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PP2B and PP1 cooperatively disrupt 7SK snRNP to release P-TEFb for transcription in response to Ca²⁺ signaling

¹ Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian, China; ² Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, California 94720, USA

The positive transcription elongation factor b (P-TEFb), consisting of Cdk9 and cyclin T, stimulates RNA polymerase II elongation and cotranscriptional pre-mRNA processing. To accommodate different growth conditions and transcriptional demands, a reservoir of P-TEFb is kept in an inactive state in the multisubunit 7SK snRNP. Under certain stress or disease conditions, P-TEFb is released to activate transcription, although the signaling pathway(s) that controls this is largely unknown. Here, through analyzing the UV- or hexamethylene bisacetamide (HMBA)-induced release of P-TEFb from 7SK snRNP, an essential role for the calcium ion (Ca²⁺)–calmodulin–protein phosphatase 2B (PP2B) signaling pathway is revealed. However, Ca²⁺ signaling alone is insufficient, and PP2B must act sequentially and cooperatively with protein phosphatase 1 (PP1) to disrupt 7SK snRNP. Activated by UV/HMBA and facilitated by a PP2B-induced conformational change in 7SK snRNP, PP1 releases P-TEFb through dephosphorylating phospho-Thr186 in the Cdk9 T-loop. This event is also necessary for the subsequent recruitment of P-TEFb by the bromodomain protein Brd4 to the preinitiation complex, where Cdk9 remains unphosphorylated and inactive until after the synthesis of a short RNA. Thus, through cooperatively dephosphorylating Cdk9 in response to Ca²⁺ signaling, PP2B and PP1 alter the P-TEFb functional equilibrium through releasing P-TEFb from 7SK snRNP for transcription.

[Keywords: P-TEFb; CDK activation; transcriptional elongation; Ca²⁺ signal transduction; protein phosphatases]

Received November 21, 2007; revised version accepted March 31, 2008.

⁴ Corresponding authors.

E-MAIL qzhou{at}berkeley.edu; FAX (510) 643-6334.

⁵ E-MAIL chenrc{at}xmu.edu.cn; FAX 86-592-2183984.

Supplemental material is available at http://www.genesdev.org.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1636008.

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