Abstract
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
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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ADP-Ribosylation Factors / genetics
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ADP-Ribosylation Factors / metabolism
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Animals
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Autoantigens / metabolism*
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Cell Line
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Cell Line, Transformed
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Cyclin-Dependent Kinase Inhibitor p16 / genetics
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Cyclin-Dependent Kinase Inhibitor p16 / metabolism
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Cyclin-Dependent Kinase Inhibitor p21 / genetics
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
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Embryo, Mammalian / cytology
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Embryo, Mammalian / metabolism
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Fibroblasts / cytology
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Fibroblasts / metabolism
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Humans
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Mice
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Mice, Knockout
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Proteasome Endopeptidase Complex / deficiency
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Proteasome Endopeptidase Complex / metabolism*
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Proteasome Inhibitors
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Protein Binding / genetics
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RNA, Small Interfering / genetics
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Ubiquitin / genetics
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Ubiquitin / metabolism*
Substances
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Autoantigens
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CDKN1A protein, human
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Cdkn1a protein, mouse
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Cyclin-Dependent Kinase Inhibitor p16
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Cyclin-Dependent Kinase Inhibitor p21
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Ki antigen
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Proteasome Inhibitors
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RNA, Small Interfering
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Ubiquitin
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Proteasome Endopeptidase Complex
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ADP-Ribosylation Factors