Speckle Cdk12信号调控P-TEFb应激活化的功能机制

正性转录延伸因子P-TEFb由Cdk9激酶及其调节亚基CyclinT1组成，是调控应激性基因转录延伸的核心因子。P-TEFb活性调控过程包括应激释放、应激活化和应激募集等环节，我们的报道已基本阐明P-TEFb应激释放和应激募集的信号和分子调控机制，但对P-TEFb的应激活化调控机制仍不了解。我们的前期结果提示：“募集因子Brd4及AFF诱导P-TEFb应激活化”，以及“Cdk12信号调控P-TEFb应激活化”，可能是细胞内P-TEFb应激活化的两个核心模式。本项目拟通过阐明募集因子诱导P-TEFb应激活化的分子机制，探讨Cdk12调控Speckle核心组分SRSF蛋白磷酸化的机制、及其对募集因子诱导P-TEFb应激活化的调控作用和机制，从而解决P-TEFb应激活化的信号和分子调控机制，为完善P-TEFb活性调控模式提供依据。

Positive transcription elongation factor P-TEFb is a kinase composed of Cdk9 and its partner CyclinT1, and plays a central role in regulating the transition elongation of signal inducible genes. Its activity regulation consists of three steps: stress-induced release, activation and recruitment. Our previous reports have revealed the mechanisms of stress-induced P-TEFb release and recruitment. However, how the stress-induced P-TEFb activation is regulated still remains unclear. Our previous data suggest that the recruitment factors Brd4 and AFF might play a role in stress-induced P-TEFb activation, and this activation might be regulated by Speckle Cdk12 signaling. Therefore, we will study the molecular mechanism of recruitment factor-induced P-TEFb activation, and the role of Cdk12 signaling-controlled Speckle SRSF phosphorylation in stress-induced P-TEFb activation. We expect to reveal how and where the stress-induced P-TEFb activation is regulated inside the nuclear, thereby providing intact picture of P-TEFb activity regulation.