Regulation of p21(WAF1/CIP1) stability by WISp39, a Hsp90 binding TPR protein.
p21(WAF1/CIP1), a cyclin-dependent kinase inhibitor and a critical regulator of cell cycle, is controlled transcriptionally by p53-dependent and -independent mechanisms and posttranslationally by the proteasome. We have identified WISp39, a tetratricopeptide repeat (TPR) protein that binds p21. WISp39 stabilizes newly synthesized p21 protein by preventing its proteasomal degradation. WISp39, p21, and hsp90 form a trimeric complex in vivo. The interaction of WISp39 with Hsp90 is abolished by point mutations within the C-terminal TPR domain of WISp39. Although this WISp39 TPR mutant binds p21 in vivo, it fails to stabilize p21. Our results suggest that WISp39 recruits Hsp90 to regulate p21 protein stability. WISp39 downregulation by siRNA prevents the accumulation of p21 and cell cycle arrest after ionizing radiation. The results demonstrate the importance of posttranslational stabilization of p21 protein by WISp39 in regulating cellular p21 activity.
Jascur
Thomas
T
Sidney Kimmel Cancer Center, 10835 Altman Road, San Diego, CA 92121, USA.
Brickner
Howard
H
Salles-Passador
Isabelle
I
Barbier
Valerie
V
El Khissiin
Abdelhamid
A
Smith
Brian
B
Fotedar
Rati
R
Fotedar
Arun
A
D000595:Amino Acid Sequence; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004791:Enzyme Inhibitors / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D020104:Immunophilins; D051379:Mice; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes; D017354:Point Mutation; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011839:Radiation, Ionizing; D016415:Sequence Alignment; D022021:Tacrolimus Binding Proteins; D014018:Tissue Distribution; D020798:Two-Hybrid System Techniques
D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D020104:Immunophilins; D046912:Multiprotein Complexes; D034741:RNA, Small Interfering; D022021:Tacrolimus Binding Proteins; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; C400101:FKBPL protein, human; C000598204:FKBPL protein, mouse