Abstract
The positive transcription elongation factor b (P-TEFb), composed of CDK9 and cyclin T, stimulates transcriptional elongation by RNA polymerase (Pol) II and regulates cell growth and differentiation. Recently, we demonstrated that P-TEFb also controls the expression of EMT regulators to promote breast cancer progression. In the nucleus, more than half of P-TEFb are sequestered in the inactive-state 7SK snRNP complex. Here, we show that the assembly of the 7SK snRNP is preceded by an intermediate complex between HEXIM1 and P-TEFb that allows transfer of the kinase active P-TEFb from Hsp90 to 7SK snRNP for its suppression. Down-regulation of HEXIM1 locks P-TEFb in the Hsp90 complex, keeping it in the active state to enhance breast cancer progression, but also rendering the cells highly sensitive to Hsp90 inhibition. Because HEXIM1 is often down-regulated in human triple-negative breast cancer (TNBC), these cells are particularly sensitive to Hsp90 inhibition. Our study provides a mechanistic explanation for the increased sensitivity of TNBC to Hsp90 inhibition.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Animals
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Cell Line, Tumor
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Cell Nucleus / metabolism
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Cyclin-Dependent Kinase 9 / genetics
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Female
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HSP90 Heat-Shock Proteins / genetics
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HSP90 Heat-Shock Proteins / metabolism
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Humans
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Mice
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Mice, Nude
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Nucleic Acid Conformation
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Positive Transcriptional Elongation Factor B / metabolism*
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Positive Transcriptional Elongation Factor B / physiology
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Protein Binding
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RNA Polymerase II / metabolism
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RNA, Long Noncoding / genetics
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RNA, Long Noncoding / metabolism*
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RNA-Binding Proteins / metabolism*
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RNA-Binding Proteins / physiology
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Ribonucleoproteins, Small Nuclear / genetics
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Ribonucleoproteins, Small Nuclear / metabolism
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Transcription Factors / metabolism*
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Transcription Factors / physiology
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Triple Negative Breast Neoplasms / metabolism
Substances
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HEXIM1 protein, human
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HSP90 Heat-Shock Proteins
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RNA, Long Noncoding
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RNA-Binding Proteins
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Ribonucleoproteins, Small Nuclear
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Transcription Factors
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long non-coding RNA 7SK, human
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Positive Transcriptional Elongation Factor B
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CDK9 protein, human
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Cyclin-Dependent Kinase 9
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RNA Polymerase II