Cloning and characterization of the cDNA and gene for human epitheliasin

Jacquinet, Eric; Rao, Narayanam V.; Rao, Gopna V.; Wang, Zhengming; Albertine, Kurt H.; Hoidal, John R.

doi:10.1046/j.1432-1327.2001.02165.x

Cited by 61 publications

(56 citation statements)

References 46 publications

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“…Cells-To first decipher the consequences of the reduction of DHT glucuronidation on the cellular response to androgens, the mRNA levels of eight androgen-regulated genes were compared in control and UGT-deficient LNCaP cells cultured in the presence or absence of 1 nM concentration of R1881 and DHT for 12 h. As illustrated in Table 3, this set of genes (six up-regulated: PSA, KLK4, NKX3.1, SLC16A6, TMPRSS2, and VEGF; two down-regulated: ABCG1 and RAD23A) was chosen based on previous studies having reported the androgen-dependent regulation of their expression in LNCaP cells (31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43). As expected, the two AR agonists induced PSA, KLK4, NKX3.1, SLC16A6, and TMPRSS2 transcript levels in control cells, whereas VEGF expression was only significantly stimulated by R1881 (Fig.…”

Section: Inhibition Of Ugt2b15/b17 Enhances the Androgen Signaling Pamentioning

confidence: 99%

UDP-glucuronosyltransferase 2B15 (UGT2B15) and UGT2B17 Enzymes Are Major Determinants of the Androgen Response in Prostate Cancer LNCaP Cells

Chouinard

Barbier

Bélanger

2007

Journal of Biological Chemistry

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Uridine diphosphate-glucuronosyltransferase 2 (UGT2)B15 and B17 enzymes conjugate dihydrotestosterone (DHT) and its metabolites androstane-3␣,17␤-diol (3␣-DIOL) and androsterone (ADT). The presence of UGT2B15/B17 in the epithelial cells of the human prostate has been clearly demonstrated, and significant 3␣-DIOL glucuronide and ADT-glucuronide concentrations have been detected in this tissue. The human androgen-dependent cancer cell line, LNCaP, expresses UGT2B15 and -B17 and is also capable of conjugating androgens. To assess the impact of these two genes in the inactivation of androgens in LNCaP cells, their expression was inhibited using RNA interference. The efficient inhibitory effects of a UGT2B15/B17 small interfering RNA (siRNA) probe was established by the 70% reduction of these UGT mRNA levels, which was further confirmed at the protein levels. The glucuronidation of dihydrotestosterone (DHT), 3␣-DIOL, and ADT by LNCaP cell homogenates was reduced by more than 75% in UGT2B15/B17 siRNA-transfected LNCaP cells when compared with cells transfected with a nontarget probe. In UGT2B15/B17-deficient LNCaP cells, we observe a stronger response to DHT than in control cells, as determined by cell proliferation and expression of eight known androgen-sensitive genes. As expected, the amounts of DHT in cell culture media from control cells were significantly lower than that from UGT2B15/B17 siRNA-treated cells, which was caused by a higher conversion to its corresponding glucuronide derivative. Taken together these data support the idea that UGT2B15 and -B17 are critical enzymes for the local inactivation of androgens and that glucuronidation is a major determinant of androgen action in prostate cells.Production and secretion of testosterone by the testis has long been considered one of the major factors influencing androgen function in androgen target tissues, namely, the prostate. Thus, circulating testosterone taken up from the circulation is converted by 5␣-reductase to dihydrotestosterone (DHT), 4 the natural androgen receptor agonist (1). There is clear evidence now that adrenal steroid precursors, namely dehydroepiandrosterone and its sulfate, are converted to testosterone in several tissues (2, 3). The observation that the DHT concentration in prostate is only decreased by 50% in castrated patients treated for prostate cancer further support the role of adrenal steroid precursors as a source of androgens (4 -6). These findings of local transformation of circulating steroids into bioactive testosterone and DHT have been integrated in the process called "intracrinology," where several steroidogenic enzymes, including 3␣-hydroxysteroid dehydrogenase-⌬4 -5 isomerase (3␣-HSD type 1), 17␤-HSDs, and 5␣-reductase, contribute to the formation of DHT (2, 7). Growing evidence indicates that tissue DHT concentrations are also modulated by 3␣-hydroxysteroid dehydrogenase (3␣-HSD) type 3 and 17␤-HSD type 7, which form inactive androstane-3␣,17␤-diol (3␣-DIOL) and androsterone (ADT) (8, 9). Although extremely important in...

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Section: Inhibition Of Ugt2b15/b17 Enhances the Androgen Signaling Pamentioning

confidence: 99%

UDP-glucuronosyltransferase 2B15 (UGT2B15) and UGT2B17 Enzymes Are Major Determinants of the Androgen Response in Prostate Cancer LNCaP Cells

Chouinard

Barbier

Bélanger

2007

Journal of Biological Chemistry

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“…The human TMPRSS2 gene comprises 14 exons and is located on chromosome 21q22.2 (21,35). The murine Tmprss2 orthologue, also known as epitheliasin, encompasses 14 exons on chromosome 16C4 (20).…”

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confidence: 99%

“…In addition to the fulllength TMPRSS2 protein, analyses of extracts from tissues and cell lines demonstrate an ϳ32-kDa polypeptide consistent with the free serine protease domain of TMPRSS2 that results from autoactivated proteolytic cleavage (1). TMPRSS2 is expressed in several human tissues that comprise large populations of epithelial cells (21), with the highest level of transcripts measured in the prostate gland (27). In accord with the human tissue distribution, the mouse prostate and kidney exhibit the highest level of Tmprss2 expression (20,21).…”

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Phenotypic Analysis of Mice Lacking the Tmprss2-Encoded Protease

Kim¹,

Heinlein²,

Hackman

et al. 2006

Molecular and Cellular Biology

221

193

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Tmprss2 encodes an androgen-regulated type II transmembrane serine protease (TTSP) expressed highly in normal prostate epithelium and has been implicated in prostate carcinogenesis. Although in vitro studies suggest protease-activated receptor 2 may be a substrate for TMPRSS2, the in vivo biological activities of TMPRSS2 remain unknown. We generated Tmprss2 ؊/؊ mice by disrupting the serine protease domain through homologous recombination. Compared to wild-type littermates, Tmprss2 ؊/؊ mice developed normally, survived to adulthood with no differences in protein levels of prostatic secretions, and exhibited no discernible abnormalities in organ histology or function. Loss of TMPRSS2 serine protease activity did not influence fertility, reduce survival, result in prostate hyperplasia or carcinoma, or alter prostatic luminal epithelial cell regrowth following castration and androgen replacement. Lack of an observable phenotype in Tmprss2 ؊/؊ mice was not due to transcriptional compensation by closely related Tmprss2 homologs. We conclude that the lack of a discernible phenotype in Tmprss2 ؊/؊ mice suggests functional redundancy involving one or more of the type II transmembrane serine protease family members or other serine proteases. Alternatively, TMPRSS2 may contribute a specialized but nonvital function that is apparent only in the context of stress, disease, or other systemic perturbation.

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“…6 TMPRSS2, which encodes a serine protease with a transmembrane domain, 7 is highly expressed in both normal and neoplastic prostate epithelium, 8,9 and its expression in prostate cancer cells is androgen-regulated. 8,10 In prostate tumors harboring rearrangements, most frequently the non-coding first exon of TMPRSS2 has been found fused to the fourth exon of ERG in the expressed transcript. The rearrangement thereby places ERG under the androgen-regulated transcriptional control of TMPRSS2.…”

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confidence: 99%

A variant TMPRSS2 isoform and ERG fusion product in prostate cancer with implications for molecular diagnosis

et al. 2007

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Prostate cancer is the most commonly diagnosed cancer among men in the United States. Recently, fusion of TMPRSS2 with ETS family oncogenic transcription factors has been identified as a common molecular alteration in prostate cancer, where most often the rearrangement places ERG under the androgen-regulated transcriptional control of TMPRSS2. Here, we carried out rapid amplification of cDNA ends (RACE) on a prostate cancer specimen carrying an atypical aberration discovered by array-based comparative genomic hybridization (array CGH), suggesting an alternative fusion partner of ERG. We identified novel transcribed sequences fused to ERG, mapping 4 kb upstream of the TMPRSS2 start site. The sequences derive from an apparent second TMPRSS2 isoform, which we found also expressed in some prostate tumors, suggesting similar androgenregulated control. In a reverse transcription-polymerase chain reaction (RT-PCR)-based survey of 63 prostate tumor specimens (54 primary and nine lymph node metastases), 44 (70%) cases expressed either the known or novel variant TMPRSS2-ERG fusion, 28 (44%) expressed both, 10 (16%) expressed only the known, and notably six (10%) expressed only the variant isoform fusion. In this specimen set, the presence of a TMPRSS2-ERG fusion showed no statistical association with tumor stage, Gleason grade or recurrence-free survival. Nonetheless, the discovery of a novel variant TMPRSS2 isoform-ERG fusion adds to the characterization of ETS-family rearrangements in prostate cancer, and has important implications for the accurate molecular diagnosis of TMPRSS2-ETS fusions. Recently, by examining outlier values of gene expression in human cancers, Tomlins et al 5 discovered elevated expression of the ETS family members ERG (v-ets erythroblastosis virus E26 oncogene like) and ETV1 (Ets variant gene 1) to be a common feature of prostate cancer. Elevated expression resulted from chromosomal rearrangement fusing TMPRSS2 (transmembrane protease, serine 2) (chr 21q22.3) to ERG (chr 21q22.2), an apparent intra-chromosomal deletion of B3 Mb on chromosome 21, or less frequently to ETV1, an interchromosomal rearrangement between chr 21q22.3 and chr 7p21.2.

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Cloning and characterization of the cDNA and gene for human epitheliasin

Cited by 61 publications

References 46 publications

UDP-glucuronosyltransferase 2B15 (UGT2B15) and UGT2B17 Enzymes Are Major Determinants of the Androgen Response in Prostate Cancer LNCaP Cells

UDP-glucuronosyltransferase 2B15 (UGT2B15) and UGT2B17 Enzymes Are Major Determinants of the Androgen Response in Prostate Cancer LNCaP Cells

Phenotypic Analysis of Mice Lacking the Tmprss2-Encoded Protease

A variant TMPRSS2 isoform and ERG fusion product in prostate cancer with implications for molecular diagnosis

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