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

Mol Cell. 2007 Jun 22;26(6):831-42. doi: 10.1016/j.molcel.2007.05.028.


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).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism*
  • Animals
  • Autoantigens / genetics
  • Autoantigens / metabolism*
  • Cell Cycle / genetics
  • Cell-Free System / enzymology
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
  • HeLa Cells
  • Histone Acetyltransferases / genetics
  • Histone Acetyltransferases / metabolism
  • Humans
  • Mice
  • Mice, Knockout
  • Nuclear Receptor Coactivator 3
  • Proteasome Endopeptidase Complex / genetics
  • Proteasome Endopeptidase Complex / metabolism*
  • RNA, Small Interfering
  • Thyroid Neoplasms / enzymology
  • Thyroid Neoplasms / genetics
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Ubiquitin / genetics
  • Ubiquitin / metabolism*


  • Autoantigens
  • CDKN1A protein, human
  • Cdkn1a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p21
  • Ki antigen
  • RNA, Small Interfering
  • Trans-Activators
  • Ubiquitin
  • Adenosine Triphosphate
  • Histone Acetyltransferases
  • NCOA3 protein, human
  • Ncoa3 protein, mouse
  • Nuclear Receptor Coactivator 3
  • Proteasome Endopeptidase Complex