Functional characterization of an androgen response element in the first intron of the C3(1) gene of prostatic binding protein

Claessens, Frank; Celis, Linda; Peeters, Benjamin; Heyns, Walter; Verhoeven, Guido; Rombauts, Wilfried

doi:10.1016/0006-291x(89)91534-9

Cited by 116 publications

(39 citation statements)

References 22 publications

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“…The 51 kDa PLCz band was not detected in mice in the absence of DOX treatment, nor was it found in nontransgenic mice in the presence of DOX (Figure 2a). We did not detect PLCz in the ventral prostate and seminal vesicles, consistent with reports of C3(1) being expressed only in the dorsal prostate ( Figure 2b; Claessens et al, 1989;Maroulakou et al, 1994;Tehranian et al, 1996).…”

Section: Resultssupporting

confidence: 92%

PLCγ contributes to metastasis of in situ-occurring mammary and prostate tumors

et al. 2006

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Phospholipase C-c (PLCc ) has been implicated in tumor cell motility required for invasiveness and metastasis. Diminished tumor dissemination has been demonstrated in xenograft models, but studies in naturally-occurring tumors are lacking, having been limited by the timing of the interventions. Therefore, we generated mice that express a doxycycline (DOX)-inducible dominantnegative fragment of PLCc, PLCz; this approach avoids the in utero lethality caused by the absence of PLCc. As we targeted two de novo-occurring carcinomas of the mammary (MMTV-driven polyoma middle T antigen model, PyVmT) and prostate (TRAMP model) glands, we limited expression to these epithelial cells by driving DOX transactivator from the prostatein C3 promoter. This avoids the confounding variable of potentially abrogating motility in stromal and endothelial cells. These mice developed normally in the presence of DOX, except for limited mammary development if treated before 6 weeks and immaturity of the prostate gland if treated before 2 weeks of age. DOX-mediated induction of PLCz from age 8 to 16 weeks in PyVmT mice decreased the number of lung metastases by >10-fold (Po0.06) without a detectable effect on in situ tumor cell proliferation or tumor size. Lung metastases were also significantly decreased in the TRAMP model in which the mice expressed the PLCz fragment (Po0.05). DOX treatment itself had no effect on tumor size or metastasis in control mice, nor did it affect tumor dissemination in nontransgenic littermates. In conclusion, abrogation of the PLCc signaling pathway can limit the metastatic potential of carcinomas.

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Section: Resultssupporting

confidence: 92%

PLCγ contributes to metastasis of in situ-occurring mammary and prostate tumors

et al. 2006

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“…The expression of C3 and C1 subunits of rat prostatin is regulated by androgen (Zhang et al, 1988). These findings, together with in vitro androgen receptor binding to DNA sequences from intron 1 of the prostatin C3 subunit gene, suggest that its expression is a function of the quantitative expression levels of the androgen receptor (Claessens et al, 1989). If prostatins and lipophilins are functionally synonymous, expression of the latter may also be androgen-regulated and dependent on the androgen receptor.…”

Section: Discussionmentioning

confidence: 85%

Evaluation of Lipophilins as Determinants of Tumor Cell Response to Estramustine

Tucker

Lipatova

Beljanski

et al. 2005

J Pharmacol Exp Ther

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Estramustine administered orally as estramustine phosphate (EMP) remains a major tool in hormone refractory prostate cancer chemotherapy. The presence of estramustine binding protein, prostatin, in prostate tissue may be a determinant of response to treatment. Lipophilins are secretory proteins with homology to prostatin. Reverse transcription-polymerase chain reaction was performed to estimate expression patterns of lipophilins A to C in human biopsies and cell lines resistant to estramustine. Although lipophilin A was not expressed in prostate tissue, both lipophilins B and C were expressed in normal and tumor prostate without significant differences. For lipophilin C, a somatic mutation (T to C transition at positions 409 and 412) was found in human tumor samples and absent in normal prostate tissue. No consistent response to EMP was observed in enhanced green fluorescent protein (EGFP)-tagged lipophilin C-transfected PC3 cells compared with parental controls. Among these EGFP-lipophilin C clones, no direct correlation between response to EMP treatment (IC 50 values) and EGFP expression was observed (p ϭ 0.73). Lipophilin C mRNA levels did not vary significantly between wild-type and estramustineresistant cells in prostate (DU145 and PC3) and ovarian (SKOV3) cancer cell lines. Overall, these results suggest that lipophilins are not specific determinants of estramustine efficacy.

