A la-related protein modulates 7SK snRNP integrity to suppress P-TEFb-dependent transcriptional elongation and tumorigenesis
A la-related protein modulates 7SK snRNP integrity to suppress P-TEFb-dependent transcriptional elongation and tumorigenesis
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DOI：
10.1016/j.molcel.2008.01.003
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发表时间：
2008-03-14
期刊：
影响因子：
16
通讯作者：
Zhou, Qiang
中科院分区：
文献类型：
--
作者：
He, Nanhai;Jahchan, Nadine S.;Zhou, Qiang
通用转录因子P - TEFb刺激RNA聚合酶II的延伸以及前体mRNA的共转录加工。对于生长控制至关重要的一种功能平衡而言，P - TEFb的一个储存库维持在一种无活性的小核核糖核蛋白（snRNP）中，其中7SK小核RNA是一个核心支架。在此，我们将PIP7S鉴定为一种与7SK snRNP完整性稳定相关且为其所需的类La蛋白。PIP7S通过3' - UUU - OH结合并稳定几乎所有的核7SK，导致P - TEFb的隔离和失活。这一功能需要其La结构域和完整的C末端。由于微卫星不稳定性相关的突变，后者在人类肿瘤中经常缺失。与PIP7S的果蝇同源物的肿瘤抑制作用一致，PIP7S功能的丧失使P - TEFb平衡向活性状态偏移，破坏上皮分化，并导致依赖于P - TEFb的恶性转化。通过PIP7S对P - TEFb的调节，我们的数据因此将一种通用延伸因子与生长控制和肿瘤发生联系起来。
The general transcription factor P-TEFb stimulates RNA polymerase 11 elongation and cotranscriptional processing of pre-mRNA. Contributing to a functional equilibrium important for growth control, a reservoir of P-TEFb is maintained in an inactive snRNP where 7SK snRNA is a central scaffold. Here, we identify PIP7S as a La-related protein stably associated with and required for 7SK snRNP integrity. PIP7S binds and stabilizes nearly all the nuclear 7SK via 3'-UUU-OH, leading to the sequestration and inactivation of P-TEFb. This function requires its La domain and intact C terminus. The latter is frequently deleted in human tumors due to microsatellite instability-associated mutations. Consistent with the tumor suppressor role of a Drosophila homolog of PIP7S, loss of PIP7S function shifts the P-TEFb equilibrium toward the active state, disrupts epithelial differentiation, and causes P-TEFb-dependent malignant transformation. Through PIP7S modulation of P-TEFb, our data thus link a general elongation factor to growth control and tumorigenesis.