domain, cyclin T contains a putative coiled-coil motif, a His-rich motif, and a C-terminal PEST sequence. The CDK9/cyclin T complex is able to activate gene expression in a catalytic-dependent manner, phosphorylating the carboxy-terminal domain (CTD) of RNA polymerase II. In addition, only cyclin T1 supports interactions between Tat and TAR. The interaction of Tat with cyclin T1 alters the conformation of Tat to enhance the affinity and specificity of the Tat:TAR interaction. On the other hand, CDK9/cyclin T2 complexes are involved in the regulation of terminal differentiation in muscle cells.

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A Novel CDK9-Associated C-Type Cyclin Interacts Directly with HIV-1 Tat and Mediates Its High-Affinity, Loop-Specific Binding to TAR RNA

Cited by 1,162 publications

References 48 publications

Upregulation of cyclin T1/CDK9 complexes during T cell activation

Upregulation of cyclin T1/CDK9 complexes during T cell activation

Physical interaction between CDK9 and B-Myb results in suppression of B-Myb gene autoregulation

Cyclin T: Three forms for different roles in physiological and pathological functions

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