The putative androgen receptor-A form results from in vitro proteolysis

Gregory, Chris; He, Bin; Wilson, Elizabeth M.

doi:10.1677/jme.0.0270309

Cited by 60 publications

(41 citation statements)

References 52 publications

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“…Our results differ from the ones reported in the study on colon cancer by Catalano, et al, in that AR-B, was still the dominant AR protein present in all PCa tissues, though the AR-A/B ratio was increased (9). The study by Gregory et al in 2001 did not show any evidence of a functional AR-A isoform (22). However, a later study demonstrated that the overexpression of AR-A reduced DHT-dependent DNA synthesis when transfected together with AR-B in AR-defective HOB and GSF-540 cells.…”

Section: Discussioncontrasting

confidence: 99%

Differential expression and function of AR isoforms in prostate cancer

Zeng

Li²,

Sun

et al. 2011

Oncol Rep

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Abstract. The androgen receptor (AR) plays a key role in prostate cancer (PCa). Two isoforms of AR, are AR-A and -B, which differ by a lack of the first 187 amino acids in the NH2-terminal transactivation domain of AR-A. Since little is known about the expression and basic function of the AR-A/B isoforms in prostate cancer, the aim of this study was to analyze this possible association. The AR-A, -B and AR-A/B ratio was determined in the tissues of healthy controls, benign prostate hyperplasia (BPH) and PCa by means of Western blot analysis and immunofluorescence. The elevation of AR-A, and -B, as well as the AR-A/B ratio with regard to Gleason scores, were assessed in prostate cancer compared to BPH and normal prostate. In order to further investigate the role of AR A/B isoform function, we transfected PC3 cells with an AR or AR-A expression vector. The overexpression of AR-A and -B significantly decreased the invasion and proliferation of PC3 cells. However, the overexpression of AR-A further decreased proliferation but accelerated the invasion of PC3 cells compared to AR-B. In conclusion, the elevation of AR-A and -B, and the AR-A/B ratio, is associated with prostate cancer occurrence and progression. Furthermore, AR-A could provide a new potential therapy with regard to the decrease in the invasion and proliferation of prostate cancer cells. Our study provides insight into further understanding the biological role of AR-A in its interaction with AR-B and its impact on PCa clinical treatment.

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Section: Discussioncontrasting

confidence: 99%

Differential expression and function of AR isoforms in prostate cancer

Zeng

Li²,

Sun

et al. 2011

Oncol Rep

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“…The weaker band under the 110-kDa AR in lane 5 (Fig. 3A, ii) likely resulted from in vitro proteolytic cleavage of AR, which has been described in prostate cancer cells previously (36).…”

Section: Methodsmentioning

confidence: 55%

Transcription Factor Stat5 Synergizes with Androgen Receptor in Prostate Cancer Cells

et al. 2008

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The molecular mechanisms underlying progression of prostate cancer to the hormone-independent state are poorly understood. Signal transducer and activator of transcription 5a and 5b (Stat5a/b) is critical for the viability of human prostate cancer cells. We have previously shown that Stat5a/b is constitutively active in high-grade human prostate cancer, but not in normal prostate epithelium. Furthermore, activation of Stat5a/b in primary human prostate cancer predicted early disease recurrence. We show here that transcription factor Stat5a/b is active in 95% of clinical hormone-refractory human prostate cancers. We show for the first time that

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“…Caspase-3 is suggested to be the enzyme responsible for the cleavage of this pathologic AR (19)(20)(21)(22). Based on these observations of AR in neurodegenerative diseases, caspase-3 is implicated to cleave AR in prostate cancer cells (15,23). However, we found that, under physiologic conditions, caspase-3 is not present in its activated form in exponentially growing LNCaP cells and caspase-3 is not part of the AR-CaM complex.…”

Section: Discussionmentioning

confidence: 67%

“…First, AR is degraded to small (V10 residues) peptides by the threonine proteases of the ubiquitin-proteasome system (4)(5)(6)(7)(8)(9). Second, AR can be cleaved by serine proteases (10)(11)(12)(13)(14)(15)(16). These studies established that, structurally, AR consists of at least three domains, the ligand-binding domain (LBD), the DNA-binding domain (DBD), and the NH 2 -terminal domain (ATD), separated by protease-sensitive linker regions.…”

Section: Introductionmentioning

confidence: 99%

Calmodulin-Androgen Receptor (AR) Interaction: Calcium-Dependent, Calpain-Mediated Breakdown of AR in LNCaP Prostate Cancer Cells

Pelley¹,

Chinnakannu²,

Murthy³

et al. 2006

Cancer Research

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Chemotherapy of prostate cancer targets androgen receptor (AR) by androgen ablation or antiandrogens, but unfortunately, it is not curative. Our attack on prostate cancer envisions the proteolytic elimination of AR, which requires a fuller understanding of AR turnover. We showed previously that calmodulin (CaM) binds to AR with important consequences for AR stability and function. To examine the involvement of Ca 2+ /CaM in the proteolytic breakdown of AR, we analyzed LNCaP cell extracts that bind to a CaM affinity column for the presence of low molecular weight forms of AR (intact AR size, f114 kDa). Using an antibody directed against the NH 2 -terminal domain (ATD) of AR on Western blots, we identified f76-kDa, f50-kDa, and 34/31-kDa polypeptides in eluates of CaM affinity columns, suggesting the presence of CaM-binding sites within the 31/34-kDa ATD of AR. Under cell-free conditions in the presence of phenylmethylsulfonyl fluoride, AR underwent Ca 2+ -dependent degradation. AR degradation was inhibited by N-acetyl-leu-leu-norleu, an inhibitor of thiol proteases, suggesting the involvement of calpain. In intact cells, AR breakdown was accelerated by raising intracellular Ca 2+ using calcimycin, and increased AR breakdown was reversed with the cell-permeable Ca 2+ chelator bis-(O-aminophenoxy)-ethane-N,N,N ¶,N ¶-tetraacetic acid tetra-(acetoxymethyl)-ester. In CaM affinity chromatography studies, the Ca 2+ -dependent protease calpain was bound to and eluted from the CaM-agarose column along with AR. Caspase-3, which plays a role in AR turnover under stress conditions, did not bind to the CaM column and was present in the proenzyme form. Similarly, AR immunoprecipitates prepared from wholecell extracts of exponentially growing LNCaP cells contained both calpain and calpastatin. Nuclear levels of calpain and calpastatin (its endogenous inhibitor) changed in a reciprocal fashion as synchronized LNCaP cells progressed from G 1 to S phase. These reciprocal changes correlated with changes in AR level, which increased in late G 1 phase and decreased as S phase progressed. Taken together, these observations suggest potential involvement of AR-bound CaM in calciumcontrolled, calpain-mediated breakdown of AR in prostate cancer cells. (Cancer Res 2006; 66(24): 11754-62)

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The putative androgen receptor-A form results from in vitro proteolysis

Cited by 60 publications

References 52 publications

Differential expression and function of AR isoforms in prostate cancer

Differential expression and function of AR isoforms in prostate cancer

Transcription Factor Stat5 Synergizes with Androgen Receptor in Prostate Cancer Cells

Calmodulin-Androgen Receptor (AR) Interaction: Calcium-Dependent, Calpain-Mediated Breakdown of AR in LNCaP Prostate Cancer Cells

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