کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8324193 | 1539907 | 2013 | 10 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Targeted disruption of the p160 coactivator interface of androgen receptor (AR) selectively inhibits AR activity in both androgen-dependent and castration-resistant AR-expressing prostate cancer cells
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کلمات کلیدی
HbdATCCECLGRERPMIRT-PCRVDRCRPCGSTLUCRLUDMESGK1FBSSRC-1Dulbecco's modified Eagle Medium - Eagle Medium اصلاح شده DulbeccoPCA - PCASmall interfering RNA - RNA تداخل کوچکsiRNA - siRNAenhanced chemiluminescence - بهبود شیمیایی لومنanalysis of variance - تحلیل واریانسANOVA - تحلیل واریانس Analysis of variancehormone binding domain - دامنه اتصال هورمونProstate cancer - سرطان پروستاتCastration resistant prostate cancer - سرطان پروستات مقاوم در برابر کاتتراسیونfetal bovine serum - سرم جنین گاوGlucocorticoid response element - عنصر پاسخ گلوکوکورتیکوئیدluciferase - لوسیفرازAmerican Type Culture Collection - مجموعه فرهنگی نوع آمریکاییreverse transcription-PCR - معکوس رونویسی PCRRoswell Park Memorial Institute medium - موسسه خاطرات Roswell Park mediumrelative light units - واحدهای نسبی نورPeptide - پپتید glutathione S-transferase - گلوتاتیون S-ترانسفرازAndrogen Receptor - گیرنده آندروژنیsteroid receptor coactivator - گیرنده استروئید گیرندهVitamin D receptor - گیرنده ویتامین DProgesterone receptor - گیرنده پروژسترونglucocorticoid receptor - گیرنده گلوکوکورتیکوئید
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
زیست شیمی
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چکیده انگلیسی
The evidence that androgen blockade-resistant prostate cancer, termed castration resistant, remains androgen receptor (AR) dependent is compelling. AR is re-activated through multiple mechanisms including expression of constitutively active splice variants that lack hormone binding domains (HBDs). This highlights the need to develop therapies that target regions other than the HBD. Because the p160 coactivators interact most strongly with the amino-terminus of AR, we examined the consequences of disrupting this interaction. We identified two overlapping SRC-1 peptides that interact with AR, but not with progesterone receptor. These peptides reduce AR and AR variant AR-V7 dependent induction of an AR responsive reporter. Using mammalian two hybrid assays, we found that the peptides interrupt the AR/SRC-1, AR/SRC-2 and AR N/C interactions, but not SRC-1/CARM-1 interactions. Consistent with the SRC-1 dependence of induced, but not repressed genes, in LNCaP cells, the peptides inhibited hormone dependent induction of endogenous target genes including PSA and TMPRSS2, but did not block AR dependent repression of UGT2B17 or inhibit vitamin D receptor activity. Simultaneous detection of SRC-1 peptides and PSA by double immunofluorescence in transfected LNCaP cells clearly demonstrated a strong reduction in PSA levels in cells expressing the peptides. The peptides also inhibited the AR dependent expression of PSA in castration resistant C4-2 cells. Moreover they inhibited androgen dependent proliferation of LNCaP cells and proliferation of C4-2 cells in androgen depleted medium without affecting AR negative PC-3 cells. Thus, the p160 coactivator binding site is a novel potential therapeutic target to inhibit AR activity.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: The International Journal of Biochemistry & Cell Biology - Volume 45, Issue 4, April 2013, Pages 763-772
Journal: The International Journal of Biochemistry & Cell Biology - Volume 45, Issue 4, April 2013, Pages 763-772
نویسندگان
Manjula Nakka, Irina U. Agoulnik, Nancy L. Weigel,