title: The c10orf10 gene product is a new link between oxidative stress and autophagy.
abstract: The human c10orf10 gene product, also known as decidual protein induced by progesterone (DEPP), is known to be differentially regulated in mouse tissues in response to hypoxia and oxidative stress, however its biological function remains unknown. We found that mice lacking extracellular superoxide dismutase (EC-SOD) show attenuated expression of DEPP in response to acute hypoxia. DEPP mRNA levels, as well as the activity of a reporter gene expressed under the control of the DEPP 5'-flanking region, were significantly upregulated in Hep3B and Vero cells overexpressing EC-SOD. Subcellular fractionation and immunofluorescent microscopy indicated that overexpressed DEPP is co-localized with both protein aggregates and aggresomes. Further biochemical characterization indicates that DEPP protein is unstable and undergoes rapid degradation. Inhibition of proteasome activities significantly increases DEPP protein levels in soluble and insoluble cytosolic fractions. Attenuation of autophagosomal activity by 3-methyladenine increases DEPP protein levels while activation of autophagy by rapamycin reduced DEPP protein levels. In addition, ectopic overexpression of DEPP leads to autophagy activation, while silencing of DEPP attenuates autophagy. Collectively, these results indicate that DEPP is a major hypoxia-inducible gene involved in the activation of autophagy and whose expression is regulated by oxidative stress.
authors: Department of Medicine, University of Louisville, Louisville, KY 40202, USA; Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, KY 40202, USA.
authors: Marcus W
authors: MW
authors: Stepp
authors: Department of Medicine, University of Louisville, Louisville, KY 40202, USA; Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, KY 40202, USA.
authors: Rodney J
authors: RJ
authors: Folz
authors: Department of Medicine, University of Louisville, Louisville, KY 40202, USA; Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, KY 40202, USA.
authors: Jerry
authors: J
authors: Yu
authors: Department of Medicine, University of Louisville, Louisville, KY 40202, USA; Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, KY 40202, USA. Electronic address: igor.zelko@louisville.edu.
authors: Igor N
authors: IN
authors: Zelko
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001343:Autophagy; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D002522:Chlorocebus aethiops; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D006801:Humans; D000860:Hypoxia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress; D011506:Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000502:physiology*; D014709:Vero Cells
chemical_list: D015415:Biomarkers; C506096:DEPP1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C025946:3-methyladenine; C499090:Sod3 protein, mouse; D013482:Superoxide Dismutase; D000225:Adenine
keywords: Aggresomes; Autophagy; DEPP; Extracellular superoxide dismutase; Hypoxia; Oxidative stress