Src supports UDP-glucuronosyltransferase-2B7 detoxification of catechol estrogens associated with breast cancer.

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.

• Authors: Partha S Mitra, Nikhil K Basu, Ida S Owens
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 382 Issue 4 Pg. 651-6 (May 15 2009) ISSN: 1090-2104 [Electronic] United States
• PMID: 19289110 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• AG 1879
• Benzoquinones
• Estrogens, Catechol
• Lactams, Macrocyclic
• Protein Kinase Inhibitors
• Pyrimidines
• Receptors, Estrogen
• Rifabutin
• herbimycin
• Genistein
• UGT2B7 protein, human
• Glucuronosyltransferase
• src-Family Kinases
• Protein Kinase C

Topics

• Animals
• Benzoquinones (pharmacology)
• Breast Neoplasms (enzymology)
• COS Cells
• Chlorocebus aethiops
• DNA Damage
• Estrogens, Catechol (metabolism)
• Genistein (pharmacology)
• Glucuronosyltransferase (genetics, metabolism)
• Humans
• Lactams, Macrocyclic (pharmacology)
• Phosphorylation
• Protein Kinase C (antagonists & inhibitors, metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Pyrimidines (pharmacology)
• Receptors, Estrogen (metabolism)
• Rifabutin (analogs & derivatives)
• Transfection
• src-Family Kinases (antagonists & inhibitors, metabolism)