Cross-regulation of protein stability by p53 and nuclear receptor SHP.
We report here a novel interplay between tumor suppressor p53 and nuclear receptor SHP that controls p53 and SHP stability. Overexpression of p53 causes rapid SHP protein degradation, which does not require the presence of Mdm2 and is mediated by the proteosome pathway. Overexpressing SHP alone does not affect p53 stability. However, SHP destabilizes p53 by augmentation of Mdm2 ubiquitin ligase activity toward p53. The single amino acid substitution in the SHP protein SHPK170R increases SHP binding to p53 relative to SHP wild-type, whereas SHPG171A variant shows a diminished p53 binding. As a result of the cross-regulation, the tumor suppressor function of p53 and SHP in inhibition of colon cancer growth is compromised. Our findings reveal a unique scenario for a cross-inhibition between two tumor suppressors to keep their expression and function in check.
Departments of Medicine and Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.
Zhihong
Z
Yang
Yuxia
Y
Zhang
Jongsook Kim
JK
Kemper
Li
L
Wang
D000818:Animals; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D011506:Proteins; D018160:Receptors, Cytoplasmic and Nuclear; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C099713:nuclear receptor subfamily 0, group B, member 2; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D046988:Proteasome Endopeptidase Complex