A HECT E3 ubiquitin-protein ligase with sequence similarity to E6AP does not target p53 for degradation in the softshell clam (Mya arenaria).
Numerous reports have raised the level of national concern that chemicals found in the environment may have adverse effects on the health of humans and wildlife. Environmental exposure to pollutants, such as dioxin, has been implicated in gonadal tumor formation in Maine softshell clams (Mya arenaria). Prevalence of these tumors is as high as 40% in some populations. Although their etiology is still unknown, investigations into the mechanisms of tumor formation have revolved around a hypothesis of dioxin-induced toxicity. The aryl hydrocarbon receptor (AHR) was initially investigated, but was later determined to 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 has been 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) levels. While the function of MaE3 as a HECT E3 was verified, results from three methods agree that MaE3 does not associate with Map53. However, alteration in Map53 levels may still play a role in clam gonadal tumorigenesis. Due to upregulation of MaE3 in neoplastic reproductive tissue, further investigations will focus on determining the proteolytic targets of MaE3. In conjunction with our previous findings that dioxin toxicity in the softshell clam is not mediated by AHR, the results from our current investigation suggest a complex etiology for the clam germinomas.
Department of Biochemistry, Microbiology and Molecular Biology, University of Maine, 5751 Murray Hall, Orono, ME 04469, USA.
Kristen E
KE
Olberding
Melissa L
ML
Kelley
Rondi A
RA
Butler
Rebecca J
RJ
Van Beneden
D000818:Animals; D049872:Bivalvia / Q000235:genetics*; D005260:Female; D016158:Genes, p53 / Q000187:drug effects*; D006066:Gonads; D008297:Male; D016297:Mutagenesis, Site-Directed; D009369:Neoplasms / Q000378:metabolism; D009856:Oncogene Proteins, Viral / Q000378:metabolism; D012097:Repressor Proteins; D020798:Two-Hybrid System Techniques; D044767:Ubiquitin-Protein Ligases / Q000494:pharmacology*
C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D012097:Repressor Proteins; D044767:Ubiquitin-Protein Ligases