Serine 123 phosphorylation modulates p21 protein stability and activity by suppressing ubiquitin-independent proteasomal degradation.
The cyclin-dependent kinase inhibitor p21(Waf1/Cip1) is a major regulator of the cell cycle and plays an important role in many cellular processes, including differentiation, stress response, apoptosis, and tumorigenesis. We previously cloned the gene encoding dog p21 and found that unlike its human ortholog, dog p21 is expressed as two isoforms, one high molecular mass band of 23 kDa and one low molecular mass band of 19 kDa. In the current study, we found that the high molecular mass band is phosphorylated, whereas the low molecular mass band is hypophosphorylated. Moreover, by generating multiple mutants of dog p21, we found that serine 123 and proline 124, which form a consensus site for proline-directed phosphorylation, are required for expression of the high molecular mass p21 isoform through phosphorylation at serine 123. Most importantly, we showed that serine 123 phosphorylation inhibits ubiquitin-independent proteasomal degradation of p21 protein and subsequently, prolongs p21 protein half-life and enhances the ability of p21 to suppress cell proliferation. Taken together, these data reveal that serine 123 phosphorylation modulates p21 protein stability and activity by suppressing ubiquitin-independent proteasomal degradation.
Comparative Oncology Laboratory, University of California, Davis, California 95616, USA.
Xiangling
X
Chen
Jin
J
Zhang
Min
M
Zhang
Shou
S
Liu
Wensheng
W
Yan
JinHyuk
J
Jung
Xinbin
X
Chen
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D004285:Dogs; D006801:Humans; D010766:Phosphorylation / Q000502:physiology; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms; D055550:Protein Stability; D059748:Proteolysis; D012694:Serine / Q000235:genetics / Q000378:metabolism; D013045:Species Specificity; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism*
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D020033:Protein Isoforms; D025801:Ubiquitin; D012694:Serine; D046988:Proteasome Endopeptidase Complex