Erk And P38 MAPKs Dictate MTOR-mediated Renewal And Aging Of Intestinal Villi

The mTOR pathway is the sensor of growth factors and nutrients,its activation promotes cell proliferation whereas its inactivation mediates diet restriction-induced lifespan extension in model animals.It is hypothesized mTOR-induced accelerated cell proliferation and incurred stressors cause cell replicative senescence and cell damage and thus aging.Tsc1 is an upstream negative regulator of mTOR,and its mutation or deletion can active mTOR signaling.In this study,we generate Villin-Cre;Tsc1^f/f and Lgr5-EGFP-Cre/ERT;Tsc1^f/f mice,and show that in rapidly cycling intestinal villi,mTOR activation by deletion of Tsc1 in enteroblasts or Lgr5⁺intestinal stem cells(ISCs)led to villus and crypt overgrowth and regeneration defect at 2 month of age,followed by ISC attrition and villus premature aging at 8 month of age.To understand the molecular mechanism of the overgrowth and premature phenotype caused by mTOR activation,we take several biochemical experiments.The results show that mTOR activation increased protein synthesis of Mek1 and MKK6 and potentiated the activation of Mek1-Erk and MKK6-p38 MAPK pathways.To test the physiological function of upregulated Mek1-Erk pathway and MKK6-p38 MAPK pathway,we generated Villin-Cre;Tsc1^f/f;Mek1^f/f and Villin-Cre;Tsc1^f/f;p38?^f/f/f mice.Ablation of Mek1 in Villin-Cre;Tsc1^f/fmice rescued villus overgrowth,whereas ablation of p38?in Villin-Cre;Tsc1^f/f/f mice rescued villus regeneration defect and premature aging and led to overgrowth and tumorigenesis via p53 and p16.Thus enhanced Erk activation mediates intestine overgrowth,whereas enhanced p38 activation,via induction of p53 as well as p16,puts a brake on growth and mediates the regeneration defects of ISC,which prevents tumorigenesis of Tsc1deficient intestine.In response to mTOR activation,elevated MKK6-p38 MAPK pathway thus acts as a safeguard mechanism to balance Mek1-Erk-mediated overproliferation,prevent tumorigenesis,and cause ISC attrition in response to stress.Furthermore,mTOR promotes ISC and villus aging through sensitizing ISCs to p38-mediated stress response.