Gene Regulation Protein Synthesis and Degradation
The Evolutionarily Conserved C-terminal Domains in the Mammalian Retinoblastoma Tumor Suppressor Family Serve as Dual Regulators of Protein Stability and Transcriptional Potency*

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The retinoblastoma (RB) tumor suppressor and related family of proteins play critical roles in development through their regulation of genes involved in cell fate. Multiple regulatory pathways impact RB function, including the ubiquitin-proteasome system with deregulated RB destruction frequently associated with pathogenesis. With the current study we explored the mechanisms connecting proteasome-mediated turnover of the RB family to the regulation of repressor activity. We find that steady state levels of all RB family members, RB, p107, and p130, were diminished during embryonic stem cell differentiation concomitant with their target gene acquisition. Proteasome-dependent turnover of the RB family is mediated by distinct and autonomously acting instability elements (IE) located in their C-terminal regulatory domains in a process that is sensitive to cyclin-dependent kinase (CDK4) perturbation. The IE regions include motifs that contribute to E2F-DP transcription factor interaction, and consistently, p107 and p130 repressor potency was reduced by IE deletion. The juxtaposition of degron sequences and E2F interaction motifs appears to be a conserved feature across the RB family, suggesting the potential for repressor ubiquitination and specific target gene regulation. These findings establish a mechanistic link between regulation of RB family repressor potency and the ubiquitin-proteasome system.

Background: RB family protein abundance is dynamic and sensitive to growth conditions.

Results: RB family turnover is mediated by C-terminal degrons in a process that is phosphorylation-sensitive.

Conclusion: The RB family degrons are important regulatory domains linking stability and transcriptional potency.

Significance: Dual control of stability and potency by RB family degrons may contribute to embryonic development.

retinoblastoma, RB, p107, p130, E2F-DP, cyclin, CDK, protein stability, proteasome, degron, transcriptional repression.

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*

This work was supported, in whole or in part, by National Institutes of Health Grants R01GM095347 (to J. G. K.) and R01GM079098 (to D. N. A. and R. W. H.).

1

Supported in part by fellowships from the College of Natural Science at Michigan State University.

2

Supported in part by an undergraduate research award from the Lyman Briggs College at Michigan State University.