Disease relevance of NCOA4

• Using a yeast two-hybrid system, we were able to isolate a ligand-dependent AR-associated protein (ARA70), which functions as an activator to enhance AR transcriptional activity 10-fold in the presence of 10(-10) M dihydrotestosterone or 10(-9) M testosterone, but not 10(-6) M hydroxyflutamide in human prostate cancer DU145 cells [1].
• Expression of androgen receptor coactivator ARA70/ELE1 in androgenic alopecia [2].
• Molecular characterization of RET/PTC3; a novel rearranged version of the RETproto-oncogene in a human thyroid papillary carcinoma [3].
• Our results also suggest a role of the ARA70 gene (which encodes a major AR co-activator) in the AR pathway dysregulation observed in breast cancer [4].
• Activation of androgen receptor-associated protein 70 (ARA70) mRNA expression in ovarian cancer [5].
• Although both ARA70 alpha and ARA70 beta functioned as transcriptional co-activators of AR in cell-based reporter assays, ARA70 beta overexpression, in contrast to ARA70 alpha, promoted prostate cancer cellular proliferation and invasion through Matrigel [6].

Psychiatry related information on NCOA4

• In addition, the coexpression of RET/PTC3 and E7 oncogenes neither enhanced the malignant phenotype nor reduced the latency period of thyroid lesions with respect to parental transgenic lines [7].

High impact information on NCOA4

• The significance of this newly described E2-induced AR transcriptional activity in DU145 human prostate cancer cells was further strengthened by finding patients with Reifenstein partial-androgen-insensitive syndrome that fail in the E2-AR-ARA70 pathway [8].
• Promotion of agonist activity of antiandrogens by the androgen receptor coactivator, ARA70, in human prostate cancer DU145 cells [9].
• Using mammalian two-hybrid assay, we report that antiandrogens, hydroxyflutamide, bicalutamide (casodex), cyproterone acetate, and RU58841, and other compounds such as genistein and RU486, can promote the interaction between AR and its coactivator, ARA70, in a dose-dependent manner [9].
• The chloramphenicol acetyltransferase assay further demonstrates that these antiandrogens and related compounds significantly enhance the AR transcriptional activity by cotransfection of AR and ARA70 in a 1:3 ratio into human prostate cancer DU145 cells [9].
• Three forms of the ret/PTC oncogene have been identified; the two most common forms, ret/PTC-1 and ret/PTC-3, both result from a paracentric inversion, of the long arm of chromosome 10 [10].

Chemical compound and disease context of NCOA4

• Taken together, these findings indicate that ARA70 may contribute to the acquired agonist activity of antiandrogens and plays an important role in making prostate cancer cells resistant to androgen ablation and/or antiandrogen therapy [11].
• Because ARA70 can promote the antiandrogen hydroxyflutamide (HF)-enhanced AR transactivation, the increased ARA70 expression in hormone-refractory prostate tumors may confer the development of HF withdrawal syndrome, commonly diagnosed in patients with the later stages of prostate cancer [12].
• We examined the expression of ret/PTC in 99 German papillary thyroid carcinomas, including two recently described new variants of ret/PTC3 and identified eight ret/PTC-positive tumours (8%) but none with the new variants [13].

Biological context of NCOA4

• However, this PPARgamma-ARA70 transactivation is enhanced by the addition of ligand [14].
• Our results demonstrate that RFG alters the induction of these reporter genes very weakly (no greater than 2-fold compared with transfections without the RFG expression plasmid) [15].
• In addition, human prostate tumor cell proliferation and colony formation were markedly reduced by ELE1/ATRA70 [16].
• Expression of RFG/ELE1alpha/ARA70 in normal and malignant prostatic epithelial cell cultures and lines: regulation by methylation and sex steroids [17].
• Polymerase chain reaction analyses of monochromosomal human-rodent hybrid panels localized a putative RFG/ELE1alpha/ARA70 isoform on human chromosome 5q31.1-31 [17].

