title: Tumor suppressive role of sestrin2 during colitis and colon carcinogenesis.
abstract: The mTOR complex 1 (mTORC1) and endoplasmic reticulum (ER) stress pathways are critical regulators of intestinal inflammation and colon cancer growth. Sestrins are stress-inducible proteins, which suppress both mTORC1 and ER stress; however, the role of Sestrins in colon physiology and tumorigenesis has been elusive due to the lack of studies in human tissues or in appropriate animal models. In this study, we show that human SESN2 expression is elevated in the colon of ulcerative colitis patients but is lost upon p53 inactivation during colon carcinogenesis. In mouse colon, Sestrin2 was critical for limiting ER stress and promoting the recovery of epithelial cells after inflammatory injury. During colitis-promoted tumorigenesis, Sestrin2 was shown to be an important mediator of p53's control over mTORC1 signaling and tumor cell growth. These results highlight Sestrin2 as a novel tumor suppressor, whose downregulation can accelerate both colitis and colon carcinogenesis.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States.|Department of Biochemistry, University of Nebraska, Lincoln, United States.
authors.forename: Seung-Hyun
authors.initials: SH
authors.lastname: Ro
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States.
authors.forename: Xiang
authors.initials: X
authors.lastname: Xue
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States.
authors.forename: Sadeesh K
authors.initials: SK
authors.lastname: Ramakrishnan
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States.
authors.forename: Chun-Seok
authors.initials: CS
authors.lastname: Cho
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States.
authors.forename: Sim
authors.initials: S
authors.lastname: Namkoong
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States.
authors.forename: Insook
authors.initials: I
authors.lastname: Jang
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Semple
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States.
authors.forename: Allison
authors.initials: A
authors.lastname: Ho
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States.|Department of Cell Biology, College of Medicine, Konyang University, Daejeon, Republic of Korea.|Myung-Gok Eye Research Institute, Konyang University, Seoul, Republic of Korea.
authors.forename: Hwan-Woo
authors.initials: HW
authors.lastname: Park
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States.
authors.forename: Yatrik M
authors.initials: YM
authors.lastname: Shah
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States.
authors.forename: Jun Hee
authors.identifier: http://orcid.org/0000-0002-2200-6011
authors.initials: JH
authors.lastname: Lee
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D003093:Colitis, Ulcerative / Q000473:pathology*; D003106:Colon; D003110:Colonic Neoplasms / Q000503:physiopathology*; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress; D006801:Humans; D051379:Mice; D009369:Neoplasms; D009687:Nuclear Proteins / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D000084622:Sestrins
chemical_list: D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C465398:SESN2 protein, human; D000084622:Sestrins
keywords: cell biology; colitis; colon cancer; human; human biology; medicine; mouse; p53; sestrin2; tumor suppressor