biostudies-literatureMogre SPennsylvania State UniversityU.S. Department of AgricultureNCI NIH HHSNational Institutes of Health958-971https://www.ebi.ac.uk/biostudies/studies/S-EPMC9486931biostudies-literatureUnknown61(10)Transforming Growth Factor β1 (TGFβ1) is a critical regulator of tumor progression in response to HRas. Recently, TGFβ1 has been shown to trigger ER stress in many disease models; however, its role in oncogene-induced ER stress is unclear. Oncogenic HRas induces the unfolded protein response (UPR) predominantly via the Inositol-requiring enzyme 1α (IRE1α) pathway to initiate the adaptative responses to ER stress, with importance for both proliferation and senescence. Here, we show a role of the UPR sensor proteins IRE1α and (PKR)-like endoplasmic reticulum kinase (PERK) to mediate the tumor-suppressive roles of TGFβ1 in mouse keratinocytes expressing mutant forms of HRas. TGFβ1 suppressed IRE1α phosphorylation and activation by HRas both in in vitro and in vivo models while simultaneously Molecular carcinogenesisTGFβ1 regulates HRas-mediated activation of IRE1α through the PERK-RPAP2 axis in keratinocytes.PMC9486931R01 CA197942Glick ABMogre SWalsh HIbinson JMinnich CAndrew Hu CCBlazanin NfalseTGFβ1 regulates HRas-mediated activation of IRE1α through the PERK-RPAP2 axis in keratinocytes.Transforming Growth Factor β1 (TGFβ1) is a critical regulator of tumor progression in response to HRas. Recently, TGFβ1 has been shown to trigger ER stress in many disease models; however, its role in oncogene-induced ER stress is unclear. Oncogenic HRas induces the unfolded protein response (UPR) predominantly via the Inositol-requiring enzyme 1α (IRE1α) pathway to initiate the adaptative responses to ER stress, with importance for both proliferation and senescence. Here, we show a role of the UPR sensor proteins IRE1α and (PKR)-like endoplasmic reticulum kinase (PERK) to mediate the tumor-suppressive roles of TGFβ1 in mouse keratinocytes expressing mutant forms of HRas. TGFβ1 suppressed IRE1α phosphorylation and activation by HRas both in in vitro and in vivo models while simultaneously 2022-01-01T00:00:00Z2022 Oct2025-04-05T09:42:56.631Z2025-04-05T09:42:56.631ZS-EPMC94869313597591010.1002/mc.23453