Anatomical context of NCOA4

• Genetic evidence to exclude the androgen receptor co-factor, ARA70 (NCOA4) as a candidate gene for the causation of undermasculinised genitalia [18].
• Finally, we show that AR can squelch PPARgamma-ARA70 transactivation, which suggests that cross-talk may occur between PPARgamma- and AR-mediated responses in adipocytes [14].
• Here we describe the cloning of the cDNA for ELE1/ARA70 by RT-PCR from RNA derived from different cell lines (HeLa, DU-145, and LNCaP) [19].
• Overexpression of either ELE1 isoform in DU-145, HeLa, or COS cells had only minor effects on the transcriptional activity of the human AR [19].
• Thus, ARA70 is a coactivator for ERalpha and may represent a functional link between ERalpha/AR modulating their cross-talk in models of estrogen signaling in MCF-7 and HeLa cells [20].

Associations of NCOA4 with chemical compounds

• PPARgamma and ARA70 interact in the absence of the PPARgamma ligand 15-deoxy-Delta12,14-prostaglandin J2, although the addition of exogenous ligand enhances this interaction [14].
• Interaction of the putative androgen receptor-specific coactivator ARA70/ELE1alpha with multiple steroid receptors and identification of an internally deleted ELE1beta isoform [19].
• Together, these data suggest that AR may need a specific coactivator(s) such as ARA70 for optimal androgen activity [1].
• Transcriptional activity of hAR(M745I) was stimulated by 1 or 10nM R1881 and activity was further enhanced by co-expression of ARA70 similar to that of the hAR(wt) [21].
• In contrast to this finding, an active metabolite of dehydroepiandrosterone, 7-oxo-dehydroepiandrosterone, does not activate AR target gene in the absence or presence of ARA70 [22].

Physical interactions of NCOA4

• Taken together, we have identified two isoforms of the putative coactivator ARA70/ELE1 that may act as a bridging factor between steroid receptors and components of the transcription initiation complex but which lack some fundamental properties of a classic nuclear receptor coactivator [19].
• Endogenous coactivator ARA70 interacts with estrogen receptor alpha (ERalpha) and modulates the functional ERalpha/androgen receptor interplay in MCF-7 cells [20].

Regulatory relationships of NCOA4

• Identification of ARA70 as a ligand-enhanced coactivator for the peroxisome proliferator-activated receptor gamma [14].
• Moreover, a dominant negative ARA70 down-regulated ERalpha transcriptional activity as well as pS2 mRNA [20].
• Our previous reports suggest that ARA70 can enhance the androgenic activity of 17 beta-estradiol (E2) and antiandrogens toward AR [23].
• SU11248 caused a complete morphological reversion of transformed NIH-RET/PTC3 cells and inhibited the growth of TPC-1 cells that have an endogenous RET/PTC1 [24].

Other interactions of NCOA4

• Thus, while our findings are in agreement with published reports which indicate that RFG interacts with AR-HBD in a ligand-dependent fashion, in our assays RFG does not exert major effects on the activity of the hAR in response to androgen or to other steroid hormones [15].
• In an effort to understand transcriptional regulation by the peroxisome proliferator-activated receptor gamma (PPARgamma), we have investigated its potential interaction with coregulators and have identified ARA70 as a ligand-enhanced coactivator [14].
• Sequence analysis of this clone revealed that it encoded a portion of a protein that had been previously characterized as RFG (RET Fused Gene) [15].
• RFG/ELE1alpha/ARA70 mRNA levels in PC-3 cells, which express both estrogen receptor subtypes, were upregulated by 17beta-estradiol and inhibited by the antiestrogen ICI-182780 [17].
• The LXXLL motif of ARA70 is essential for interaction with VDR and partially responsible for its function as a coactivator of VDR [25].

Analytical, diagnostic and therapeutic context of NCOA4

• Here we show that ARA70 and PPARgamma specifically interact by coimmunoprecipitation and in a mammalian two-hybrid assay [14].
• ARA70 expression is also increased in high-grade prostate cancer tissues as well as the hormone-refractory LNCaP xenografts and prostate cancer cell lines [12].
• PCR analysis of DNA from a selected panel of human-rodent somatic cell hybrids and fluorescent in situ hybridization (FISH) analysis allowed us to localize the human ELE1 gene [26].
• In addition, Northern blot, together with semi-quantitative PCR analysis, confirmed that there is increased expression of ARA70 in myostatin-null biceps femoris muscle when compared to wild-type muscle [27].
• Western blot analysis for ARA70 expression performed on frozen breast biopsies of normal or malignant breast tissue from four patients revealed a 70 kDa immunoreactive band in all four normal tissue samples, with an additional 35 kDa band in two of the breast cancer samples and in human breast cancer MCF-7 cells [28].

References