Mameli, Giuseppe and Deshmane, Satish L. and Ghafouri, Mohammad and Cui, Jianqi and Simbiri, Kenneth and Khalili, Kamel and Mukerjee, Ruma and Dolei, Antonina and Amini, Shohreh and Sawaya, Bassel E. (2007) C/EBPβ regulates human immunodeficiency virus 1 gene expression through its association with cdk9. Journal of General Virology, Vol. 88 (2), p. 631-640. eISSN 1465-2099. Article.
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Transcriptional regulation of the human immunodeficiency virus type 1 (HIV-1) is a complex event that requires the cooperative action of both viral (e.g. Tat) and cellular (e.g. C/EBPβ, NF-κB) factors. The HIV-1 Tat protein recruits the human positive transcription elongation factor P-TEFb, consisting of cdk9 and cyclin T1, to the HIV-1 transactivation response (TAR) region. In the absence of TAR, Tat activates the HIV-1 long terminal repeat (LTR) through its association with several cellular factors including C/EBPβ. C/EBPβ is a member of the CCAAT/enhancer-binding protein family of transcription factors and has been shown to be a critical transcriptional regulator of HIV-1 LTR. We examined whether Tat–C/EBPβ association requires the presence of the P-TEFb complex. Using immunoprecipitation followed by Western blot, we demonstrated that C/EBPβ–cyclin T1 association requires the presence of cdk9. Further, due to its instability, cdk9 was unable to physically interact with C/EBPβ in the absence of cyclin T1 or Tat. Using kinase assays, we demonstrated that cdk9, but not a cdk9 dominant-negative mutant (cdk9-dn), phosphorylates C/EBPβ. Our functional data show that co-transfection of C/EBPβ and cdk9 leads to an increase in HIV-1 gene expression when compared to C/EBPβ alone. Addition of C/EBP homologous protein (CHOP) inhibits C/EBPβ transcriptional activity in the presence and absence of cdk9 and causes a delay in HIV-1 replication in T-cells. Together, our data suggest that Tat–C/EBPβ association is mediated through cdk9, and that phosphorylated C/EBPβ may influence AIDS progression by increasing expression of HIV-1 genes.
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