TY  - JOUR
AB  - The secretin receptor (SR), a G protein-coupled receptor, mediates the effects of the gastrointestinal hormone secretin on digestion and water homeostasis. Recently, high SR expression has been observed in pancreatic ductal adenocarcinomas, cholangiocellular carcinomas, gastrinomas, and bronchopulmonary carcinoid tumors. Receptor overexpression associates with enhanced secretin-mediated signaling, but whether this molecule plays an independent role in tumorigenesis is currently unknown. We recently discovered that pheochromocytomas developing in rats affected by the MENX (multiple endocrine neoplasia-like) syndrome express at very high-level Sctr, encoding SR. We here report that SR are also highly abundant on the membranes of rat adrenal and extraadrenal pheochromocytoma, starting from early stages of tumor development, and are functional. PC12 cells, the best characterized in vitro pheochromocytoma model, also express Sctr at high level. Thus, we used them as model to study the role of SR in neoplastic transformation. Small interfering RNA-mediated knockdown of Sctr decreases PC12 cells proliferation and increases p27 levels. The proproliferative effect of SR in PC12 cells is mediated, in part, by the phosphatidylinositol 3 kinase (PI3K)/serine-threonine protein kinase (AKT) pathway. Transfection of Sctr in Y1 adrenocortical carcinoma cells, expressing low endogenous levels of Sctr, stimulates cell proliferation also, in part, via the PI3K/AKT signaling cascade. Because of the link between SR and PI3K/AKT signaling, tumor cells expressing high levels of the receptor (MENX-associated primary pheochromocytoma and NCI-H727 human bronchopulmonary carcinoid cells) respond well and in a SR-dependent manner to PI3K inhibitors, such as NVP-BEZ235. The association between SR levels and response to PI3K inhibition might open new avenues for the treatment of tumors overexpressing this receptor.
AU  - Lee, M.S.
AU  - Waser, B.*
AU  - Reubi, J.-C.*
AU  - Pellegata, N.S.
C1  - 8388
C2  - 30097
SP  - 1394-1405
TI  - Secretin receptor promotes the proliferation of endocrine tumor cells via the PI3K/AKT pathway.
JO  - Mol. Endocrinol.
VL  - 26
IS  - 8
PB  - Endocrine Society
PY  - 2012
SN  - 0888-8809
ER  - 

TY  - JOUR
AB  - Bile acids are synthesized from cholesterol and are major risk factors for Barrett adenocarcinoma (BAC) of the esophagus. Caveolin-1 (Cav1), a scaffold protein of membrane caveolae, is transcriptionally regulated by cholesterol via sterol-responsive element-binding protein-1 (SREBP1). Cav1 protects squamous epithelia by controlling cell growth and stabilizing cell junctions and matrix adhesion. Cav1 is frequently down-regulated in human cancers; however, the molecular mechanisms that lead to this event are unknown. We show that the basal layer of the nonneoplastic human esophageal squamous epithelium expressed Cav1 mainly at intercellular junctions. In contrast, Cav1 was lost in 95% of tissue specimens from BAC patients (n = 100). A strong cytoplasmic expression of Cav1 correlated with poor survival in a small subgroup (n = 5) of BAC patients, and stable expression of an oncogenic Cav1 variant (Cav1-P132L) in the human BAC cell line OE19 promoted proliferation. Cav1 was also detectable in immortalized human squamous epithelial, Barrett esophagus (CPC), and squamous cell carcinoma cells (OE21), but was low in BAC cell lines (OE19, OE33). Mechanistically, bile acids down-regulated Cav1 expression by inhibition of the proteolytic cleavage of 125-kDa pre-SREBP1 from the endoplasmic reticulum/Golgi apparatus and nuclear translocation of active 68-kDa SREBP1. This block in SREBP1's posttranslational processing impaired transcriptional activation of SREBP1 response elements in the proximal human Cav1 promoter. Cav1 was also down-regulated in esophagi from C57BL/6 mice on a diet enriched with 1% (wt/wt) chenodeoxycholic acid. Mice deficient for Cav1 or the nuclear bile acid receptor farnesoid X receptor showed hyperplasia and hyperkeratosis of the basal cell layer of esophageal epithelia, respectively. These data indicate that bile acid-mediated down-regulation of Cav1 marks early changes in the squamous epithelium, which may contribute to onset of Barrett esophagus metaplasia and progression to BAC. (Molecular Endocrinology 26: 819-832, 2012)
AU  - Prade, E.*
AU  - Tobiasch, M.*
AU  - Hitkova, I.*
AU  - Schaffer, I.*
AU  - Lian, F.*
AU  - Xing, X.B.*
AU  - Tänzer, M.*
AU  - Rauser, S.
AU  - Walch, A.K.
AU  - Feith, M.*
AU  - Post, S.*
AU  - Röcken, C.*
AU  - Schmid, R.M.*
AU  - Ebert, M.P.A.*
AU  - Burgermeister, E.*
C1  - 7959
C2  - 30020
SP  - 819-832
TI  - Bile acids down-regulate caveolin-1 in esophageal epithelial cells through sterol responsive element-binding protein.
JO  - Mol. Endocrinol.
VL  - 26
IS  - 5
PB  - Endocrine Society
PY  - 2012
SN  - 0888-8809
ER  - 

