The calcium-binding domain of the stress protein SEP53 is required for survival in response to deoxycholic acid-mediated injury

Joanne Darragh, Mairi Hunter, Elizabeth Pohler, Lenny Nelson, John F. Dillon, Rudolf Nenutil, Borek Vojtesek, Peter E. Ross, Neil Kernohan, Ted R. Hupp

    Research output: Contribution to journalArticlepeer-review

    27 Citations (Scopus)

    Abstract

    Stress protein responses have evolved in part as a mechanism to protect cells from the toxic effects of environmental damaging agents. Oesophageal squamous epithelial cells have evolved an atypical stress response that results in the synthesis of a 53 kDa protein of undefined function named squamous epithelial-induced stress protein of 53 kDa (SEP53). Given the role of deoxycholic acid (DCA) as a potential damaging agent in squamous epithelium, we developed assays measuring the effects of DCA on SEP53-mediated responses to damage. To achieve this, we cloned the human SEP53 gene, developed a panel of monoclonal antibodies to the protein, and showed that SEP53 expression is predominantly confined to squamous epithelium. Clonogenic assays were used to show that SEP53 can function as a survival factor in mammalian cell lines, can attenuate DCA-induced apoptotic cell death, and can attenuate DCA-mediated increases in intracellular free calcium. Deletion of the highly conserved EF-hand calcium-binding domain in SEP53 neutralizes the colony survival activity of the protein, neutralizes the protective effects of SEP53 after DCA exposure, and permits calcium elevation in response to DCA challenge. These data indicate that the squamous cell-stress protein SEP53 can function as a modifier of the DCA-mediated calcium influx and identify a novel survival pathway whose study may shed light on mechanisms relating to squamous cell injury and associated cancer development.
    Original languageEnglish
    Pages (from-to)1930-1947
    Number of pages18
    JournalFEBS Journal
    Volume273
    Issue number9
    DOIs
    Publication statusPublished - 2006

    Keywords

    • Barrett's apoptosis
    • Calcium
    • SEP53
    • Stress response
    • Deoxycholic acid

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