title: Role for DUSP1 (dual-specificity protein phosphatase 1) in the regulation of autophagy.
abstract: Accumulating evidence suggests that mitogen-activated protein kinases (MAPKs) regulate macroautophagy/autophagy. However, the involvement of dual-specificity protein phosphatases (DUSPs), endogenous inhibitors for MAPKs, in autophagy remains to be determined. Here we report that DUSP1/MKP-1, the founding member of the DUSP family, plays a critical role in regulating autophagy. Specifically, we demonstrate that DUSP1 knockdown by shRNA in human ovarian cancer CAOV3 cells and knockout in murine embryonic fibroblasts, increases both basal and rapamycin-increased autophagic flux. Overexpression of DUSP1 had the opposite effect. Importantly, knockout of Dusp1 promoted phosphorylation of ULK1 at Ser555, and BECN1/Beclin 1 at Ser15, and the association of PIK3C3/VPS34, ATG14, BECN1 and MAPK, leading to the activation of the autophagosome-initiating class III phosphatidylinositol 3-kinase (PtdIns3K) complex. Furthermore, knockdown and pharmacological inhibitor studies indicated that DUSP1-mediated suppression of autophagy reflected inactivation of the MAPK1-MAPK3 members of the MAPK family. Knockdown of DUSP1 sensitized CAOV3 cells to rapamycin-induced antigrowth activity. Moreover, CAOV3-CR cells, a line that had acquired cisplatin resistance, exhibited an elevated DUSP1 level and were refractory to rapamycin-induced autophagy and cytostatic effects. Knockdown of DUSP1 in CAOV3-CR cells restored sensitivity to rapamycin. Collectively, this work identifies a previously unrecognized role for DUSP1 in regulating autophagy and suggests that suppression of DUSP1 may enhance the therapeutic activity of rapamycin.
authors.affiliation: a Molecular Therapeutics Program , Karmanos Cancer Institute, Wayne State University School of Medicine , Detroit , MI , USA.|b Departments of Oncology and Pathology , Wayne State University School of Medicine , Detroit , MI , USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
authors.affiliation: a Molecular Therapeutics Program , Karmanos Cancer Institute, Wayne State University School of Medicine , Detroit , MI , USA.|b Departments of Oncology and Pathology , Wayne State University School of Medicine , Detroit , MI , USA.
authors.forename: Jun-Ying
authors.initials: JY
authors.lastname: Zhou
authors.affiliation: a Molecular Therapeutics Program , Karmanos Cancer Institute, Wayne State University School of Medicine , Detroit , MI , USA.|b Departments of Oncology and Pathology , Wayne State University School of Medicine , Detroit , MI , USA.
authors.forename: Dhonghyo
authors.initials: D
authors.lastname: Kho
authors.affiliation: a Molecular Therapeutics Program , Karmanos Cancer Institute, Wayne State University School of Medicine , Detroit , MI , USA.|c Institute of Environmental Health Sciences, Wayne State University , Detroit , MI , USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Reiners
authors.affiliation: a Molecular Therapeutics Program , Karmanos Cancer Institute, Wayne State University School of Medicine , Detroit , MI , USA.|b Departments of Oncology and Pathology , Wayne State University School of Medicine , Detroit , MI , USA.
authors.forename: Gen Sheng
authors.initials: GS
authors.lastname: Wu
mesh_terms: D000818:Animals; D000071182:Autophagosomes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000473:pathology / Q000648:ultrastructure; D000071456:Sequestosome-1 Protein / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology
chemical_list: D046912:Multiprotein Complexes; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; D002945:Cisplatin; D020123:Sirolimus
keywords: DUSP1; MAPK/ERK; autophagy; cisplatin resistance; ovarian cancer