TY  - JOUR
AU  - Ebert, R.*
AU  - Jovanovic, M.*
AU  - Ulmer, M.*
AU  - Schneider, D.*
AU  - Meissner-Weigl, J.*
AU  - Adamski, J.
AU  - Jakob, F.*
C1  - 1562
C2  - 22123
SP  - 2440-2450
TI  - Down-regulation by nuclear factor kB of human 25-hydroxyvitamin D3 1alpha-hydroxylase promoter.
JO  - Mol. Endocrinol.
VL  - 18
PY  - 2004
SN  - 0888-8809
ER  - 

TY  - JOUR
AU  - Marijanovic, Z.
AU  - Laubner, D.
AU  - Möller, G.
AU  - Gege, C.*
AU  - Husen, B.*
AU  - Adamski, J.
AU  - Breitling, R.*
C1  - 22329
C2  - 21169
SP  - 1715-1725
TI  - Closing the gap : Identification of human 3-ketosteroid reductase, the last unknown enzyme of mammalian cholesterol biosynthesis.
JO  - Mol. Endocrinol.
VL  - 17
PY  - 2003
SN  - 0888-8809
ER  - 

TY  - JOUR
AB  - The vitamin D hormone 1,25-dihydroxyvitamin D-3 [1,25-(OH)(2)D-3] the biologically active form of vitamin D, is essential for an intact mineral metabolism. Using gene targeting, we sought to generate vitamin D receptor (VDR) null mutant mice carrying the reporter gene lacZ driven by the endogenous VDR promoter. Here we show that our gene-targeted mutant mice express a VDR with an intact hormone binding domain, but lacking the first zinc finger necessary for DNA binding. Expression of the lacZ reporter gene was widely distributed during embryogenesis and postnatally. Strong lacZ expression was found in bones, cartilage, intestine, kidney, skin, brain, heart, and parathyroid glands. Homozygous mice are a phenocopy of mice totally lacking the VDR protein and showed growth retardation, rickets, secondary hyperparathyroidism, and alopecia. Feeding of a diet high in calcium, phosphorus, and lactose normalized blood calcium and serum PTH levels, but revealed a profound renal calcium leak in normocalcemic homozygous mutants. When mice were treated with pharmacological doses of vitamin D metabolites, responses in skin, bone, intestine, parathyroid glands, and kidney were absent in homozygous mice, indicating that the mutant receptor is nonfunctioning and that vitamin D signaling pathways other than those mediated through the classical nuclear receptor are of minor physiological importance. Furthermore, rapid, nongenomic responses to 1,25-(OH)(2)D-3 in osteoblasts were abrogated in homozygous mice, supporting the conclusion that the classical VDR mediates the nongenomic actions of 1,25-(OH)(2)D-3.
AU  - Erben, R.G.*
AU  - Soegiarto, D.W.
AU  - Weber, K.*
AU  - Zeitz, U.*
AU  - Lieberherr, M.*
AU  - Gniadecki, R.*
AU  - Möller, G.
AU  - Adamski, J.
AU  - Balling, R.
C1  - 9987
C2  - 20428
SP  - 1524-1537
TI  - Deletion of Deoxyribonucleic Acid Binding Domain of the Vitamin D Receptor Abrogates Genomic and Nongenomic Functions of Vitamin D. 
JO  - Mol. Endocrinol.
VL  - 16
PB  - Society
PY  - 2002
SN  - 0888-8809
ER  - 

