In aging men, the prostate gland becomes hyperproliferative and displays a propensity toward carcinoma. Although this hyperproliferative process has been proposed to represent an inappropriate reactivation of an embryonic differentiation program, the regulatory genes responsible for normal prostate development and function are largely undefined. Here we show that the murine Nkx3.1 homeobox gene is the earliest known marker of prostate epithelium during embryogenesis and is subsequently expressed at all stages of prostate differentiation in vivo as well as in tissue recombinants. A null mutation for Nkx3.1 obtained by targeted gene disruption results in defects in prostate ductal morphogenesis and secretory protein production. Notably, Nkx3.1 mutant mice display prostatic epithelial hyperplasia and dysplasia that increases in severity with age. This epithelial hyperplasia and dysplasia also occurs in heterozygous mice, indicating haploinsufficiency for this phenotype. Because human NKX3.1 is known to map to a prostate cancer hot spot, we propose that NKX3.1 is a prostate-specific tumor suppressor gene and that loss of a single allele may predispose to prostate carcinogenesis. The Nkx3.1 mutant mice provide a unique animal model for examining the relationship between normal prostate differentiation and early stages of prostate carcinogenesis.

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It is widely accepted that the specific actions of transcriptional regulatory proteins are mediated through their selective association with other protein factors. Such interactions allow transcription factors to distinguish relevant target sequences from the many fortuitous binding sites in the genome and confer highly precise transcriptional regulatory properties. Selective protein-protein interactions are thought to be particularly important for specifying the actions of homeodomaincontaining transcriptional regulatory proteins. Homeoproteins are notorious for their promiscuous DNA binding specificities, which contrast with their highly selective biological functions. It is therefore presumed that specificity is achieved through their interactions with other protein factors. Protein-protein interactions are likely to be particularly important for specifying the transcriptional activities of Msx homeoproteins. The murine Msx family includes three members, two of which (Msx1 and Msx2) have been well characterized with respect to their DNA binding and transcriptional properties (3-5, 40, 43) and one of which (Msx3) has been recently described (14, 33). The homeodomain sequences of Msx proteins are highly conserved (Ͼ90%), and Msx proteins also share several other conserved features, including nearly identical sequences that flank the homeodomain (the extended homeodomain [EHD]) and three other regions of similarity located N terminal and C terminal of the homeodomain (Msx homology regions) (see Fig. 1). In addition, the DNA binding specificities of Msx1 and Msx2 are virtually identical, and both proteins function as transcriptional repressors (4, 40). Moreover, Msx1 and Msx2 share an unusual feature in which repression is mediated through interactions with other protein factors rather than binding to homeodomain DNA sites (4,5,43). Therefore, the Msx1 homeodomain interacts directly with the TATA-binding protein (TBP), and the residues in the homeodomain that mediate this interaction are also required for repression by Msx1 (43). However, the ability of Msx proteins to regulate specific target genes undoubtedly requires additional, as yet undefined, interactions with protein factors that exhibit tissuerestricted expression and promoter-specific activities.The embryonic expression patterns of Msx genes, as well as the phenotypic consequences of targeted disruption of Msx1, are consistent with a role for Msx proteins in inductive signaling between epithelial and mesenchymal tissues. Msx genes are expressed primarily in regions of epithelial-mesenchymal interactions, such as the limb bud, tooth, heart, and neural tube (2,4,6,9,13,18,22,23,25,31), and targeted disruption of Msx1 leads to significant defects in the development of craniofacial structures (32). Moreover, a role for Msx proteins in active morphogenesis is further suggested by the lack of Msx1 expression in cells undergoing terminal differentiation (35,40) and by the restricted expression of Msx1 transcripts during periods of rapid cellular proliferatio...

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The chemotactic cytokine interleukin 8 (IL-8) is produced upon stimulation by various agents in many cell types, including connective-tissue fibroblasts. Tumor An earlier study described a set of genes activated by TNF in human fibroblasts (8). Some of the genes activated by TNF were also inducible by IFN-,3 or IFN-y. In contrast, IFN-,B or IFN-y inhibited the TNF-induced expression of one of these genes, termed TSG-1. Sequencing of the TSG-1 cDNA revealed that this gene was identical to the gene encoding an important inflammatory cytokine known as IL-8 or NAP-1 (8). IL-8 is a member ofthe family of8-to 10-kDa chemotactic cytokines that includes platelet factor 4, IP-10, Gro, macrophage inflammatory peptides 1 and 2, macrophage chemotactic and activating factor, and several others (reviewed in refs. 15 and 16). In the present study we investigated the inhibitory actions of IFN-13 on TNF-induced IL-8 gene expression in human fibroblasts. Our data indicate that IFN treatment leads to a selective depletion of IL-8 mRNA; this inhibitory effect correlates with a decrease in the rate of IL-8 mRNA transcription. The mechanism responsible for this action appears to be unique in that the inhibitory effect of IFN is established very rapidly and it is not diminished in the presence of inhibitors of protein synthesis, consistent with the idea that this effect is due to a transient modification of a preexisting factor. MATERIALS AND METHODSMaterials. Recombinant human TNF-a (specific activity, 3x 107 units/mg) and IFN-y (5 x 106 units/mg) were from M. Tsujimoto, Suntory Institute for Biomedical Research, Osaka. Escherichia coli-derived recombinant human IFN-f3 (Betaseron, 2 X 108 units/mg) was from Triton Biosciences, Alameda, CA, and recombinant human IFN-p derived from CHO cells (Betaferon, 3 x 108 units/mg) was provided by Wieland Wolf, Bioferon, Laupheim, Germany. The E. coliderived IFN-/3 preparation was used unless specified. Re