Mutant p53 promotes tumor cell malignancy by both positive and negative regulation of TGF-β pathway

Specific p53 mutations abrogate the tumor suppressive functions by gaining new abilities to promote tumorigenesis. Inactivation of p53 is known to distort the TGF-β signaling, which paradoxically displays both tumor-suppressive and pro-oncogenic function. The molecular mechanisms how mutant p53 simultaneously antagonizes tumor-suppressive and synergizes tumor-promoting function of TGF-β pathway remain elusive. Here we demonstrate that mutant p53 differentially regulates subsets of TGF-β target genes, by an enhanced binding to the MH2 domain in Smad3 upon the integration of ERK signaling, therefore disrupting the Smad3/Smad4 complex formation. Silencing Smad2, inhibition of ERK or introducing a phosphorylation defective mutation at Ser392 in p53 abrogates the R175H mutant p53 dependent regulation of these TGF- β target genes. Our study provide a mechanism to reconcile the seemingly contradictory observations that mutant p53 can both attenuate and cooperate with the TGF-β pathway to promote cancer cell malignancy in a same cell type.