Regulation of prostatic genes: role of androgens and zinc in gene expression

Matusik, Robert J.; Kreis, Christophe; McNicol, Patricia J.; Sweetland, Robert; Mullin, Carola; Fleming, William H.; Dodd, Janice G.

doi:10.1139/o86-083

Cited by 72 publications

(36 citation statements)

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“…In humans, Zn intake is positively correlated with circulating levels of insulinlike growth factor 1 (Holmes et al 2002) and testosterone (Prasad et al 1996) that are directly related to the proliferation of prostate cell (Leake et al 1984). By now, much data has been obtained related both to the direct and indirect actions of Zn on the DNA polymeric organization, replication and lesions, and to its vital role for cell division (Schwartz 1975;Matusik et al 1986;Blok et al 1995). Moreover, it is known that Zn is an inhibitor of the Ca-dependent apoptotic endonuclease, which takes part in the internucleosomal fragmentation of DNA.…”

Section: Discussionmentioning

confidence: 99%

Age-related histological and zinc content changes in adult nonhyperplastic prostate glands

Zaichick

2013

AGE

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To clarify age-related histological and Zn content changes in nonhyperplastic adult prostate glands, a quantitative morphometric and energy-dispersive X-ray fluorescence analyses were performed. The prostates were obtained from autopsies of 63 subjects aged 21-70 years who died mainly from trauma. It was found that histologically normal prostate tissue undergoes substantial changes throughout aging. These changes are reflected in an increase of the percent volume of the glandular lumen for the third to fifth decades, reaching a maximum for the decade 41-50 years. Over the same period, the percent volume of the stroma remains steady, but the percent volume of epithelium decreases, approximately, linearly with age. The percent volume of glandular lumen (reflects the volume of prostatic fluid) in the prostate gland of men aged 41 to 50 years is 1.5-fold higher than that in men aged 21 to 30 years, but the epithelium/lumen (prostatic fluid) ratio is approximately twofold lower. This suggests that accumulation of the prostatic fluid develops from 30 to 50 years of age. This accumulation of the prostatic fluid results in an increase of the Zn mass fraction in the prostate. In turn, when the intraprostatic Zn level exceeds a certain level by the end of the fifth decade, it begins to work as a trigger for different factors, all of which increase the proliferation of stromal cells. Deductions from these results allow possible partial explanations of both relevant prostatic aging mechanisms and the effects of dietary interventions using supplementary Zn.

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Section: Discussionmentioning

confidence: 99%

Age-related histological and zinc content changes in adult nonhyperplastic prostate glands

Zaichick

2013

AGE

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“…The rPB gene encodes an androgen-and zinc-regulated protein specific to the dorsolateral epithelium (6)(7)(8). Isolation of the rPB gene has facilitated identification of cis-acting androgen-response regions within the 5' flanking region (9).…”

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confidence: 99%

Prostate cancer in a transgenic mouse.

