TAILIEUCHUNG - Báo cáo khoa học: Cyclin T1 stabilizes expression levels of HIV-1 Tat in cells

Transcription from HIV-1 proviral DNA is a rate-determining step for HIV-1 replication. Interaction between the cyclin T1 (CycT1) subunit of positive transcription elongation factor b (P-TEFb) and the Tat transacti-vator protein of HIV-1 is crucial for viral transcription. | ễFEBS Journal Cyclin T1 stabilizes expression levels of HIV-1 Tat in cells Kenichi Imai1 Kaori Asamitsu1 Ann Florence B. Victoriano1 Marni E. Cueno1 Koh Fujinaga2 and Takashi Okamoto1 1 Department of Molecular and Cellular Biology Nagoya City University Graduate Schoolof MedicalSciences Nagoya Japan 2 Department of BiologicalChemistry University of Michigan Medical School Ann Arbor MI USA Keywords cyclin T1 HIV protein stability Tat transcription Correspondence T. Okamoto Department of Molecular and Cellular Biology Nagoya City University Graduate Schoolof MedicalSciences 1 Kawasumi Mizuho-cho Mizuho-ku Nagoya Aichi 467-8601 Japan Fax 81 52 859 1235 Tel 81 52 853 8204 E-mail tokamoto@ Received 2 July 2009 revised 16 September 2009 accepted 5 October 2009 doi Transcription from HIV-1 proviral DNA is a rate-determining step for HIV-1 replication. Interaction between the cyclin T1 CycT1 subunit of positive transcription elongation factor b P-TEFb and the Tat transactivator protein of HIV-1 is crucial for viral transcription. CycT1 also interacts directly with the transactivation-responsive element TAR located on the 5 end of viral mRNA as well as with Tat through the Tat-TAR recognition motif TRM . These molecular interactions represent a critical step for stimulation of HIV transcription. Thus Tat and CycT1 are considered to be feasible targets for the development of novel anti-HIV therapies. In this study we demonstrate that CycT1 is positively involved in the Tat protein stability. Selective degradation of CycT1 by small interfering RNA siRNA culminated in proteasome-mediated degradation of Tat and eventual inhibition of HIV-1 gene expression. We noted that the siRNA-mediated knockdown of CycT1 could inhibit HIV-1 transcription without affecting cell viability and Tat mRNA levels. These findings clearly indicate that CycT1 is a feasible therapeutic target and inactivation or depletion of CycT1 should effectively .

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