Flowchart: Preparation: Ar

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Text Box: MainPage

                                                                        

Text Box: PSA 

Text Box: Caspase-8Text Box: AKT

 

                                   

Text Box: P13KText Box: Ar

Breast                                                                  

Prostate

Text Box: P44/Mep50                                                                         

Text Box: eNOSText Box: His-5/Ara55 Text Box: His-5/Ara55 Text Box: KGF                                                                                        

2009/11/20                                                        

Mol Cells. 2009 Oct 21. [Epub ahead of print]

Insulin-like growth factor-I-induced androgen receptor activation is mediated by the PI3K/Akt pathway in C2C12 skeletal muscle cells.

Lee WJ.

Department of Exercise Science, College of Health Sciences, Ewha Womans University, Seoul, 120-750, Korea, jun@ewha.ac.kr.

Although insulin-like growth factor-I (IGF-I) and androgen receptor (AR) are well known effectors of skeletal muscle, the molecular mechanism by which signaling pathways integrating AR and IGF-I in skeletal muscle cells has not been previously examined. In this study, the role of PI3K/Akt on IGF-I-induced gene expression and activation of AR in skeletal muscle cells was investigated. C2C12 cells were treated with IGF-I in the absence or presence of inhibitors of PI3K/Akt pathway (LY294002 and Wortmannin). Inhibition of the PI3K/Akt pathway with LY294002 or Wortmannin led to a significant decrease in IGF-I-induced AR phosphorylation and total AR protein expression. Furthermore, IGF-I-induced AR mRNA and skeletal alpha-actin mRNA were blocked by LY294002 or Wortmannin. Confocal images showed that IGF-I-induced AR translocation from cytosol to nucleus was inhibited significantly in response to treatment with LY294002 or Wortmannin. The present results suggest that modulating effect of IGF-I on AR gene expression and activation in C2C12 mouse skeletal muscle cells is mediated at least in part by the PI3K/Akt pathway.

PMID: 19855934 [PubMed - as supplied

J Cell Mol Med. 2009 Oct 16. [Epub ahead of print]

Androgen receptor coactivator p44/Mep50 in breast cancer growth and invasion.

Peng Y, Li Y, Gellert LL, Zou X, Wang J, Singh B, Xu R, Chiriboga L, Daniels G, Pan R, Zhang DY, Garabedian M, Schneider R, Wang Z, Lee P.

Department of Pathology, New York University School of Medicine, New York, New York.

Hormones and their receptors play an important role in the development and progression of breast carcinoma. Although the primary focus has been on estrogen and estrogen receptor (ER), androgen, androgen receptor (AR) and its coactivator(s) have been implicated in tumorigenesis of ductal carcinoma and warrant further investigation. Androgen receptor coactivator p44/Mep50 is identified as a subunit of methylosome complex and lately characterized as an androgen receptor coactivator that enhances androgen receptor mediated transcription activity in a ligand-dependent manner. In prostate cancer, p44 is expressed in the nucleus of benign epithelia and translocated into the cytoplasm in cancer cells. Furthermore, nuclear expression of p44 inhibits prostate cancer growth. In this report, we examined the expression and function of p44 in breast cancer. In addition to being an AR coactivator, p44 also functions as an ER coactivator. In contrast to findings in prostate cancer, the expression of p44 shows strong cytoplasmic expression in morphologically normal terminal ductal lobular units, while nuclear p44 is observed in both ductal carcinoma in situ (DCIS) and invasive carcinoma. Further, overexpression of nuclear-localized p44 stimulates proliferation and invasion in MCF7 breast cancer cells in the presence of estrogen and is ERalpha-dependent. These findings strongly suggest that p44 plays a role in mediating the effects of hormones during tumorigenesis in breast.

PMID: 19840198 [PubMed

EMBO J.2006 Dec 14; [Epub ahead of print]Click here to read Links

·  A novel function of caspase-8 in the regulation ofandrogen-receptor-driven gene expression

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·  Qi W,Wu H,Yang L,Boyd DD,Wang Z.

Department of Cancer Biology, The University ofTexas MD Anderson Cancer Center, Houston, TX, USA.

Transcriptional regulation by the androgen receptor(AR) is critical for male sexual development and prostate cancer. In thisstudy, we used an expression cloning strategy to identify molecules thatregulate AR-driven transcription. Screening of a human cDNA libraryresulted in isolation of caspase-8 (Casp8), an initiator caspase thatmediates death-receptor-induced apoptosis. Casp8 repressed AR-dependentgene expression independently of its apoptotic protease activity bydisrupting AR amino-terminal and carboxy-terminal (N/C) interaction andinhibiting androgen-induced AR nuclear localization. Protein-proteininteraction analysis revealed that three motifs in Casp8 specificallyinteracted with the motifs that are known to be involved in AR N/Cinteraction. Substitutions of the amino-acid residues critical for AR-Casp8interactions abolished the Casp8-mediated inhibition of AR transactivation.In addition, knockdown of Casp8 by RNA interference specifically affectedthe androgen-dependent expression of AR-targeting genes in LNCaP cells.These results indicate that Casp8 has a novel function beyond its knownrole in the mediation of apoptosis.

PMID: 17170703 [PubMed - as supplied by publisher]

Steroids.2006 Dec 11; [Epub ahead of print]Click here to read Links

Hic-5/ARA55 a prostatestroma-specific AR coactivator.

