Induction of the HIV-1 Tat co-factor cyclin T1 during monocyte differentiation is required for the regulated expression of a large portion of cellular mRNAs.
BACKGROUND
P-TEFb, a general RNA polymerase II elongation factor, is composed of CDK9 (cyclin-dependent kinase 9) as a catalytic unit and either cyclin T1, T2 or K as a regulatory subunit. The cyclin T1/P-TEFb complex is targeted by HIV to mediate Tat transactivation. Cyclin T1 protein expression is induced during early macrophage differentiation, suggesting a role in regulation of mRNA expression during the differentiation process. To study the functional significance of cyclin T1 induction during differentiation, we utilized the human Mono Mac 6 (MM6) monocytic cell line.


RESULTS
We found that cyclin T1 protein expression is induced by a post-transcriptional mechanism following PMA treatment of MM6 cells, similar to its induction in primary monocytes and macrophages. Also in agreement with findings in primary cells, cyclin T2a is present at relatively high levels in MM6 cells and is not induced by PMA. Although the knock-down of cyclin T1 in MM6 cells by shRNA inhibited HIV-1 Tat transactivation, MM6 cell growth was not affected by the depletion of cyclin T1. Using DNA microarray technology, we found that more than 20% of genes induced by PMA require cyclin T1 for their normal level of induction, and approximately 15% of genes repressed by PMA require cyclin T1 for their normal level of repression. Gene ontology analysis indicates that many of these cyclin T1-dependent genes are related to immune response and signal transduction.


CONCLUSIONS
These results suggest that cyclin T1 serves a critical role in the program of macrophage differentiation, and this raises questions about the feasibility of cyclin T1 serving as an antiviral therapeutic target.
Yu
Wendong
W
Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas 77030, USA. wy132177@bcm.tmc.edu
Wang
Yan
Y
Shaw
Chad A
CA
Qin
Xiao-Feng
XF
Rice
Andrew P
AP
D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D056906:Cyclin T; D016213:Cyclins / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D015756:Genes, tat; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D012319:RNA Polymerase II / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015533:Transcriptional Activation
C503684:CCNT1 protein, human; D056906:Cyclin T; D016213:Cyclins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D012319:RNA Polymerase II; D013755:Tetradecanoylphorbol Acetate