title: Eomesodermin, HAND1, and CSH1 proteins are induced by cellular stress in a stress-activated protein kinase-dependent manner.
abstract: Eomesodermin (Eomes) is a transcription factor essential for trophoblast development. Stress stimuli activate stress-activated protein kinase (MAPK8/9) and modulate transcription factors in trophoblast stem cells (TSC). In this study, we test the hypothesis that stress-induced Eomes upregulation and downstream trophoblast development are MAPK8/9-dependent. Immunocytochemical and immunoblot assays suggest that Eomes is induced by hyperosmolar stress in a dose- and time-dependent manner. Two MAPK8/9 inhibitors that work by different mechanisms, LJNKl1 and SP600125, block induction of Eomes protein by stress. During normal TSC differentiation, the transcription factor heart and neural crest derivatives expressed 1 (HAND1) is dependent on Eomes, and chorionic somatomammotropin hormone 1 (CSH1) expression is dependent on HAND1. Similar to Eomes, HAND1 and CSH1 induction by stress are MAPK8/9-dependent, and CSH1 is induced in nearly all stressed TSC. CSH1 induction normally requires downregulation of the transcription factor inhibitor of differentiation 2 (ID2) as well as HAND1 upregulation. It was shown previously that hyperosmolar stress induces AMP-activated protein kinase (PRKAA1/2)-dependent ID2 loss in a MAPK8/9-independent manner. Inhibition of PRKAA1/2 with compound C and LJNKl1, more than MAPK8/9 inhibitors alone, inhibits the induction of CSH1 by stress. Taken together these data suggest that stress-induced MAPK8/9 and PRKAA1/2 regulate transcription factors Eomes/HAND1 and ID2, respectively. Together this network mediates induction of CSH1 by stress. Therefore, stress triggers a proportional increase in a normal early TSC differentiation event that could be adaptive in inducing CSH1. But the flexibility of TSC to undergo stress-induced differentiation could lead to pathophysiological consequences if stress endured and TSC differentiation became unbalanced.
authors.affiliation: C.S. Mott Center for Human Growth and Development, Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
authors.forename: A O
authors.initials: AO
authors.lastname: Awonuga
authors.forename: W
authors.initials: W
authors.lastname: Zhong
authors.forename: M E
authors.initials: ME
authors.lastname: Abdallah
authors.forename: J A
authors.initials: JA
authors.lastname: Slater
authors.forename: S C
authors.initials: SC
authors.lastname: Zhou
authors.forename: Y F
authors.initials: YF
authors.lastname: Xie
authors.forename: E E
authors.initials: EE
authors.lastname: Puscheck
authors.forename: D A
authors.initials: DA
authors.lastname: Rappolee
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis*; D015153:Blotting, Western; D002460:Cell Line; D004591:Electrophoresis, Polyacrylamide Gel; D007150:Immunohistochemistry; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009994:Osmolar Concentration; D013012:Sorbitol; D013234:Stem Cells / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D013312:Stress, Physiological / Q000502:physiology*; D020825:T-Box Domain Proteins / Q000096:biosynthesis*; D014327:Trophoblasts / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D020928:Mitogen-Activated Protein Kinases; D013012:Sorbitol; D020825:T-Box Domain Proteins; C491198:Eomes protein, mouse; C095572:Hand1 protein, mouse