Src supports UDP-glucuronosyltransferase-2B7 detoxification of catechol estrogens associated with breast cancer |
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Authors: | Partha S. Mitra Ida S. Owens |
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Affiliation: | Section on Genetic Disorders of Drug Metabolism, Program on Developmental Endocrinology and Genetics, National Institute of Child Health and Human Development, National Institutes of Health, Building 10, Room 9D-42, Bethesda, MD 20892-1830, USA |
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Abstract: | Mammary gland-distributed and ER-bound UDP-glucuronosyltransferase (UGT)-2B7 metabolizes genotoxic catechol-estrogens (CE) associated with breast cancer initiation. Although UGT2B7 has 3 PKC- and 2 tyrosine kinase (TK)-sites, its inhibition by genistein, herbimycin-A and PP2 with parallel losses in phospho-tyrosine and phospho-Y438-2B7 content indicated it requires tyrosine phosphorylation, unlike required PKC phosphorylation of UGT1A isozymes. 2B7 mutants at PKC-sites had essentially normal activity, while its TK-sites mutants, Y236F- and Y438F-2B7, were essentially inactive. Overexpression of regular or active Src, but not dominant-negative Src, in 2B7-transfected COS-1 cells increased 2B7 activity and phospho-Y438-2B7 by 50%. Co-localization of 2B7 and regular SrcTK in COS-1 cells that was dissociated by pretreatment with Src-specific PP2-inhibitor provided strong evidence Src supports 2B7 activity. Consistent with these findings, evidence indicates an appropriate set of ER proteins with Src-homology binding-domains, including 2B7 and well-known multi-functional Src-engaged AKAP12 scaffold, supports Src-dependent phosphorylation of CE-metabolizing 2B7 enabling it to function as a tumor suppressor. |
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Keywords: | UDP-glucuronosyltransferase (UGT) Catechol estrogen 4-Hydroxy estrone Phosphorylation Src Tyrosine kinase Curcumin PP2 Genistein Colocalization |
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