title: c-Abl regulates estrogen receptor alpha transcription activity through its stabilization by phosphorylation.
abstract: Estrogen receptors are members of the steroid hormone superfamily of nuclear receptors that act as ligand-activated transcription factors. Similar to other steroid hormone receptors, estrogen receptor alpha (ERalpha) is a substrate for protein kinases, and phosphorylation has profound effects on the function of this receptor. In this study, we show that ERalpha associates with c-Abl nonreceptor tyrosine kinase. The direct interaction is mediated by two PXXP motifs of ERalpha and the c-Abl SH3 domain. Mutational analysis and in vitro kinase assays show that ERalpha can be phosphorylated on two sites, tyrosine 52 (Y-52) and tyrosine 219 (Y-219). ERalpha phosphorylation by c-Abl stabilizes ERalpha, resulting in enhanced ERalpha transcriptional activity and increased expression of endogenous ERalpha target genes. Furthermore, ERalpha phosphorylation at the Y-219 site affects DNA binding and dimerization by ERalpha. Both the c-Abl inhibitor and the c-Abl kinase dead mutation abolish the c-Abl-induced accumulation of ERalpha and enhancement of ERalpha transcriptional activity, indicating that c-Abl kinase activity is required for regulation of the ERalpha function. Moreover, the ERalpha (Y52,219F) mutant shows reduced breast cancer cell growth and invasion. Taken together, these results show that c-Abl is a novel kinase that upregulates ERalpha expression and promotes breast cancer cell proliferation, suggesting a great potential for this kinase to function as a therapeutic target for breast cancer.
authors.affiliation: State key Laboratory of Pathogen and Biosecurity, Beijing Institute of Biotechnology, Beijing, PR China.
authors.forename: X
authors.initials: X
authors.lastname: He
authors.forename: Z
authors.initials: Z
authors.lastname: Zheng
authors.forename: T
authors.initials: T
authors.lastname: Song
authors.forename: C
authors.initials: C
authors.lastname: Wei
authors.forename: H
authors.initials: H
authors.lastname: Ma
authors.forename: Q
authors.initials: Q
authors.lastname: Ma
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: Y
authors.initials: Y
authors.lastname: Xu
authors.forename: W
authors.initials: W
authors.lastname: Shi
authors.forename: Q
authors.initials: Q
authors.lastname: Ye
authors.forename: H
authors.initials: H
authors.lastname: Zhong
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004247:DNA / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D055503:Protein Multimerization; D055550:Protein Stability; D020836:Protein Structure, Quaternary; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: D047628:Estrogen Receptor alpha; D004247:DNA; D016315:Proto-Oncogene Proteins c-abl