The Rbm38-p63 feedback loop is critical for tumor suppression and longevity.

The RNA-binding protein Rbm38 is a target of p63 tumor suppressor and can in-turn repress p63 expression via mRNA stability. Thus, Rbm38 and p63 form a negative feedback loop. To investigate the biological significance of the Rbm38-p63 loop in vivo, a cohort of WT, Rbm38, TAp63, and Rbm38;TAp63 mice were generated and monitored throughout their lifespan. While mice deficient in Rbm38 or TAp63 alone died mostly from spontaneous tumors, compound Rbm38;TAp63 mice had an extended lifespan along with reduced tumor incidence. We also found that loss-of-Rbm38 markedly decreased the percentage of liver steatosis in TAp63 mice. Moreover, we found that Rbm38 deficiency extends the lifespan of tumor-free TAp63 mice along with reduced expression of senescence-associated biomarkers. Consistent with this, Rbm38;TAp63 MEFs were resistant, whereas Rbm38 or TAp63 MEFs were prone, to cellular senescence. Importantly, we showed that the levels of inflammatory cytokines (IL17D and Tnfsf15) were significantly reduced by Rbm38 deficiency in senescence-resistant Rbm38;TAp63 mouse livers and MEFs. Together, our data suggest that Rbm38 and p63 function as intergenic suppressors in aging and tumorigenesis and that the Rbm38-p63 loop may be explored for enhancing longevity and cancer management.