共查询到20条相似文献,搜索用时 407 毫秒
1.
2.
3.
Han G Foster BA Mistry S Buchanan G Harris JM Tilley WD Greenberg NM 《The Journal of biological chemistry》2001,276(14):11204-11213
We have used the autochthonous transgenic adenocarcinoma of mouse prostate (TRAMP) model to investigate the relationship between somatic mutation in the androgen receptor (AR) and the emergence of androgen-independent prostate cancer. Here we report the identification, isolation, and characterization of distinct classes of AR variants from spontaneous prostate tumors in the TRAMP model. Using cDNA cloning, single stranded conformation polymorphism and sequencing strategies, 15 unique somatic mutations in the AR were identified in prostate tumors obtained from eight TRAMP mice between 24 and 29 weeks of age. At least one mutation was isolated from each mouse. All mutations were single base substitutions, 10 were missense and 5 were silent. Nine mutations in the AR were identified in tumors of four mice that were castrated at 12 weeks of age. Interestingly, the majority of mutations (seven out of nine, 78%) identified in the androgen-independent tumors colocalized in the AR transactivation domain. The remaining mutations colocalized in the AR ligand binding domain. In general, the AR variants demonstrated promoter-, cell-, and cofactor-specific activities in response to various hormones. All AR variants isolated in this study maintained strong sensitivity for androgens, and four AR variants isolated from castrated mice demonstrated increased activities in the absence of ligand. The K638M and F677S variants demonstrated increased activities in response to androgen, and K638M also demonstrated increased response to estradiol. In the presence of AR coactivator ARA70 the E231G variant demonstrated increased activity in response to both androgen and estradiol. However, in the presence of AR coactivator ARA160 the E231G variant was selectively responsive to androgen. Collectively these analyses not only indicate that somatic mutations in the AR gene occur spontaneously in TRAMP tumors but also how changes in the hormonal environment may drive the selection of spontaneous somatic mutations that provide a growth advantage. 相似文献
4.
5.
Butler LM Centenera MM Neufing PJ Buchanan G Choong CS Ricciardelli C Saint K Lee M Ochnik A Yang M Brown MP Tilley WD 《Molecular endocrinology (Baltimore, Md.)》2006,20(5):1009-1024
There is increasing evidence that sensitization of the androgen receptor (AR) signaling pathway contributes to the failure of androgen ablation therapy for prostate cancer, and that direct targeting of the AR may be a useful therapeutic approach. To better understand how AR function could be abrogated in prostate cancer cells, we have developed a series of putative dominant-negative variants of the human AR, containing deletions or mutations in activation functions AF-1, AF-5, and/or AF-2. One construct, AR inhibitor (ARi)-410, containing a deletion of AF-1 and part of AF-5 of the AR, had no intrinsic transactivation activity but inhibited wild-type AR (wtAR) in a ligand-dependent manner by at least 95% when transfected at a 4:1 molar ratio. ARi-410 was an equally potent inhibitor of gain-of-function AR variants. Ectopic expression of ARi-410 inhibited the proliferation of AR-positive LNCaP cells, but not AR-negative PC-3 cells. Whereas ARi-410 also marginally inhibited progesterone receptor activity, this was far less pronounced than the effect on AR (50% vs. 95% maximal inhibition, respectively), and there was no inhibition of either vitamin D or estrogen receptor activity. In the presence of ligand, ARi-410 interacted with wtAR, and both receptors translocated into the nucleus. Whereas the amino-carboxy terminal interaction was not necessary for optimal dominant-negative activity, disruption of dimerization through the ligand binding domain reduced the efficacy of ARi-410. In addition, although inhibition of AR function by ARi-410 was not dependent on DNA binding, the DNA binding domain was required for dominant-negative activity. Taken together, our results suggest that interaction between ARi-410 and the endogenous AR in prostate cancer cells, potentially through the DNA binding and ligand binding domains, results in a functionally significant reduction in AR signaling and AR-dependent cell growth. 相似文献
6.
S Mukherjee O Cruz-Rodríguez E Bolton JA Iñiguez-Lluhí 《The Journal of biological chemistry》2012,287(37):31195-31206
7.
8.
9.
Shenk JL Fisher CJ Chen SY Zhou XF Tillman K Shemshedini L 《The Journal of biological chemistry》2001,276(42):38472-38479
Prostate-specific antigen (PSA) is highly overexpressed in prostate cancer. One important regulator of PSA expression is the androgen receptor (AR), the nuclear receptor that mediates the biological actions of androgens. AR is able to up-regulate PSA expression by directly binding and activating the promoter of this gene. We provide evidence here that that this AR activity is repressed by the tumor suppressor protein p53. p53 appears to exert its inhibition of human AR (hAR) by disrupting its amino- to carboxyl-terminal (N-to-C) interaction, which is thought to be responsible for the homodimerization of this receptor. Consistent with this, p53 is also able to block hAR DNA binding in vitro. Our previous data have shown that c-Jun can mediate hAR transactivation, and this appears to result from a positive effect on hAR N-to-C interaction and DNA binding. Interestingly, c-Jun is able to relieve the negative effects of p53 on hAR transactivation, N-to-C interaction, and DNA binding, demonstrating antagonistic activities of these two proteins. Importantly, a p53 mutation found in metastatic prostate cancer severely disrupts the p53 negative activity on hAR, suggesting that the inability of p53 mutants to down-regulate hAR is, in part, responsible for the metastatic phenotype. 相似文献
10.
11.
12.
13.
Modulation of androgen receptor activation function 2 by testosterone and dihydrotestosterone 总被引:1,自引:0,他引:1
Askew EB Gampe RT Stanley TB Faggart JL Wilson EM 《The Journal of biological chemistry》2007,282(35):25801-25816
14.
Hodgson MC Astapova I Cheng S Lee LJ Verhoeven MC Choi E Balk SP Hollenberg AN 《The Journal of biological chemistry》2005,280(8):6511-6519
15.
16.
17.
18.
Liao G Chen LY Zhang A Godavarthy A Xia F Ghosh JC Li H Chen JD 《The Journal of biological chemistry》2003,278(7):5052-5061
19.
Linking beta-catenin to androgen-signaling pathway. 总被引:14,自引:0,他引:14
Fajun Yang Xiaoyu Li Manju Sharma Carl Y Sasaki Dan L Longo Bing Lim Zijie Sun 《The Journal of biological chemistry》2002,277(13):11336-11344