The primary long-term objective of this research is to understand the role of AKT-signaling cross-talk with the estrogen receptor (ER) in the control of cell survival and in the development of anti-estrogen resistance. We hypothesize that the AKT pathway functions to target and phosphorylate the p160 coactivator GRIP and ER proteins leading to regulation of CoA-recruitment, receptor-activation and gene expression. We further hypothesize that convergence of the AKT and estrogen signaling at the ER-CoA-transcriptional level is critical in the regulation of cell survival and influences selective estrogen receptor modulator (SERM) activity in hormone dependent cell systems such as breast carcinoma.
The Specific Aims are proposed to 1) Determine the mechanisms of AKT-ER cross-talk by examining specific targeting, phosphorylation and activation of ER-AF2 and/or the p160 CoA GRIP by AKT and 2) Determine the physiological relevance of this cross-talk by examining effects of AKT-ER-CoA on the regulation of endogenous estrogen-responsive genes, alteration of SERM-activity and gene expression, and long-term cell survival.
Specific Aim #1, To determine the role of AKT targeting and phosphorylation of ER-AF2 as a mechanism for cross-talk. We propose to determine if the ER-AF2 targeting occurs through direct phosphorylation by AKT and the role of specific phosphorylation sites in AKT-ER cross-talk.
Specific Aim #2, To implicate AKT regulation of p160 coactivator-(GRIP) phosphorylation as a mechanism for activation of and recruitment to estrogen receptors. Studies will determine if AKT phosphorylates and activates GRIP though specific targeting of the GRIP-NRID (nuclear receptor interaction domain) or GRIP-AD2 (activation domain-2) as mechanisms for AKT regulation of GRIP in control of ER transcription.
Specific Aim #3, to determine the requirement for GRIP phosphorylation/function in AKT-mediated regulation of ER-dependent cell survival, gene expression and SERM activity. In this aim, we will determine the role for specific AKT induced ER-CoA recruitment/activation in the regulation of cell survival gene expression (Bcl-2) and the influence of AKT-ER-CoA cross-talk on SERM activity. These studies will also determine if the mechanisms for AKT-phosphorylation of ER or GRIP from above are critical in the AKT-ER mediated regulation of cell survival. It is expected as a whole that this proposal will establish the mechanisms used by the investigator3K-AKT cascade to target the ER and the subsequent components of the ER transcription complex required for potentiation of activity by this pathway. This cross-talk and the mechanisms identified will be used to establish the biological relevancy of the pathway in terms of cell survival and altered SERM activity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK059389-05
Application #
7163550
Study Section
Biochemical Endocrinology Study Section (BCE)
Program Officer
Margolis, Ronald N
Project Start
2003-02-18
Project End
2008-12-31
Budget Start
2007-01-01
Budget End
2007-12-31
Support Year
5
Fiscal Year
2007
Total Cost
$281,609
Indirect Cost
Name
Tulane University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
053785812
City
New Orleans
State
LA
Country
United States
Zip Code
70118
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Bratton, Melyssa R; Frigo, Daniel E; Segar, H Chris et al. (2012) The organochlorine o,p'-DDT plays a role in coactivator-mediated MAPK crosstalk in MCF-7 breast cancer cells. Environ Health Perspect 120:1291-6
Bratton, Melyssa R; Antoon, James W; Duong, Bich N et al. (2012) Gýýo potentiates estrogen receptor ýý activity via the ERK signaling pathway. J Endocrinol 214:45-54
Antoon, James W; Bratton, Melyssa R; Guillot, Lori M et al. (2012) Pharmacology and anti-tumor activity of RWJ67657, a novel inhibitor of p38 mitogen activated protein kinase. Am J Cancer Res 2:446-58
Martin, Elizabeth C; Bratton, Melyssa R; Zhu, Yun et al. (2012) Insulin-like growth factor-1 signaling regulates miRNA expression in MCF-7 breast cancer cell line. PLoS One 7:e49067
Rhodes, Lyndsay V; Short, Sarah P; Neel, Nicole F et al. (2011) Cytokine receptor CXCR4 mediates estrogen-independent tumorigenesis, metastasis, and resistance to endocrine therapy in human breast cancer. Cancer Res 71:603-13
Antoon, James W; Meacham, William D; Bratton, Melyssa R et al. (2011) Pharmacological inhibition of sphingosine kinase isoforms alters estrogen receptor signaling in human breast cancer. J Mol Endocrinol 46:205-16
Bratton, Melyssa R; Duong, Bich N; Elliott, Steven et al. (2010) Regulation of ERalpha-mediated transcription of Bcl-2 by PI3K-AKT crosstalk: implications for breast cancer cell survival. Int J Oncol 37:541-50
Antoon, James W; White, Martin D; Meacham, William D et al. (2010) Antiestrogenic effects of the novel sphingosine kinase-2 inhibitor ABC294640. Endocrinology 151:5124-35
Zimmermann, M Carla; Tilghman, Syreeta L; Boué, Stephen M et al. (2010) Glyceollin I, a novel antiestrogenic phytoalexin isolated from activated soy. J Pharmacol Exp Ther 332:35-45

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