Abstract
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.
Highlights
Small heterodimer partner (SHP, NROB2) plays a critical role in metabolic diseases [1], including bile acid biosynthesis [2,3], bile acid and bile duct ligation (BDL) induced cholestatic liver injury [4,5], fatty liver [6,7], hypercholesterolemia [8], glucose metabolism [9,10], obesity [11,12,13], and liver fibrosis [14]
We showed that the SHPG171A and p53 interaction was lost in 293T (Fig. 2B) and Hela cells (Fig. 3C), and that SHP did not interfere with p53 and Mdm2 interaction in both cells (Fig. 3D–3E)
We provide convincing evidence for a cross-talk between p53 and nuclear receptor SHP
Summary
Small heterodimer partner (SHP, NROB2) plays a critical role in metabolic diseases [1], including bile acid biosynthesis [2,3], bile acid and bile duct ligation (BDL) induced cholestatic liver injury [4,5], fatty liver [6,7], hypercholesterolemia [8], glucose metabolism [9,10], obesity [11,12,13], and liver fibrosis [14]. Growing evidence suggests SHP as a tumor suppressor [27] in hepatocellular carcinoma (HCC) by inhibiting hepatocyte proliferation [28], activating apoptosis [29], and repressing the expression of DNA methyltransferase [30,31]. In spite of these important studies, the relationship between SHP and other tumor suppressors remains largely unexplored. We further identified a cross-talk between SHP and Mdm via a feedback regulatory loop [38] These studies raised an interesting question whether p53 and SHP cross-regulate each other’s stability. The findings provide new insight into the mechanisms of cross-regulation of protein stability between two tumor suppressors, which are important for our better understanding the tumor suppressor function of p53 and SHP
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