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

Oncogene. 2018 May;37(21):2863-2872. doi: 10.1038/s41388-018-0176-5. Epub 2018 Mar 9.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aging / genetics*
  • Animals
  • Fatty Liver / genetics*
  • Feedback, Physiological
  • Female
  • Humans
  • Interleukin-17 / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Neoplasms, Experimental / genetics*
  • Neoplasms, Experimental / mortality
  • RNA Stability
  • RNA, Messenger / chemistry*
  • RNA-Binding Proteins / chemistry
  • RNA-Binding Proteins / genetics*
  • RNA-Binding Proteins / metabolism
  • Transcription Factors / chemistry
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Tumor Necrosis Factor Ligand Superfamily Member 15
  • Tumor Suppressor Proteins / chemistry
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism


  • IL17D protein, human
  • Interleukin-17
  • RBM38 protein, human
  • RNA, Messenger
  • RNA-Binding Proteins
  • TNFSF15 protein, human
  • TP63 protein, human
  • Transcription Factors
  • Tumor Necrosis Factor Ligand Superfamily Member 15
  • Tumor Suppressor Proteins