TY  - JOUR
AB  - Autoregulation is a control mechanism common to several proteins of the steroid/thyroid hormone receptor superfamily. In this work the effect of androgens and antiandrogens on the expression of the human androgen receptor (hAR) in prostate and breast cancer cell lines was studied. Northern blot analysis revealed a decrease in hAR steady state RNA levels in LNCaP cells by 3.3 nM of the synthetic androgen mibolerone. Maximal down-regulation of hAR RNA to 30% of control levels occurred 48 h after hormone addition. T47D breast cancer cells showed a similar effect with mibolerone, while hAR expression in normal skin fibroblasts did not respond to androgen treatment. As shown by nuclease S1 analysis, hAR transcripts initiate at three principal start sites, all of which are equally sensitive to androgen. Steroidal as well as nonsteroidal antiandrogens were capable of partially antagonizing androgen-mediated hAR RNA down-regulation in LNCaP and T47D cells, while not exerting a significant effect when administered alone. While hAR RNA stability was increased by hormone, nuclear run-on analysis revealed a 4-fold reduction of hAR gene transcription 96 h after androgen treatment. Although decreased hAR RNA levels did not coincide with a parallel decrease in AR protein levels, analysis of androgen-inducible reporter constructs demonstrated that prolonged androgen administration to cells results in a progressively impaired sensitivity of the intracellular androgen response mechanism. These results show that prolonged androgen exposure leads, besides its effect on hAR RNA levels, to functional inactivation of the AR. Thus, in vivo, posttranslational control of AR activity appears to be a novel mechanism of negative autoregulation of an-drogen effects on gene expression.
AU  - Wolf, D.A.
AU  - Herzinger, T.*
AU  - Hermeking, H.
AU  - Blaschke, D.*
AU  - Hörz, W.*
C1  - 40319
C2  - 40058
SP  - 924-936
TI  - Transcriptional and posttranscriptional regulation of human androgen receptor expression by androgen.
JO  - Mol. Endocrinol.
VL  - 7
IS  - 7
PY  - 1993
SN  - 0888-8809
ER  - 

TY  - JOUR
AB  - The whey acidic protein (WAP) promoter has been previously used to target the expression of heterologous genes to the mammary glands of transgenic mice. To direct the expression of human GH (hGH) to mouse mammary glands, hGH-coding sequences have been coupled to WAP promoter sequences (WAP-hGH). Female transgenic mice carrying the WAP-hGH constructs show expression of hGH in the mammary gland, demonstrating the functionality of the transgenes. However, when other organs from these transgenic mice were examined, high level expression of hGH was unexpectedly observed in the brains of all male and female mice. Using in situ hybridization or immunohistochemistry, hGH expression from the transgene was seen to occur specifically in Bergman glia cells. In contrast, mice carrying hGH-coding sequences linked to the metallothionein promoter do not express hGH in these cells. Neither the endogenous WAP gene nor at least three other transgenes in which heterologous genes have been placed under the transcriptional control of the WAP promoter are expressed in the brain. Thus, we propose that the combination of the WAP promoter and the hGH structural gene results in a novel tissue specificity in the Bergman glia.
AU  - Günzburg, W.H.
AU  - Salmons, B.*
AU  - Zimmermann, B.
AU  - Müller, M.L.*
AU  - Erfle, V.F.
AU  - Brem, G.*
C1  - 33319
C2  - 40255
SP  - 123-133
TI  - A mammary-specific promoter directs expression of growth hormone not only to the mammary gland, but also to Bergman glia cells in transgenic mice.
JO  - Mol. Endocrinol.
VL  - 5
IS  - 1
PY  - 1991
SN  - 0888-8809
ER  -