Ubiquitin-independent degradation of cell-cycle inhibitors by the REGgamma proteasome.
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.
Chen
Xueyan
X
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Barton
Lance F
LF
Chi
Yong
Y
Clurman
Bruce E
BE
Roberts
James M
JM
D020727:ADP-Ribosylation Factors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001324:Autoantigens / Q000378:metabolism*; D002460:Cell Line; D002461:Cell Line, Transformed; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D046988:Proteasome Endopeptidase Complex / Q000172:deficiency / Q000378:metabolism*; D061988:Proteasome Inhibitors; D011485:Protein Binding / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism*
D001324:Autoantigens; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; C099558:Ki antigen; D061988:Proteasome Inhibitors; D034741:RNA, Small Interfering; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex; D020727:ADP-Ribosylation Factors