·  Heitzer MD,Defranco DB.

Department of Pharmacology, University ofPittsburgh School of Medicine, 200 Lothrop St., Pittsburgh, PA 15261,United States.

Growth factors and cytokines mediate communicationbetween the epithelial and stromal compartments of the prostate. Inprostate cancer (PCa), changes in the spatial arrangements of the twocompartments (i.e. basement membrane invasion), DNA mutations, or cellulardedifferentiation (i.e. myofibroblasts) leads to significant changes ingene expression within both compartments. This results in altered cytokineand/or growth factor signaling in PCa. Recently, a stromal-specific androgenreceptor (AR) coactivator, Hic-5/ARA55, has been identified that may play arole in regulating expression of the growth factor and/or cytokineexpression in the prostate. Specifically, Hic-5/ARA55 expression influencesandrogen-induced keratinocyte growth factor (KGF) expression in WPMY-1prostate stromal cells. Because Hic-5/ARA55's expression is also altered inPCa, it may play a role in the differential cellular signaling events thatoccur during tumor progression.

PMID: 17166536 [PubMed - as supplied by publisher

BiochemBiophys Res Commun.2006 Dec 22; [Epub ahead of print]

Signaling pathway ofnitric oxide production induced by ginsenoside Rb1 in human aorticendothelial cells: A possible involvement of androgen receptor.

·  Yu J,Eto M,Akishita M,Kaneko A,Ouchi Y,Okabe T.

Department of Integrated Traditional Medicine,University of Tokyo Graduate School of Medicine, Tokyo, Japan.

Ginsenosides have been shown to stimulate nitric oxide(NO) production in aortic endothelial cells. However, the signalingpathways involved have not been well studied in human aortic endothelialcells. The present study was designed to examine whether purifiedginsenoside Rb1, a major active component of ginseng could actually induceNO production and to clarify the signaling pathway in human aorticendothelial cells. NO production was rapidly increased by Rb1. The rapidincrease in NO production was abrogated by treatment with nitric oxidesynthetase inhibitor, L-NAME. Rb1 stimulated rapid phosphorylation of Akt(Ser473), ERK1/2 (Thr202/Thr204) and eNOS (Ser1177). Rapid phosphorylationof eNOS (Ser1177) was prevented by SH-5, an Akt inhibitor or wortmannin,PI3-kinase inhibitor and partially attenuated by PD98059, an upstreaminhibitor for ERK1/2. Interestingly, NO production and eNOS phosphorylationat Ser1177 by Rb1 were abolished by androgen receptor antagonist,nilutamide. The results suggest that PI3kinase/Akt and MEK/ERK pathways andandrogen receptor are involved in the regulation of acute eNOS activationby Rb1 in human aortic endothelial cells.

PMID: 17196933 [PubMed - as supplied by publisher]

MolEndocrinol.2006 Dec 27; [Epub ahead of print]Click here to read Links

PELP1/MNAR enhancesandrogen receptor functions through LIM-only coactivator FHL2.

·  Nair SS,Guo Z,Mueller JM,Koochekpour S,Qiu Y,Tekmal RR,Schule R,Kumar

 R

,Vadlamudi RK.

Departmentof Obstetrics and Gynecology, University of Texas Health Science Center,San Antonio, TX, USA; Department of Microbiology and Immunology and StanleyS. Scott Cancer Center, Louisiana State University Health Sciences Center,New Orleans, LA, USA; Universitaets-Frauenklinik und Zentrale KlinischeForschung, Freiburg, Germany; Department of Pharmacology and ExperimentalTherapeutics, University of Maryland School of Medicine, Baltimore, MD,USA; Department of Biological Chemistry, University of California at Davis,Sacramento, California; The University of Texas MD Anderson Cancer Center,Houston, TX, USA.

Proline-,glutamic acid-, and leucine-rich protein-1 (PELP1) is a coregulator ofmultiple nuclear receptors. Molecular mechanisms of PELP1 function are notcompletely understood, but its expression is upregulated inhormonal-dependent cancers. Using a yeast two-hybrid screen, we found thatfour-and-a-half LIM-only protein 2 (FHL2) interacted with PELP1. FHL2 is atranscriptional regulator that associates with nuclear cofactors, includingandrogen receptors (AR), and contains an intrinsic activation domain. PELP1and FHL2 interact in vitro, in vivo, and co-localize in the nuclearcompartment. PELP1 interacts with FHL2 via LIM domains 3 and 4 andsynergistically enhances the transcriptional activity of FHL2. Src kinaseis required for PELP1-mediated enhancement of FHL2 functions, as knock downof Src kinase expression or function, abolished PELP1-mediated FHL2activation functions. PELP1 interacted with androgen receptor (AR) andenhanced FHL2-mediated AR transactivation functions. PELP1 knock down bysiRNA or PELP1 mutant, which lacks an activation domain, reduced FHL2-mediatedAR transactivation. Biochemical analyses revealed a complex consisting ofPELP1, FHL2, and AR in prostate cancer cells. PELP1/MNAR expression waselevated in high-grade prostate tumors. Our results suggest that PELP1functions as a molecular adaptor, coupling FHL2 with nuclear receptors, andPELP1-FHL2 interactions may have a role in prostate cancer progression.

PMID:17192406 [PubMed - as supplied by publisher]

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