TGFβ1 regulates HRas-mediated activation of IRE1α through the PERK-RPAP2 axis in keratinocytes.
TGFβ1 regulates HRas-mediated activation of IRE1α through the PERK-RPAP2 axis in keratinocytes.
复制标题
DOI：
10.1002/mc.23453
复制
发表时间：
2022-10
影响因子：
4.6
通讯作者：
中科院分区：
文献类型：
--
作者：
转化生长因子β1（TGFβ1）是响应于HRas的肿瘤进展的关键调节因子。近年来，TGFβ1在许多疾病模型中被证实可触发ER应激;然而，其在癌基因诱导的ER应激中的作用尚不清楚。致癌HRas主要通过肌醇需要酶1α（IRE 1 α）途径诱导未折叠蛋白反应（UPR），启动对内质网应激的适应性反应，对细胞增殖和衰老都具有重要意义。在这里，我们展示了UPR传感器蛋白IRE 1 α和（PKR）样内质网激酶（PERK）介导TGFβ1在表达HRas突变形式的小鼠角质形成细胞中的肿瘤抑制作用。在体外和体内模型中，TGFβ1抑制IRE 1 α磷酸化和HRas激活，同时激活PERK通路。然而，ER应激的增加表明ER应激与TGFβ1激活的IRE 1 α解偶联。药理学和遗传学方法表明，TGFβ1依赖性的IRE 1 α去磷酸化是由PERK通过RNA聚合酶II相关蛋白2（RPAP 2）介导的，RPAP 2是PERK依赖性的IRE 1 α磷酸酶。此外，TGFβ1介导的致癌HRas角质形成细胞生长停滞部分依赖于PERK诱导的IRE 1 α去磷酸化和失活。总之，这些结果表明UPR蛋白之间存在关键的串扰，这对于TGFβ1介导的肿瘤抑制反应非常重要。
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 activating the PERK pathway. However, the increase in ER stress indicated an uncoupling of ER stress and IRE1α activation by TGFβ1. Pharmacological and genetic approaches demonstrated that TGFβ1-dependent dephosphorylation of IRE1α was mediated by PERK through RNA Polymerase II Associated Protein 2 (RPAP2), a PERK-dependent IRE1α phosphatase. In addition, TGFβ1-mediated growth arrest in oncogenic HRas keratinocytes was partially dependent on PERK-induced IRE1α dephosphorylation and inactivation. Together, these results demonstrate a critical cross-talk between UPR proteins that is important for TGFβ1-mediated tumor suppressive responses.
登录
查看更多内容
DOI：
10.1073/pnas.1701757114
发表时间：
2017-09-12
影响因子：
11.1
作者：
Blazanin, Nicholas;Son, Jeongin;Glick, Adam B.
通讯作者：
Glick, Adam B.
DOI：
10.1073/pnas.220247197
发表时间：
2000-11-07
影响因子：
11.1
作者：
Brewer, JW;Diehl, JA
通讯作者：
Diehl, JA
DOI：
10.1073/pnas.96.26.14949
发表时间：
1999-12-21
影响因子：
11.1
作者：
Glick, A;Popescu, N;Yuspa, SH
通讯作者：
Yuspa, SH
影响因子：
64.8
作者：
Chen, Xi;Iliopoulos, Dimitrios;Zhang, Qing;Tang, Qianzi;Greenblatt, Matthew B.;Hatziapostolou, Maria;Lim, Elgene;Tam, Wai Leong;Ni, Min;Chen, Yiwen;Mai, Junhua;Shen, Haifa;Hu, Dorothy Z.;Adoro, Stanley;Hu, Bella;Song, Minkyung;Tan, Chen;Landis, Melissa D.;Ferrari, Mauro;Shin, Sandra J.;Brown, Myles;Chang, Jenny C.;Liu, X. Shirley;Glimcher, Laurie H.
通讯作者：
Glimcher, Laurie H.
影响因子：
16
作者：
Egloff, Sylvain;Zaborowska, Justyna;Laitem, Clelia;Kiss, Tames;Murphy, Shona
通讯作者：
Murphy, Shona