Accession Number:

ADA488056

Title:

Mechanistic Basis of Calmodulin Mediated Estrogen Receptor Alpha Activation and Antiestrogen Resistance

Descriptive Note:

Annual rept. 15 May 2007-14 May 2008

Corporate Author:

GEORGIA UNIV ATHENS

Personal Author(s):

Report Date:

2008-06-01

Pagination or Media Count:

38.0

Abstract:

Estrogen receptor alpha ERa is the principle chemotherapeutic target for estrogen dependent breast cancers. Calmodulin CaM is an obligatory ERa activator. Moreover, antiestrogens tamoxifen bind tightly to CaM, and some therapeutic benefits of antiestrogens for breast cancers are hypothesized to derive from this interaction. The purpose and scope of the research is to define the structural requisites of ERa activation by CaM and the relationship between tamoxifen binding to CaM, CaM oxidation and antiestrogen resistance. We localized a high affinity CaM binding site on ERa residues 287-311 and a second, low affinity site 241-273. We produced a protein construct for structural studies residues 286-552 and initiated structural studies of this complex. We determined that a shorter region of ERa 295-311, reported previously to be the CaM binding domain, does not represent the entire domain. We localized and quantified the structural changes that occur in CaM when bound to the high affinity CaM binding domain of ERa, and showed that this CaM binding region of ERa forms a helix when bound to CaM. Localization of the CaM binding sites of ERa is critical for understanding the CaM activation process. We also found that oxidation of the methionine residues in CaM abrogates the binding of tamoxifen and hydroxytamoxifen, suggesting oxididative stress contributions to development of antiestrogen resistance.

Subject Categories:

  • Anatomy and Physiology
  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE