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V X Jin, H Sun, T T Pohar, S Liyanarachchi, S K Palaniswamy, T H-M Huang and R V Davuluri

Introduction The estrogen receptors (ER) α and β are steroid hormone receptors that play important roles in the normal development of various organs, such as the brain, heart, bone, breast, uterus and prostate. Malignancy of the ER

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Barry V L Potter

% of endometrial cancer patients. Thus, STS as a prognostic factor in endometrial cancer patients requires more analysis. Prostate cancer Androgen-dependent prostate cancer represents a very large unmet medical need. STS activity has been

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Marta Labeur, Barbara Wölfel, Johanna Stalla and Günter K Stalla

predominantly expressed in prostate and brain ( Uchida et al . 1999 , Horie et al . 2000 , Liang et al . 2000 , Glynne-Jones et al . 2001 , Young et al . 2001 , Gery et al . 2002 ) and has been implicated in cell signaling ( Uchida et al . 1999

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N Rosemblit and C-L C Chen

ABSTRACT

Clusterin, also known as sulphated glycoprotein-2 or testosterone-repressed prostate message-2, is a ubiquitous protein found in a variety of tissues and species. In the reproductive tract of the male rat, clusterin is regulated in a complex age-dependent and cell-specific manner. It is expressed at high levels in the epididymis and testis and at very low levels in the prostate under basal conditions. The expression of this gene in the prostate and seminal vesicles is associated with androgen withdrawal, while in the testis clusterin mRNA is repressed by cyclic AMP (cAMP). To understand the mechanisms that control the expression of the clusterin gene better, we isolated and characterized the gene encoding rat clusterin, and analysed its cytosine methylation pattern in various tissues. Several putative regulatory DNA elements were identified, including a consensus AP-1 site in the 5′ flanking region. Two AP-1 sites and two transforming growth factor-β inhibitory elements, one AP-2 site and eight half-sites for glucocorticoid/androgen response elements were found within the first intron, and one cAMP response element was found in the first exon. The cytosine methylation pattern indicated that testicular or epididymal DNA in the rat is hypomethylated in the region between positions −534 and −99 of the clusterin gene, when compared with tissues with lower levels of expression such as prostate as well as liver, lung, kidney and spleen.

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Suryaprakash Raichur, Patrick Lau, Bart Staels and George E O Muscat

and RORγt. RORγ1 is preferentially expressed in skeletal muscle and several other tissues, including pancreas, thymus, prostate, liver and testis of human ( Hirose et al. 1994 , Ortiz et al. 1995 ). RORγt isoform lacks 20 amino acids at amino

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JL Garibay-Tupas, S Bao, MT Kim, LS Tashima and GD Bryant-Greenwood

The human has two relaxins, termed H1 and H2, both of which are biologically active and co-expressed in the decidua, placenta and prostate; in the corpus luteum, the main source of circulating relaxin, only the H2 form is expressed. The reasons for this differential expression of the relaxin genes are unknown. The possibility that their 3'-untranslated regions (UTRs) contribute to this differential expression by affecting their mRNA stabilities was investigated. Thus the 3'-UTRs of both relaxin genes were isolated through a combined 3'-rapid amplification of cDNA ends-PCR (RACE-PCR) using poly (A)(+)RNA from human decidua, placenta, prostate and corpus luteum. The sequences obtained for each 3'-UTR were identical in the tissues examined, were AT-rich (72%) and showed 91% homology between relaxin H1 and H2 when maximally aligned to include several gaps, the significance of which is unknown. Relaxin H1 has two, and relaxin H2 has one, poly (A)(+) signal, in addition to one cytoplasmic polyadenylation element 30 nucleotides upstream of this. The mRNA levels of relaxin H1 and H2 in the prostate adenocarcinoma LNCaP.FGC cell line were determined by quantitative competitive RT-PCR. Relaxin H1 had a 10-fold greater number of molecules (approximately 2.5x10(7)) per microgram of total RNA than relaxin H2 (approximately 2.5x10(6)). The stability of relaxin H1 and H2 mRNAs were compared in LNCaP cells treated with the transcription inhibitor actinomycin D (10 mM) for 0, 1, 2, 4, 8, 10, 14, or 24 h. Half-lives of 3.17 days for relaxin H1 mRNA and 11. 4 h for relaxin H2 mRNA were obtained from semi-logarithmic plots. Thus both mRNAs are relatively stable; however, relaxin H1 mRNA is considerably more stable than relaxin H2, at least in LNCaP cells. This difference in their mRNA stability may partly explain the greater level of expression of relaxin H1 in these cells.

