Animal development is specified by a family of transcription factors; each carrying a DNA-recognition motif referred to as the homeodomain. Nkx3.1 is one member of this extended family, and a homeodomain protein that specifies the development of the human and mouse prostate gland. Indeed, Nkx3.1 is the earliest known marker of prostate differentiation. Inactivation of Nkx3.1 leads to prostate hyperplasia and prostatic intraepithelial neoplasia (PIN) in mice, and a large fraction of advanced human prostate tumors exhibit little or no Nkx3.1 expression. Despite intensive efforts to elucidate mechanisms used by homeodomain proteins to coordinate animal development, little is known about how tissue-specific target genes are identified and regulated. This deficiency in our knowledge extends to the mechanism(s) by which Nkx3.1 regulates prostate-specific gene expression. Evidence from a variety of species, including yeast, Drosophila, zebrafish, mice, and humans suggests that homeodomain proteins may collaborate with zinc-""""""""finger""""""""-containing transcription factors to identify and regulate target genes. Consistent with these reports, preliminary data supplied in this proposal indicates that Nkx3.1 and members of the Sp/XKLF-family of transcription factors physically interact via the zinc-""""""""finger"""""""" portion of the latter proteins. Additionally, we provide evidence that (i) Nkx3.1 and a subset of Sp/XKLF proteins collaborate in the regulation of the human prostate-specific antigen (PSA) promoter, (ii) Nkx3.1 regulates PSA transcription by HDAC1-dependent and -independent mechanisms, (iii) a discrete portion of the PSA promoter is required for regulation of Sp/XKLF proteins by Nkx3.1, (iv) Sp/XKLF and Nkx3.1 proteins can form ternary protein/DNA complexes, and (v) binding sites for Sp/XKLF proteins map to the amino-terminus and homeodomain of Nkx3.1. Studies proposed here exploit these preliminary observations and are designed to determine the mechanism(s) by which Nkx3.1 regulates Sp/XKLF proteins and prostate-specific gene expression. Additionally, our proposed studies seek to identify novel Nkx3.1-associated proteins and define the mechanisms utilized by Nkx3.1 to regulate prostate cell growth and differentiation.
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