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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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3' Untranslated Regions
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Animals
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Autoantigens / genetics
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Autoantigens / metabolism*
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Cell Differentiation / physiology
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Cell Line
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Cell Transformation, Neoplastic
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HIV-1 / genetics
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HIV-1 / metabolism
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Humans
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Mammary Glands, Human / cytology
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Mammary Glands, Human / metabolism
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Neoplasms* / genetics
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Neoplasms* / metabolism
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Positive Transcriptional Elongation Factor B / genetics
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Positive Transcriptional Elongation Factor B / metabolism*
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Protein Binding
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RNA Interference
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RNA-Binding Proteins / genetics
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RNA-Binding Proteins / metabolism
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Ribonucleoproteins / genetics
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Ribonucleoproteins / metabolism*
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Ribonucleoproteins, Small Nuclear / genetics
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Ribonucleoproteins, Small Nuclear / metabolism*
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SS-B Antigen
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Transcription Factors
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Transcription, Genetic*
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Uridine / chemistry
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Uridine / metabolism
Substances
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3' Untranslated Regions
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Autoantigens
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HEXIM1 protein, human
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RNA-Binding Proteins
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Ribonucleoproteins
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Ribonucleoproteins, Small Nuclear
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Transcription Factors
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Positive Transcriptional Elongation Factor B
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Uridine