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“…1) It is located in an intron (intron 8) of the SCAP gene. Intronic localization of androgen-responsive regions has also been reported for the genes encoding the C1 and C3 components of prostatic binding protein (16,17) and for the gene encoding ␤-glucuronidase (18). 2) Gel retardation studies reveal that the relevant 122-bp fragment interacts directly with the AR, suggesting that it may contain an ARE.…”

Section: Discussionmentioning

confidence: 93%

Identification of an Androgen Response Element in Intron 8 of the Sterol Regulatory Element-binding Protein Cleavage-activating Protein Gene Allowing Direct Regulation by the Androgen Receptor

Heemers

Verrijdt

Organe

et al. 2004

Journal of Biological Chemistry

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SREBPs are synthesized as 125-kDa inactive precursor proteins, and immediately upon their synthesis they are inserted into the membranes of the endoplasmic reticulum where they form tight complexes with an escort protein known as the SREBP cleavage-activating protein (SCAP). SCAP plays a pivotal role in the control of SREBP signaling. In fact, SCAP does not only bind SREBP but, through its amino-terminal sterolsensing domain, it also interacts with a retention protein complex consisting of at least two endoplasmic reticulum proteins (designated insulin-induced gene 1 and 2; Insig 1 and 2) that serve to retain the SREBP⅐SCAP complex into the membranes of the endoplasmic reticulum. In the "classical" SREBP activation pathway, a decrease in the intracellular concentration of sterols changes the conformation of the sterol-sensing part of SCAP, weakens its interaction with the retention proteins, and allows translocation of the SREBP⅐SCAP complex to the Golgi apparatus where SREBP is proteolytically cleaved and activated. The active 68-kDa SREBP fragment migrates to the nucleus where it increases the transcription of a large set of sterol-responsive element (SRE) containing genes encoding lipogenic enzymes belonging to the pathways of fatty acid and cholesterol synthesis (1-7).Our studies on the mechanisms by which androgens provoke a coordinated activation of lipogenic pathways in androgenresponsive prostate tumor lines have suggested an alternative pathway of SREBP activation in which androgens change the expression rather than the conformation of SCAP (8,9). In this pathway, increased expression of SCAP shifts the balance between SCAP and its retention proteins and favors translocation of the SREBP⅐SCAP complex to the Golgi apparatus. Evidence for the existence of this pathway was derived from several observations (9). 1) In two independent prostate tumor lines (LNCaP and MDA-PCa-2a) androgens cause major changes in the expression of SCAP both at the mRNA and at the protein level, whereas no or only minor changes were observed for other critical components of the SREBP pathway (the SREBP precursor proteins SREBP-1a, -1c, and -2; the site 1 and site 2 proteases responsible for SREBP cleavage).2) The observed increase in SCAP expression was shown to be a cause rather than a consequence of SREBP activation. Induction of SCAP expression coincided with nuclear translocation of SREBP but

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Functional characterization of an androgen response element in the first intron of the C3(1) gene of prostatic binding protein

Cited by 116 publications

References 22 publications

PLCγ contributes to metastasis of in situ-occurring mammary and prostate tumors

PLCγ contributes to metastasis of in situ-occurring mammary and prostate tumors

Evaluation of Lipophilins as Determinants of Tumor Cell Response to Estramustine

Identification of an Androgen Response Element in Intron 8 of the Sterol Regulatory Element-binding Protein Cleavage-activating Protein Gene Allowing Direct Regulation by the Androgen Receptor

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