Abstract
Survivin is a prosurvival protein overexpressed in many cancers through mechanisms that remain poorly explored, and is implicated in control of tumor progression and resistance to cancer chemotherapeutics. Here, we report a critical role for survivin in the induction of apoptosis by transforming growth factor-beta (TGF-beta). We show that TGF-beta rapidly downregulates survivin expression in prostate epithelial cells, through a unique mechanism of transcriptional suppression involving Smads 2 and 3, Rb/E2F4, and the cell-cycle repressor elements CDE and CHR. This TGF-beta response is triggered through a Smad2/3-dependent hypophosphorylation of Rb and the subsequent association of the Rb/E2F4 repressive complex to CDE/CHR elements in the proximal region of the survivin promoter. Viral-mediated gene delivery experiments, involving overexpressing or silencing survivin, reveal critical roles of survivin in apoptosis induced by TGF-beta alone or in cooperation with cancer therapeutic agents. We propose a novel TGF-beta/Rb/survivin axis with a putative role in the functional switch of TGF-beta from tumor suppressor to tumor promoter.
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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Apoptosis / physiology*
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Blotting, Western
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E2F4 Transcription Factor / genetics
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E2F4 Transcription Factor / metabolism*
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Electrophoretic Mobility Shift Assay
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Humans
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Inhibitor of Apoptosis Proteins
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Male
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Microtubule-Associated Proteins / genetics*
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Microtubule-Associated Proteins / metabolism
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Neoplasm Proteins / genetics*
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Neoplasm Proteins / metabolism
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Promoter Regions, Genetic
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Prostatic Neoplasms / genetics
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Prostatic Neoplasms / metabolism
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Prostatic Neoplasms / pathology
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Protein Binding
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Protein Serine-Threonine Kinases / metabolism
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Receptor, Transforming Growth Factor-beta Type I
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Receptors, Transforming Growth Factor beta / metabolism
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Response Elements
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Retinoblastoma Protein / genetics
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Retinoblastoma Protein / metabolism*
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Reverse Transcriptase Polymerase Chain Reaction
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Smad2 Protein / genetics
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Smad2 Protein / metabolism*
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Smad3 Protein / genetics
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Smad3 Protein / metabolism*
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Survivin
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Transcription, Genetic
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Transforming Growth Factor beta / genetics
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Transforming Growth Factor beta / metabolism*
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Tumor Cells, Cultured
Substances
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BIRC5 protein, human
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E2F4 Transcription Factor
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E2F4 protein, human
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Inhibitor of Apoptosis Proteins
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Microtubule-Associated Proteins
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Neoplasm Proteins
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Receptors, Transforming Growth Factor beta
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Retinoblastoma Protein
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SMAD2 protein, human
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SMAD3 protein, human
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Smad2 Protein
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Smad3 Protein
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Survivin
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Transforming Growth Factor beta
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Protein Serine-Threonine Kinases
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Receptor, Transforming Growth Factor-beta Type I