Ubiquitin-independent degradation of cell-cycle inhibitors by the REGgamma proteasome

Mol Cell. 2007 Jun 22;26(6):843-52. doi: 10.1016/j.molcel.2007.05.022.


The cell-cycle regulator p21(Cip1) is degraded by proteasomes independently of ubiquitination. We now show that degradation of p21 in vivo does not require the 19S proteasome lid, which contains the ubiquitin-binding subunit. Instead, the major proteasomal pathway for p21 degradation involves an alternative proteasome lid, the REGgamma complex. REGgamma binds to p21 in vivo, and deletion of p21's REGgamma-binding site greatly extends its half-life. Knockdown of REGgamma by RNA interference stabilizes p21, p21 has a significantly extended half-life in REGgamma(-/-) murine embryonic fibroblasts, and the p21 abundance is elevated in REGgamma(-/-) mice. The role of REGgamma in cell-cycle regulation may extend beyond p21 regulation, because p16(INK4A) and p19(Arf) also bind to REGgamma and are stabilized in REGgamma-deficient cells.

Publication types

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

MeSH terms

  • ADP-Ribosylation Factors / genetics
  • ADP-Ribosylation Factors / metabolism
  • Animals
  • Autoantigens / metabolism*
  • Cell Line
  • Cell Line, Transformed
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
  • Embryo, Mammalian / cytology
  • Embryo, Mammalian / metabolism
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Humans
  • Mice
  • Mice, Knockout
  • Proteasome Endopeptidase Complex / deficiency
  • Proteasome Endopeptidase Complex / metabolism*
  • Proteasome Inhibitors
  • Protein Binding / genetics
  • RNA, Small Interfering / genetics
  • Ubiquitin / genetics
  • Ubiquitin / metabolism*


  • Autoantigens
  • CDKN1A protein, human
  • Cdkn1a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p16
  • Cyclin-Dependent Kinase Inhibitor p21
  • Ki antigen
  • Proteasome Inhibitors
  • RNA, Small Interfering
  • Ubiquitin
  • Proteasome Endopeptidase Complex
  • ADP-Ribosylation Factors