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PM16 Molecular Indicators for Ecological Exposure
(PM262) Mya arenaria HECT E3 ubiquitin-protein ligase does not target p53 for degradation in gonadal tumors.
Olberding, K1, Kelley, M2, Butler, R1, Van Beneden, R1, 1 University of Maine, Orono, ME, USA2 University of Texas at Austin, Austin, TX, USA
ABSTRACT- Environmental exposure to pollutants, such as dioxin, has been implicated in gonadal tumor formation in Maine softshell clams (Mya arenaria). Prevalence of these tumors ranges from 20-40% in specific populations in eastern Maine. Although their etiology is still unknown, investigations into the mechanisms of tumor formation have revolved around a hypothesis of dioxin-induced toxicity. Initial investigations of the clam aryl hydrocarbon receptor (AHR) revealed that it did not bind the prototypical ligand, 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD), suggesting that dioxin toxicity is mediated through an AHR-independent pathway. An alternative mechanism of tumor formation was investigated, involving a protein with significant sequence similarity to mammalian E6AP, a HECT (homologous to E6AP carboxy terminus) E3 ubiquitin-protein ligase. E6AP, in association with the high-risk human papillomavirus (HPV) E6 protein, is involved in the abnormal degradation of the p53 tumor suppressor protein in human cervical cancer. Tumorigenic clam reproductive tissue revealed higher M. arenaria E3 (MaE3) protein levels concomitant with lower M. arenaria p53 (Map53) protein levels relative to nontumor-bearing clams. The ability of MaE3 to bind ubiquitin was verified. However, three methods demonstrated that MaE3 does not directly associate with Map53 suggesting that changes in Map53 levels in gonadal tumors are mediated by a different mechanism. Due to upregulation of MaE3 in neoplastic reproductive tissue, further investigations will focus on determining the proteolytic targets of MaE3. The results from our ongoing investigations suggest a complex etiology for the clam germinomas.
Key words: p53, bivalve, germinoma, dioxin
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