Paradoxical instability-activity relationship defines a novel regulatory pathway for retinoblastoma proteins

Molecular Biology of the Cell
Pankaj AcharyaDavid N Arnosti

Abstract

The retinoblastoma (RB) transcriptional corepressor and related family of pocket proteins play central roles in cell cycle control and development, and the regulatory networks governed by these factors are frequently inactivated during tumorigenesis. During normal growth, these proteins are subject to tight control through at least two mechanisms. First, during cell cycle progression, repressor potential is down-regulated by Cdk-dependent phosphorylation, resulting in repressor dissociation from E2F family transcription factors. Second, RB proteins are subject to proteasome-mediated destruction during development. To better understand the mechanism for RB family protein instability, we characterized Rbf1 turnover in Drosophila and the protein motifs required for its destabilization. We show that specific point mutations in a conserved C-terminal instability element strongly stabilize Rbf1, but strikingly, these mutations also cripple repression activity. Rbf1 is destabilized specifically in actively proliferating tissues of the larva, indicating that controlled degradation of Rbf1 is linked to developmental signals. The positive linkage between Rbf1 activity and its destruction indicates that repressor function is governed in a...Continue Reading

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Citations

Oct 23, 2012·The Journal of Biological Chemistry·Nitin RajR William Henry
Sep 1, 2015·Biochimica Et Biophysica Acta·Satyaki Sengupta, R William Henry
Aug 17, 2012·Cell Cycle·Nitin RajR William Henry
Jul 23, 2014·The Journal of Biological Chemistry·Liang ZhangDavid N Arnosti
Aug 17, 2019·Molecular Biology and Evolution·Rima MouawadDavid N Arnosti

Methods Mentioned

BETA
Transgenic
PCR
transfection
immunoprecipitation
ChIP
transfections
pull-down
coimmunoprecipitation
CoIP
immunoprecipitations

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