Abstract
The p53 tumor suppressor gene encodes a homotetrameric transcription factor which is activated in response to a variety of cellular stressors, including DNA damage and oncogene activation. p53 mutations occur in >50% of human cancers. Although p53 has been shown to regulate Wnt signaling, the underlying mechanisms are not well understood. Here we show that silencing p53 in colon cancer cells led to increased expression of Aha1, a co-chaperone of Hsp90. Heat shock factor-1 was important for mediating the changes in Aha1 levels. Increased Aha1 levels were associated with enhanced interactions with Hsp90, resulting in increased Hsp90 ATPase activity. Moreover, increased Hsp90 ATPase activity resulted in increased phosphorylation of Akt and glycogen synthase kinase-3β (GSK3β), leading to enhanced expression of Wnt target genes. Significantly, levels of Aha1, Hsp90 ATPase activity, Akt, and GSK3β phosphorylation and expression of Wnt target genes were increased in the colons of p53-null as compared with p53 wild type mice. Using p53 heterozygous mutant epithelial cells from Li-Fraumeni syndrome patients, we show that a monoallelic mutation of p53 was sufficient to activate the Aha1/Hsp90 ATPase axis leading to stimulation of Wnt signaling and increased expression of Wnt target genes. Pharmacologic intervention with CP-31398, a p53 rescue agent, inhibited recruitment of Aha1 to Hsp90 and suppressed Wnt-mediated gene expression in colon cancer cells. Taken together, this study provides new insights into the mechanism by which p53 regulates Wnt signaling and raises the intriguing possibility that p53 status may affect the efficacy of anticancer therapies targeting Hsp90 ATPase.
Highlights
The mechanism by which p53, a tumor suppressor gene, regulates Wnt signaling is incompletely understood
Pharmacological intervention with CP-31398, a p53 rescue/stabilizing compound, caused a dosedependent increase in p53 levels and transcriptional activity and reduced expression of Wnt target genes (Fig. 2, A–F). These results clearly demonstrate that p53 status, whether by silencing or pharmacological rescue, modulates Wnt signaling in human colorectal cancer cell lines
G and H, silencing of Aha1 led to reduced levels of Axin-2, c-Myc, and Naked-1. These results indicate that p53 modulates the expression of Aha1 and its interaction with Hsp90 which, in turn, affects Hsp90 ATPase activity and thereby the expression of genes regulated by Wnt signaling
Summary
The mechanism by which p53, a tumor suppressor gene, regulates Wnt signaling is incompletely understood. We have investigated the effect of p53 on Wnt signaling in human colorectal cancer cell lines and LFS-derived epithelial cells To translate these in vitro findings, the effect of p53 on Wnt-signaling including target gene expression was compared in wild type versus p53-null mice. Increased interaction of Aha and Hsp led to enhanced Hsp ATPase activity, which stimulated the Akt/GSK3 pathway This led, in turn, to increased nuclear translocation of -catenin and enhanced Wnt target gene expression. Consistent with these findings, we show that pharmacologic intervention with CP-31398, a p53 rescue compound [16], inhibited the Aha1/Hsp axis and thereby suppressed Wnt signaling. This study provides new insights into the mechanism by which p53 regulates Wnt signaling, which may be important for understanding the progression of colon cancer
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