Mechanistic Investigation Of The Regulation Of The Mdm2-p53 Pathway And P53-suppressed Tumor Metastasis

As an important tumor suppressor,p53 needs to be strictly regulated in the cell.The ubiquitin E3 ligase Mdm2,as the most critical negative regulator of p53,can bind to p53 and catalyze its modification of polyubiquitination,thereby promoting the degradation of p53 through the proteasome pathway.In our study,we identified MARCH7 as a new interacting protein of Mdm2.Interestingly,unlike the traditional ubiquitin E3 ligase,which mediates degradation of its substrate,MARCH7 can stabilize Mdm2.Therefore,MARCH7 is able to promote p53 polyubiquitination and protein degradation in a Mdm2-dependent manner.Mechanistically,MARCH7 specifically catalyzes Lys63-linked polyubiquitination of Mdm2 in vivo and in vitro,thereby inhibiting Mdm2 autoubiquitination and degradation.Functionally,MARCH7 can regulate cell proliferation,apoptosis and tumorigenesis by reducing p53 expression.In summary,our work revealed a novel regulatory mode of Mdm2 stability and proved that MARCH7 is an important regulator of the Mdm2-p53 pathway.As a tumor suppressor,p53 plays a key role in the process of tumor development.Although the function of p53's metastasis inhibition has been increasingly recognized,the underlying molecular mechanism is still not very clear.In another study,we identified WDR63 as a novel p53-inducible transcriptional target.Functionally,WDR63 can inhibit the migration and invasion of tumor cells and lung metastasis in mice.Mechanistically,WDR63 can interact with Arp2/3 complex,a key nucleator of actin,and inhibit Arp2/3-mediated branched actin polymerization.Moreover,WDR63 functions as a critical mediator of p53 in suppressing metastasis.In addition,compared with normal tissues,WDR63 shows lower expression in LUAD and LUSC.The expression of WDR63 in LUAD and LUSC is significantly correlated with the mutation status of p53.There is also a good correlation between the WDR63 expression and the malignant degree of LUSC.These findings not only broaden the understanding of the function and regulatory mechanism of Arp2/3-mediated actin polymerization in metastasis,but also imply that WDR63 plays an important role in mediating the metastasis suppression by p53.