Home Faculty and Research Faculty by Name Qiang Zhou

Qiang Zhou

Professor of Biochemistry and Molecular Biology

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Research Interests

We are studying the mechanisms and factors that control transcriptional elongation and how this control may affect HIV replication, cardiac hypertrophy, and the cellular decision between growth and differentiation.

Current Projects

The elongation stage of eukaryotic transcription is a highly dynamic and regulated process that couples transcription with other major gene expression events. The studies of elongation have benefited greatly from the analyses of the HIV-1 Tat protein and its host cellular cofactor P-TEFb. Consisting of Cdk9 and cyclin T, P-TEFb was first identified as a general transcription factor required for the expression of a vast array of protein-coding genes. It was subsequently found to play a key role in HIV replication. RNA polymerase (Pol) II transcribing the integrated HIV proviral genome has a strong tendency to pause and terminate near the start site, producing short RNA transcripts. Stimulation of Pol II elongation is essential for HIV transcription, during which P-TEFb is recruited to the nascent mRNA by Tat. Once recruited, P-TEFb phosphorylates Pol II and stimulates elongation. Besides HIV replication, recent studies have also implicated a key role for P-TEFb in promoting the onset and progression of cardiac hypertrophy and probably also breast cancer.

We have recently identified both positive and negative regulators that can alternately interact with P-TEFb to control its activity and affect transcription. Under normal growth conditions in HeLa cells, about half of nuclear P-TEFb are sequestered in an inactive complex that also contains the 7SK snRNA and the HEXIM1 protein. Within this complex, 7SK stabilizes the HEXIM1-P-TEFb interaction and HEXIM1 suppresses the kinase activity of P-TEFb in a 7SK-dependent fashion. Recently, we have found that the other half of nuclear P-TEFb exist in a separate complex with the bromodomain protein Brd4. The interaction with Brd4 is essential to form the transcriptionally active P-TEFb, recruits P-TEFb to a promoter, and enables P-TEFb to contact acetylated chromatin and the Mediator complex, both of which may serve as targets for Brd4’s recruitment of P-TEFb to transcriptional templates. Although generally required for transcription, the P-TEFb-recruitment function of Brd4 can be substituted by that of HIV Tat, which directly recruits P-TEFb for activated HIV transcription.

It is important to point out that the amount of P-TEFb sequestered in the inactive 7SK snRNP does not remain static in the cell. Rather, various conditions such as stress treatment and hypertrophic signals in heart cells can trigger a quantitative conversion of P-TEFb from the 7SK snRNP into the Brd4-bound form for activation of transcription. In contrast, the induction of terminal division and differentiation of murine erythroleukemia cells with hexamethylene bisacetamide (HMBA) is accompanied by a greatly enhanced formation of the 7SK snRNP, which may be key to the establishment/maintenance of the differentiated state.

Brd4 and HEXIM1 have both been implicated in regulating cell growth although they act in opposite ways. It is likely that their abilities to maintain the general transcription factor P-TEFb in a functional equilibrium is central to the global control of cell growth and differentiation. This equilibrium may serve as a key signal integration point whereby diverse stimuli converge and affect general and disease-specific transcription by modulating the amount of active P-TEFb in the cell. We are currently performing structure-function analyses of the two P-TEFb-containing complexes to study the mechanisms by which P-TEFb activity can be positively or negatively modulated. We are also investigating the signaling pathways that control the formation and disruption of the P-TEFb complexes and the involvement of these pathways in cell growth/differentiation, HIV replication and other diseases.

Selected Publications

Modulation of a P-TEFb functional equilibrium for the global control of cell growth and differentiation. [N. He, A. C. Pezda and Q. Zhou (2006) Mol. Cell. Biol., in press]

Regulation of two key nuclear enzymatic activities by the 7SK small nuclear RNA. [W-J. He, R. Chen, Z. Yang and Q. Zhou (2006) Cold Spring Harbor Symposia on Quantitative Biology: Regulatory RNAs, Vol. 71. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, in press]

The Yin and Yang of P-TEFb regulation: Implications for HIV gene expression and the global control of cell growth and differentiation. [J. H. N. Yik and Q. Zhou (2006) Microbiol. Mol Biol. Rev., in press]

Recruitment of P-TEFb for stimulation of transcriptional elongation by bromodomain protein Brd4. [Z. Yang, J. H. N. Yik, R. Chen, M. K. Jang, K. Ozato and Q. Zhou (2005) Mol. Cell 19, 535-545]

Compensatory contributions of HEXIM1 and HEXIM2 in maintaining the balance of active and inactive positive transcription elongation factor b complexes for control of transcription.[J. H. N. Yik, R. Chen, A. C. Pezda and Q. Zhou (2005) J. Biol. Chem. 280, 16368-16376]

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]

Last Updated 2006-08-03