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Mol Cell. 2008 Mar 14;29(5):588-99. doi: 10.1016/j.molcel.2008.01.003. Epub 2008 Jan 31.

A La-related protein modulates 7SK snRNP integrity to suppress P-TEFb-dependent transcriptional elongation and tumorigenesis.

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  • 1Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.

Abstract

The general transcription factor P-TEFb stimulates RNA polymerase II 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.

PMID:
18249148
[PubMed - indexed for MEDLINE]
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