The Role of Foxa Proteins in the Regulation of Androgen Receptor Activity
Activation of the androgen receptor is required for normal prostate physiology and in controlling the growth prostate cancer. However, the fact that multiple target organs express androgen receptor and are exposed to circulating androgens, yet fail to express prostate-specific markers and fail to develop androgen-dependent cancers, indicates that androgen receptor alone is not sufficient to dictate normal function and progression to cancer. Therefore, androgen action can be restricted in a given tissue by transcription factors that serve as co-regulators of androgen receptor. How androgen signaling acts in concert with other transcription factors, resulting in tissue-specific gene expression needs to be understood. The establishment of unique transcription factor regulatory networks is responsible, at least in part, to control androgen receptor action (1) in tissue-specific gene expression; (2) organ determination; and (3) cell differentiation. The identification of TF networks involved in these disparate events will allow researchers to elucidate the mechanisms that control prostate development, function, and pathology. Experimental evidence generated by our laboratory and others indicates that members of the Foxa subfamily of transcription factors play an important role in (1) normal prostate development; (2) the determination of prostatic cell fate; and (3) specific types of prostate pathology. This chapter reviews evidence generated by our laboratory and others regarding the important role of the Foxa transcription factors in the regulation of prostate-specific gene regulatory networks.
KeywordsAndrogen Receptor LNCaP Cell Androgen Receptor Expression Foxa2 Expression Foxa Family
This research was supported by National Institute of Health (NIH) grants to Robert J Matusik (R01-CA76142, R01-DK55748, and R01-AG023490) and Frances Williams Preston Laboratories of the T.J. Martell Foundation; and by an NIH grant to Marie-Claire Orgebin-Crist (R01-HD36900). Janni Mirosevich is a recipient of the Department of Defense (DOD) Postdoctoral David J. DeGraff was supported by the VUMC Multidisciplinary Training Grant in Molecular Endocrinology (5 T32 DK007563-21). Traineeship Award (W81XWH-04-1-0050), Qian Sun is the recipient of a DOD Predoctoral Traineeship Award (W81XWH-07-1-0042) and Srinivas Nandana is the recipient of a DOD Predoctoral Traineeship Award (W81XWH-07-1-0155). The authors wish to acknowledge the assistance of Sherri Tomlinson in the preparation of this manuscript.
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