c-Jun enhancement of androgen receptor transactivation is associated with prostate cancer cell proliferation

Sy, Chen; Cai, Changmeng; Cj, Fisher; Zheng, Zhe; Omwancha, Josephat; Cl, Hsieh; Shemshedini, Lirim

doi:10.1038/sj.onc.1209705

Cited by 65 publications

(85 citation statements)

References 60 publications

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“…Several studies have shown that functional AR is expressed throughout the multiple stages of prostate cancer (reviewed by Jenster, 1999) and disruption of AR activity results in reduced proliferation of prostate cancer cells (Eder et al, 2002;Jiang et al, 2004;Chen et al, 2006). Recently, it was also reported that AR overexpression was sufficient for converting the growth of prostate tumors from androgen-dependent to androgen-independent (Chen et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Androgen regulation of soluble guanylyl cyclaseα1 mediates prostate cancer cell proliferation

et al. 2006

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The growth and progression of prostate cancer are dependent on androgens and androgen receptor (AR), which act by modulating gene expression. Utilizing a gene microarray approach, we have identified the a1-subunit gene of soluble guanylyl cyclase (sGC) as a novel androgen-regulated gene. A heterodimeric cytoplasmic protein composed of one a and one b subunit, sGC mediates the widespread cellular effects of nitric oxide (NO). We report here that, in prostate cancer cells, androgens stimulate the expression of sGCa1. A cloned human sGCa1 promoter is activated by androgen in an AR-dependent manner, suggesting that sGCa1 may be a direct AR target gene. Disruption of sGCa1 expression severely compromises the growth of both androgendependent and androgen-independent AR-positive prostate cancer cells. Overexpression of sGCa1 alone is sufficient for stimulating prostate cancer cell proliferation. Interestingly, the major growth effect of sGCa1 is independent of NO and cyclic guanosine monophosphate, a major mediator of the sGC enzyme. These data strongly suggest that sGCa1 acts in prostate cancer via a novel pathway that does not depend on sGCb1. Tissue studies show that sGCa1 expression is significantly elevated in advanced prostate cancer. Thus, sGCa1 may be an important mediator of the procarcinogenic effects of androgens.

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Section: Discussionmentioning

confidence: 99%

Androgen regulation of soluble guanylyl cyclaseα1 mediates prostate cancer cell proliferation

et al. 2006

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“…(72) Furthermore, there may be molecular interactions between the substrate of JNK, the AP-1 transcription complex, and AR, either directly, or involving cofactors, and these interactions can either be stimulatory or inhibitory. (73)(74)(75) Since there is very little information on JNK expression in human prostate cancer specimens, it is at present not clear in what way JNK affects prostate carcinogenesis.…”

Section: Mapk Signalingmentioning

confidence: 99%

Androgen signaling and its interactions with other signaling pathways in prostate cancer

2007

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SummaryProstate cancer is the most frequently diagnosed nonskin cancer and the third leading cause of cancer mortality in men. In the initial stages, prostate cancer is dependent on androgens for growth, which is the basis for androgen ablation therapy. However, in most cases, prostate cancer progresses to a hormone refractory phenotype for which there is no effective therapy available at present. The androgen receptor (AR) is required for prostate cancer growth in all stages, including the relapsed, ''androgen-independent'' tumors in the presence of very low levels of androgens. This review focuses on AR function and AR-target genes and summarizes the major signaling pathways implicated in prostate cancer progression, their crosstalk with each other and with AR signaling. This complex network of interactions is providing a deeper insight into prostate carcinogenesis and may form the basis for novel diagnostic and therapeutic strategies. IntroductionProstate adenocarcinoma is the most frequently diagnosed non-cutaneous male malignancy and the third leading cause of cancer-related death in men in most western industrialized countries. (1) It is estimated that around 660,000 men worldwide will be diagnosed with prostate cancer and 250,000 men will die from it in 2010; thus, it will remain a major health problem in the future. (1) It was more than 60 years ago that the important role of male sex hormones (androgens) for the development and growth of prostate cancer was demonstrated. (2) Accordingly, androgen ablation therapy has been the main line of therapy for prostate cancer. Therefore, much of the focus in prostate cancer research to date has naturally been on androgens, how to decrease the androgens in the circulation and how to inhibit the androgen receptor (AR).In addition to AR signaling, it has now become evident that other signaling pathways, as well as non-genomic and genomic alterations, are involved in prostate cancer development and progression. Furthermore, recent studies indicated that signaling through AR has a critical role even after androgen ablation and disease progression (for review see Ref.3). In the following sections, we give an overview of androgen signaling in prostate cancer, with a special focus on recent findings about AR function and AR target genes. We then review the involvement of other central signaling pathways in prostate cancer, with a special focus on their cross-talk with the AR signaling pathway. Clinical implications of these findings and potential directions for future research are also outlined.

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“…As a first step, we scanned for additional sequence motifs within the AREs and identified several significantly recurring motifs, including putative sites for AP-1, RAR, ZNF42, HNF-4␣, and EGR. We note that AP-1 motifs are known to operate at several ARGs (Murtha et al 1997;Sato et al 1997;Chen et al 2006), and that increases in AR and the AP-1 factor c-Jun correlate with prostate cancer progression (LaTulippe et al 2002;Tiniakos et al 2006). Assessing regulatory cross-talk between AR and AP-1 signaling at AREs will thus be informative but technically challenging as the dimeric AP-1 factors are drawn from a superfamily of genes (c-Jun, JunB, and JunD) that can homo-or heterdimerize with c-Fos, FosB, Fra-1, and Fra-2.…”

Section: Potential Composite Aresmentioning

confidence: 99%

Cell- and gene-specific regulation of primary target genes by the androgen receptor

Bolton¹,

So²,

Chaivorapol³

et al. 2007

Genes Dev.

307

273

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The androgen receptor (AR) mediates the physiologic and pathophysiologic effects of androgens including sexual differentiation, prostate development, and cancer progression by binding to genomic androgen response elements (AREs), which influence transcription of AR target genes. The composition and context of AREs differ between genes, thus enabling AR to confer multiple regulatory functions within a single nucleus. We used expression profiling of an immortalized human prostate epithelial cell line to identify 205 androgen-responsive genes (ARGs), most of them novel. In addition, we performed chromatin immunoprecipitation to identify 524 AR binding regions and validated in reporter assays the ARE activities of several such regions. Interestingly, 67% of our AREs resided within ∼50 kb of the transcription start sites of 84% of our ARGs. Indeed, most ARGs were associated with two or more AREs, and ARGs were sometimes themselves linked in gene clusters containing up to 13 AREs and 12 ARGs. AREs appeared typically to be composite elements, containing AR binding sequences adjacent to binding motifs for other transcriptional regulators. Functionally, ARGs were commonly involved in prostate cell proliferation, communication, differentiation, and possibly cancer progression. Our results provide new insights into cell-and gene-specific mechanisms of transcriptional regulation of androgen-responsive gene networks.[Keywords: Androgen receptor (AR); androgen response element (ARE); transcription; steroid receptor; chromatin immunoprecipitation (ChIP); prostate cancer] Supplemental material is available at http://www.genesdev.org.

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c-Jun enhancement of androgen receptor transactivation is associated with prostate cancer cell proliferation

Cited by 65 publications

References 60 publications

Androgen regulation of soluble guanylyl cyclaseα1 mediates prostate cancer cell proliferation

Androgen regulation of soluble guanylyl cyclaseα1 mediates prostate cancer cell proliferation

Androgen signaling and its interactions with other signaling pathways in prostate cancer

Cell- and gene-specific regulation of primary target genes by the androgen receptor

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