TY - JOUR
T1 - The Rbm38-p63 feedback loop is critical for tumor suppression and longevity
AU - Jiang, Yuqian
AU - Xu, Enshun
AU - Zhang, Jin
AU - Chen, Mingyi
AU - Flores, Elsa
AU - Chen, Xinbin
N1 - Funding Information:
Acknowledgements This work is supported in part by the National Institutes of Health (CA195828 to X.C.).
Publisher Copyright:
© 2018 Macmillan Publishers Limited, part of Springer Nature.
PY - 2018/5/1
Y1 - 2018/5/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41388-018-0176-5
DO - 10.1038/s41388-018-0176-5
M3 - Article
C2 - 29520104
AN - SCOPUS:85043343580
SN - 0950-9232
VL - 37
SP - 2863
EP - 2872
JO - Oncogene
JF - Oncogene
IS - 21
ER -