Institut de Parasitologie et de Pathologie Tropicale, Fédération de Médecine Translationnelle, University of Strasbourg, 67000 Strasbourg, France.
Proc Natl Acad Sci U S A. 2013 Jul 30;110(31):12655-60. doi: 10.1073/pnas.1220136110. Epub 2013 Jul 12.
The positive transcription elongation factor b (P-TEFb) is involved in physiological and pathological events including inflammation, cancer, AIDS, and cardiac hypertrophy. The balance between its active and inactive form is tightly controlled to ensure cellular integrity. We report that the transcriptional repressor CTIP2 is a major modulator of P-TEFb activity. CTIP2 copurifies and interacts with an inactive P-TEFb complex containing the 7SK snRNA and HEXIM1. CTIP2 associates directly with HEXIM1 and, via the loop 2 of the 7SK snRNA, with P-TEFb. In this nucleoprotein complex, CTIP2 significantly represses the Cdk9 kinase activity of P-TEFb. Accordingly, we show that CTIP2 inhibits large sets of P-TEFb- and 7SK snRNA-sensitive genes. In hearts of hypertrophic cardiomyopathic mice, CTIP2 controls P-TEFb-sensitive pathways involved in the establishment of this pathology. Overexpression of the β-myosin heavy chain protein contributes to the pathological cardiac wall thickening. The inactive P-TEFb complex associates with CTIP2 at the MYH7 gene promoter to repress its activity. Taken together, our results strongly suggest that CTIP2 controls P-TEFb function in physiological and pathological conditions.
正转录延伸因子 b（P-TEFb）参与包括炎症、癌症、艾滋病和心肌肥厚在内的生理和病理事件。其活性和非活性形式之间的平衡受到严格控制，以确保细胞完整性。我们报告转录抑制剂 CTIP2 是 P-TEFb 活性的主要调节剂。CTIP2 与包含 7SK snRNA 和 HEXIM1 的非活性 P-TEFb 复合物共纯化并相互作用。CTIP2 直接与 HEXIM1 结合，并通过 7SK snRNA 的环 2 与 P-TEFb 结合。在这个核蛋白复合物中，CTIP2 显著抑制 P-TEFb 的 Cdk9 激酶活性。因此，我们表明 CTIP2 抑制了大量由 P-TEFb 和 7SK snRNA 敏感的基因。在肥厚性心肌病小鼠的心脏中，CTIP2 控制参与建立这种病理学的 P-TEFb 敏感途径。β-肌球蛋白重链蛋白的过表达有助于病理性心肌壁增厚。非活性 P-TEFb 复合物与 CTIP2 在 MYH7 基因启动子处结合，抑制其活性。总之，我们的结果强烈表明 CTIP2 在生理和病理条件下控制 P-TEFb 的功能。
