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Mol Cell. 2007 Jun 22;26(6):831-42.

Ubiquitin- and ATP-independent proteolytic turnover of p21 by the REGgamma-proteasome pathway.

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Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.


We previously demonstrated that the proteasome activator REGgamma directs degradation of the steroid receptor coactivator SRC-3 by the 20S proteasome in an ATP- and ubiquitin-independent manner. Our efforts to identify additional endogenous direct targets of the REGgamma proteasome revealed that p21(Waf/Cip1), a central cyclin-dependent kinase inhibitor, is another endogenous target. Gain-of-function analysis, RNAi knockdown, REGgamma-deficient MEF analysis, and pulse-chase experiments substantiate that REGgamma promotes degradation of unbound p21. Cell-free proteasome proteolysis assays using purified REGgamma, p21, and the 20S proteasome confirm that REGgamma directly mediates degradation of free p21 in an ATP- and ubiquitin-independent manner. Depletion of REGgamma in a thyroid carcinoma cell line results in cell-cycle and proliferative alterations. Our study reveals that, in addition to degrading the SRC-3 growth coactivator, REGgamma also has a role in the regulation of the cell cycle through its ability to influence the level of a cell-cycle regulator(s).

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