4.6 Article

Peptidylprolyl Isomerase Pin1 Directly Enhances the DNA Binding Functions of Estrogen Receptor α

Journal

JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 290, Issue 22, Pages 13749-13762

Publisher

AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M114.621698

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Funding

  1. McArdle Laboratories for Cancer Research

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The transcriptional activity of estrogen receptor alpha (ER alpha), the key driver of breast cancer proliferation, is enhanced by multiple cellular interactions, including phosphorylation-dependent interaction with Pin1, a proline isomerase, which mediates cis-trans isomerization of the N-terminal Ser(P)(118)-Pro(119) in the intrinsically disordered AF1 (activation function 1) domain of ER alpha. Because both ER alpha and Pin1 have multiple cellular partners, it is unclear how Pin1 assists in the regulation of ER alpha transactivation mechanisms and whether the functional effects of Pin1 on ER alpha signaling are direct or indirect. Here, we tested the specific action of Pin1 on an essential step in ER alpha transactivation, binding to specific DNA sites. DNA binding analysis demonstrates that stable overexpression of Pin1 increases endogenous ER alpha DNA binding activity when activated by estrogen but not by tamoxifen or EGF. Increased DNA binding affinity is a direct effect of Pin1 on ER alpha because it is observed in solution-based assays with purified components. Further, our data indicate that isomerization is required for Pin1-modulation of ER alpha DNA interactions. In an unbiased in vitro DNA binding microarray with hundreds of thousands of permutations of ER alpha-binding elements, Pin1 selectively enhances the binding affinity of ER alpha to consensus DNA elements. These studies reveal that Pin1 isomerization of phosphorylated ER alpha can directly regulate the function of the adjacent DNA binding domain, and this interaction is further modulated by ligand binding in the ligand-binding domain, providing evidence for Pin1-dependent allosteric regulation of ER alpha function.

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