周强（音译）博士简介
Qiang ZhouAssociate Professor of Biochemistry and Molecular BiologyE-mail: qzhou@berkeley.edu |
 |
Full Directory InformationResearch Interests
-
We are interested in the molecular mechanisms controlling HIV gene expression and the viral-host interactions.
Current Projects
- In the former area, we investigate how Tat, an essential protein encoded by HIV, and its host cellular cofactor P-TEFb regulate HIV gene expression at the stage of transcriptional elongation. Consisting of CDK9 and cyclin T, P-TEFb was originally identified as a general transcription factor required for the expression of most, if not all, protein-coding genes. It has subsequently been found to play a particularly important role in HIV replication. Moreover, recent studies have also implicated a key role for P-TEFb in promoting the onset and progression of cardiac hypertrophy and breast cancer. During HIV replication, RNA polymerase (Pol) II transcribing the HIV proviral DNA has a strong tendency to pause and terminate near the start site, producing only short RNA transcripts. Stimulation of Pol II elongation is essential for HIV transcription, during which P-TEFb is recruited to the nascent mRNA by HIV Tat. Once recruited, P-TEFb phosphorylates Pol II and stimulates transcriptional elongation.
In an attempt to isolate nuclear factors that can bind to and regulate P-TEFb’s activity, we have recently identified a novel nuclear protein called HEXIM1 and an evolutionarily conserved snRNA termed 7SK as specific P-TEFb-associated factors. HEXIM1, 7SK and P-TEFb actually exist in a single snRNP, which sequesters a major portion of P-TEFb in the cell. Within this snRNP, 7SK mediates the HEXIM1:P-TEFb interaction and HEXIM1 suppresses the kinase and transcriptional activities of P-TEFb in a 7SK-dependent fashion. Accumulating evidence has implicated this snRNP as a key signal integration point whereby diverse physiological stimuli may converge and affect general and disease-specific transcription by modulating the amount of P-TEFb sequested in this snRNP and thus the levels of active P-TEFb in the cell. Furthermore, the amount of HEXIM1 in the cell relative to that of P-TEFb appears to influence the critical cellular transition between growth and differentialtion. We are currently performing structure-function analyses of the HEXIM1:7SK:P-TEFb snRNP to study the mechanism by which HEXIM1 and 7SK cooperate to inhibit the CDK9 kinase. We are also investigating the signaling pathways that control the formation and disruption of this snRNP and the involvement of these pathways in cell growth/differentiation, HIV replication and the pathogenesis of other diseases.
In addition to its ability to stimulate HIV transcription, Tat is also known to induce apoptosis of mainly CD4+ T cells, which may contribute in part to the progressive depletion of these cells and the loss of immune competence during AIDS progression. Another ongoing research area in the lab seeks to understand the mechanism of Tat-induced apoptosis. We have recently discovered a specific interaction of Tat with tubulin/microtubules. This interaction alters microtubule dynamics, leading to the activation of a mitochondria-dependent apoptotic pathway. Our studies have revealed a pivotal role for the pro-apoptotic bcl-2 family member Bim in regulating both general and Tat-dependent apoptosis in T cells. Currently, we are further delineating the apoptotic pathway induced by Tat-perturbation of microtubule dynamics and investigating the precise role of Bim in receiving and amplifying signals along this pathway.
Selected Publications
- A human immunodeficiency virus type 1 Tat-like arginine-rich RNA-binding domain is essential for HEXIM1 to inhibit RNA polymerase II transcription through 7SK snRNA-mediated inactivation of P-TEFb. [J. H. N. Yik, R. Chen, A. C. Pezda, C. S. Samford and Q. Zhou (2004) Mol. Cell. Biol. 24, 5094-5105]
Phosphorylated P-TEFb is tagged for inhibition through association with 7SK snRNA. [R. Chen, Z. Yang and Q. Zhou (2004) J. Biol. Chem. 279, 4153-4160]
Caspase-cleavage of BimEL triggers a positive feedback amplification of apoptotic signaling. [D. Chen and Q. Zhou (2004) Proc. Natl. Acad. Sci. USA. 101, 1235-1240]
Inhibition of P-TEFb (CDK9/cyclin T) kinase and RNA polymerase II transcription by the coordinated actions of HEXIM1 and 7SK snRNA. [J. H. N. Yik, R. Chen, R. Nishimura, J. L. Jennings, A. J. Link and Q. Zhou (2003) Mol. Cell 12, 971-982]
HIV-1 Tat targets microtubules to induce apoptosis in a Bim-mediated process. [D. Chen, M. Wang, S. Zhou and Q. Zhou (2002) EMBO J. 21, 6801-6810]The 7SK small nuclear RNA inhibits the Cdk9/cyclin T1 kinase to control transcription. [Z. Yang, Q. Zhu, K. Luo, and Q. Zhou (2001) Nature 414, 317-322]
Stimulatory effect of splicing factors on transcriptional elongation. [Y. Fong and Q. Zhou (2001) Nature 414, 929-933]
Relief of two built-in autoinhibitory mechanisms in P-TEFb is required for the assembly of a multicomponent transcription elongation complex at the HIV-1 promoter. [Y. Fong and Q. Zhou (2000) Mol. Cell. Biol. 20, 5897-5907]
Requirement for a kinase-specific chaperone pathway in the production of a Cdk9/cyclin T1 heterodimer responsible for P-TEFb-mediated Tat stimulation of HIV-1 transcription. [B. O'Keeffe, Y. Fong, D. Chen, S. Zhou, and Q. Zhou (2000) J. Biol. Chem. 275, 279-287]
Specific interaction of Tat with the human but not rodent P-TEFb complex mediates the species-specific Tat activation of HIV-1 transcription. [D. Chen, Y. Fong, and Q. Zhou (1999) Proc. Natl. Acad. Sci. USA 96, 2728-2733]
Tat activates human immunodeficiency virus type 1 transcriptional elongation independent of TFIIH kinase. [D. Chen and Q. Zhou (1999) Mol. Cell. Biol. 19, 2863-2871]
Transcription elongation factor P-TEFb mediates Tat activation of HIV-1 transcription at multiple stages. [Q. Zhou, D. Chen, E. Pierstorff, and K. Luo (1998) EMBO J. 17, 3681-3691]
Last Updated 9/30/2004
- 众说风云 (已有0条评论)
