Journal
NUCLEIC ACIDS RESEARCH
Volume 40, Issue 18, Pages 9160-9170Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gks682
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Funding
- Academy of Finland [137077, 140996]
- Sigrid Juselius Foundation [4702687]
- AmFAR [108241-51-RGRL]
- National Basic Research Program of China/973 Program [2011CB504200, 2012CB910700]
- National Natural Science Foundation of China [30970625, 31171260]
- Program for New Century Excellent Talents in University of Ministry of Education of China [NCET-10-0565]
- National Institutes of Health (NIH) [P50 GM082250, R01 AI049104]
- Academy of Finland (AKA) [140996, 140996] Funding Source: Academy of Finland (AKA)
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The positive transcription elongation factor b (P-TEFb) regulates RNA polymerase II elongation. In cells, P-TEFb partitions between small active and larger inactive states. In the latter, HEXIM1 binds to 7SK snRNA and recruits as well as inactivates P-TEFb in the 7SK snRNP. Several stimuli can affect this P-TEFb equilibrium. In this study, we demonstrate that protein kinase C (PKC) phosphorylates the serine at position158 (S158) in HEXIM1. This phosphorylated HEXIM1 protein neither binds to 7SK snRNA nor inhibits P-TEFb. Phorbol esters or the engagement of the T cell antigen receptor, which activate PKC and the expression of the constitutively active (CA) PKC theta protein, which is found in T cells, inhibit the formation of the 7SK snRNP. All these stimuli increase P-TEFb-dependent transcription. In contrast, the kinase-negative PKC theta and the mutant HEXIM1 (S158A) proteins block effects of these PKC-activating stimuli. These results indicate that the phosphorylation of HEXIM1 by PKC represents a major regulatory step of P-TEFb activity in cells.
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