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B Nan, T Snabboon, E Unni, Yuan X-J, YE Whang and M Marcelli

To investigate whether the tumor suppressor gene PTEN affects the activity of the androgen receptor (AR), we monitored the expression of the apoptotic gene HA-Bax (inserted in an adenovirus where it is driven by the AR-responsive promoter ARR(2)PB) in the presence or absence of dihydrotestosterone, in PTEN (+) or (-) prostate cancer cell lines, infected with an adenovirus containing wild-type PTEN (Av-CMV-PTEN) or a control LacZ-expressing construct. Our results showed that AR transcriptional activity was antagonized by PTEN expression. This antagonism was not cell line dependent, as it was observed in both LNCaP and LAPC-4 cells, or promoter dependent, as it was observed for a reporter gene (HA-Bax) driven by an exogenous androgen-responsive promoter (the ARR(2)PB promoter), and for a native gene (prostate-specific antigen; PSA) driven by an endogenous AR-responsive promoter. Additional experiments performed with viruses containing constitutively active (Adeno-myrAkt) or dominant negative (Adeno-dnAkt) forms of Akt demonstrated that Akt, a protein kinase whose activation is known to be inhibited by PTEN, mediated the observed antagonism between PTEN and AR transcriptional activity. Recently, two putative Akt phosphorylation sites have been identified in the AR sequence. Site-directed mutagenesis was utilized to convert these two serine into alanine residues. The resulting construct, named CMV-AR S213A&S791A was transfected in AR (-) and PTEN (-) PC-3 cells in the presence or absence of Av-CMV-PTEN and of two reporter plasmids (GRE(2)E1b-Luc and PSA P/E-luc) containing the luciferase gene driven by well-characterized androgen responsive promoters. These experiments demonstrated that, similarly to the wild-type molecule, AR S213A&S791A was transcriptionally inhibited by PTEN, suggesting that Akt does not have an effect on AR transcription by direct phosphorylation, but probably by affecting the availability of a downstream molecule whose main mechanism of action is that of modulating AR transcription. The data presented here suggest that loss of PTEN function may facilitate activation of AR signaling and progression to androgen independence in prostate cancer.

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C Keil, B Husen, J Giebel, G Rune and R Walther

In the present study we demonstrate for the first time the expression of glycodelin mRNA in the female and male genital tracts of rats using non-radioactive in situ hybridisation. Glycodelin fragment 1 (+41 to +141) shares 100% homology with the human gene sequence. In the ovary, glycodelin mRNA was restricted to granulosa cells. In the uterus, glycodelin mRNA was expressed in all epithelial cells of the endometrium. In the male reproductive tract, glycodelin mRNA was distributed in all epithelial cells of the epididymis, the prostate and the seminal vesicle. However, in the testis, glycodelin mRNA was predominantly found in spermatogonia and in spermatocytes of the seminiferous epithelium. The expression in several reproductive organs of rats offers an excellent tool to study further the physiological role of glycodelin, which is so far thought to act as an immunosuppressive factor.

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KV Desai and P Kondaiah

The male accessory sex organs and epididymis regress following androgen depletion, although the onset of apoptosis varies temporally depending upon the tissue type. Transforming growth factor-beta1 (TGF-beta1) is an androgen-repressed gene and believed to be an apoptotic agent in the regressing rat ventral prostate (VP). Hence, in order to investigate the status of TGF-beta isoforms following castration in androgen-dependent tissues other than VP, this study was undertaken. Northern blot analysis using total RNA from these tissues of intact animals showed higher levels of TGF-beta1 expression as compared with VP, indicating a function other than that of an apoptotic agent for this isoform. Following orchiectomy, TGF-beta1 was induced in all organs studied and the levels were highest at day 3 following castration in seminal vesicle (SV) and the epididymis and decreased by day 5 despite the absence of androgens. This observation implies that TGF-beta1 might not be a truly androgen-repressed gene in these tissues. TGF-beta2 was up-regulated in VP, SV, caput and corpus epididymis but was undetectable in the dorsolateral prostate and cauda epididymis. On the other hand, TGF-beta3 expression was refractory to the androgen status in corpus epididymis and SV but was up-regulated in the remaining tissues. The castration-induced induction of mRNAs was attenuated after exogenous androgen administration. Most importantly, all the isoforms differed significantly in the time and magnitude of induction following castration, suggesting that a single hormone, testosterone, modulates the expression of TGF-betas in an isoform- and tissue-specific manner.

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T. S. Tiong, J. L. Stevenson and A. C. Herington

ABSTRACT

The nature and tissue distribution of prolactin receptor (PRL-R) mRNA in both male and female rats was studied. A single mRNA species of 2.2kb was identified in the liver, kidney, adrenal, prostate, lactating mammary gland and ovary but not in the male lung, heart, skeletal muscle, thymus, adipose tissue or brain. There were distinct and contrasting sex differences in abundance of PRL-R mRNA in some tissues: liver (female>>male), kidney and adrenal (male >>female). A mRNA species of 4kb was occasionally detected in the male adrenal and female liver. Given previous reports on the effects of thyroid status on PRL binding, the effects of thyroxine (T4), propylthiouracil (PTU) or combined treatment on PRL-R mRNA were assessed. In the male rat, PTU treatment markedly increased (three- to fourfold) PRL-R mRNA in the liver but decreased it (∼50%) in the kidney. These changes were reflected in similar changes in lactogenic binding activity. T4 or PTU treatment increased PRL-R mRNA in the prostate, with no obvious changes in binding. No major changes were seen in adrenal glands. In the female rat, PTU had little effect on PRL-R mRNA in any tissue, although binding of 125I-labelled lactogen was decreased in both the liver and kidney. There was an unexpected threefold rise in PRL-R mRNA in the female kidney following combined T4 and PTU treatment. Overall, there was a quite close correlation between the effects of thyroid status on PRL-R mRNA levels and specific lactogenic binding to membranes prepared from the same tissue samples. These studies provide data on the tissue distribution and size of PRL-R mRNA in rats and suggest a novel and complex tissue- and sex-dependent regulation by thyroid hormone.