Greenberg

DeMayo

Finegold

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

1,161

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Progress toward understanding the biology of prostate cancer has been slow due to the few animal research models available to study the spectrum of this uniquely human disease. To develop an animal model for prostate cancer, several lines of transgenic mice were generated by using the prostate-specific rat probasin promoter to drive expression of the simian virus 40 large tumor antigencoding region. Mice expressing high levels of the transgene display progressive forms of prostatic disease that histologically resemble human prostate cancer, ranging from mild intraepithelial hyperplasia to large multinodular malignant neoplasia. Prostate tumors have been detected specirically in the prostate as early as 10 weeks ofage. Immunohistochemical analysis of tumor tissue has demonstrated that dorsolateral prostate-specific secretory proteins were confined to welldifferentiated ductal epithelial cells adjacent to, or within, the poorly differentiated tumor mass. Prostate tumors in the mice also display elevated levels of nuclear p53 and a decreased heterogeneous pattern of androgen-receptor expression, as observed in advanced human prostate cancer. The establishment of breeding lines of transgenic mice that reproducibly develop prostate cancer provides an animal model system to study the molecular basis of transformation of normal prostatic cells and the factors influencing the progression to metastatic prostate cancer.Prostate cancer will likely claim the lives of 35,000 men in the United States this year alone, and some 200,000 more men will be diagnosed with the disease (1). However, progress toward understanding the biology of prostate cancer and the development of new therapies for this disease has been slowed, in part, by the need for in vivo model systems that adequately reproduce the spectrum of benign, latent, aggressive, and metastatic forms of the human disease.Prostate cancer is a disease quite unique to man. Although naturally occurring prostatic disease has been reported in some canine (2) and rodent (3-5) species, these animals have not provided the appropriate models to adequately study the molecular mechanisms related to the early development and progression of human prostate cancer. To this end, we initiated a research program to establish a transgenic animal model for prostate cancer by using a prostate-specific transgene expression system that has been developed in our laboratories based on the regulatory elements of the rat probasin (rPB)-encoding gene.The rPB gene encodes an androgen-and zinc-regulated protein specific to the dorsolateral epithelium (6-8). Isolation of the rPB gene has facilitated identification of cis-acting androgen-response regions within the 5' flanking region (9). More recently, the ability of the prostate-specific rPB gene promoter to target heterologous genes specifically to the prostate in transgenic mice has been demonstrated (10). InThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "adver...

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“…The expression of PB is prostate specific and is regulated by androgens and zinc. [4][5][6] Genomic analysis demonstrates that PB is found in a lipocalin cluster on the rodent X-chromosome and that the human syntenic X-chromosomal region is deleted. Six epididymal-specific lipocalins have evolved by in situ tandem duplication resulting in a locus of genes that show highly segment-specific expression patterns in the epididymis with different modes of regulation.…”

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Use of tissue recombination to predict phenotypes of transgenic mouse models of prostate carcinoma

Ishii

Shappell

Matusik

et al. 2005

Laboratory Investigation

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Transgenic mouse models of cancer represent a powerful approach for exploring disease processes and testing potential therapeutic interventions. Currently, it is difficult to predict if a specific genetic manipulation will result in a desirable phenotype. The present study tests the idea that tissue recombinants recapitulate the pathologic features of the neoplastic prostate seen in transgenic mice, and would thus be suitable predictive models for new mouse design. The large probasin-large T-antigen (LPB-Tag) transgenic lines 12T-7f and 12T-10 were used as a basis for this study. Tissue recombinants of bladder epithelium (BlE) and urogenital sinus mesenchyme (UGM) were implanted under the renal capsule of athymic mice. Recombinants composed of BlE from 12T-10 LPB-Tag and wild-type (wt) UGM faithfully recapitulated the histopathologic and temporal features of intact transgenic mice of this line. Tissue recombinants using BlE from 12T-7f mice and wt UGM developed epithelial proliferation with atypia that lacked the associated hypercellular stroma seen in the intact 12T-7f line. Recombinants using 12T-7f UGM demonstrated that the hypercellular stroma results from stromal cell expression of the SV40 large T antigen. Corresponding to the recombinant phenotypes, stromal Tag immunostaining was observed in prostate tissues from intact 12T-7f but not 12T-10 mice. Similar stromal expression of Tag was also noted in the hypercellular TRAMP prostatic stroma. Further analysis revealed a previously unreported pattern of SV40T expression in the LADY and TRAMP models including ductus deferens and seminal vesicle stroma as well as region and cell type-specific patterns in the epididymis. The present study demonstrates the utility of using tissue recombination to explore organ-specific phenotypes. Recombination strategies should enable quick and cost-effective screening for likely phenotypes in transgenic animals. This comparison of tissue recombination to existing models shows that this approach can elicit new information on well-characterized models.

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Regulation of prostatic genes: role of androgens and zinc in gene expression

Cited by 72 publications

References 1 publication

Age-related histological and zinc content changes in adult nonhyperplastic prostate glands

Age-related histological and zinc content changes in adult nonhyperplastic prostate glands

Prostate cancer in a transgenic mouse.

Use of tissue recombination to predict phenotypes of transgenic mouse models of prostate carcinoma

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