Abstract
The retinoblastoma (RB) tumor suppressor family functions as a regulatory node governing cell cycle progression, differentiation, and apoptosis. Post-translational modifications play a critical role in modulating RB activity, but additional levels of control, including protein turnover, are also essential for proper function. The Drosophila RB homolog Rbf1 is subjected to developmentally cued proteolysis mediated by an instability element (IE) present in the C terminus of this protein. Paradoxically, instability mediated by the IE is also linked to Rbf1 repression potency, suggesting that proteolytic machinery may also be directly involved in transcriptional repression. We show that the Rbf1 IE is an autonomous degron that stimulates both Rbf1 ubiquitination and repression potency. Importantly, Rbf1 IE function is promoter-specific, contributing to repression of cell cycle responsive genes but not to repression of cell signaling genes. The multifunctional IE domain thus provides Rbf1 flexibility for discrimination between target genes embedded in divergent cellular processes.
Highlights
Drosophila Rbf1-mediated transcriptional repression of E2F1-dependent genes is canonically regulated by cyclin/cdk-mediated phosphorylation
A Modular Degron Influences Rbf1 Ubiquitination and Stability—Drosophila Rbf proteins are subjected to developmentally regulated turnover, exhibiting tissue-specific modulation in both the developing embryo and the larvae [20, 28]
The steady state levels of both GFP-Rbf1-instability element (IE) and GFP-Rbf1-C were unaffected by lysine-to-arginine substitution of the same amino acids, indicating that the positive charges of the side chains are important for IE substrate destabilization and that these lysine residues are unlikely targets for ubiquitination (Fig. 1D)
Summary
Drosophila Rbf1-mediated transcriptional repression of E2F1-dependent genes is canonically regulated by cyclin/cdk-mediated phosphorylation. The RB4 tumor suppressor protein functions as a crucial regulator of the G1/S transition during cell cycle progression and plays a central role in restricting cellular proliferation [1]. RB phosphorylation by p38 MAPK at a site that is not a target for cyclin/cdks can modulate RB-mediated repression of apoptotic response genes [8, 16] This model suggests that RB is subjected to a protein modification code that enables gene-specific outcomes, namely cyclin/cdk kinases regulate cell cycle-responsive promoters and stress-responsive kinases regulate apoptosisresponsive promoters. The IE is a key protein motif directing promoter-specific activity of Rbf1 These studies reveal a novel level of regulatory discrimination within the RB protein modification code that enables gene-specific repression during development
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