The Rules of DNA Recognition by the Androgen Receptor

Denayer, Sarah; Helsen, Christine; Thorrez, Lieven; Haelens, Annemie; Claessens, Frank

doi:10.1210/me.2009-0310

Cited by 127 publications

(129 citation statements)

References 53 publications

Supporting

Mentioning

127

Contrasting

Order By: Relevance

“…S2B), some of the imperfect palindrome AREs and/or halfsites of ARE and ERE could be involved in male-specific AGT1 expression. The functional significance of imperfect AREs and half-sites of ARE or ERE is, however, still not established (29).…”

Section: Discussionmentioning

confidence: 99%

Novel cystine transporter in renal proximal tubule identified as a missing partner of cystinuria-related plasma membrane protein rBAT/SLC3A1

Nagamori

Wiriyasermkul

Guarch

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Heterodimeric amino acid transporters play crucial roles in epithelial transport, as well as in cellular nutrition. Among them, the heterodimer of a membrane protein b 0,+ AT/SLC7A9 and its auxiliary subunit rBAT/ SLC3A1 is responsible for cystine reabsorption in renal proximal tubules. The mutations in either subunit cause cystinuria, an inherited amino aciduria with impaired renal reabsorption of cystine and dibasic amino acids. However, an unsolved paradox is that rBAT is highly expressed in the S3 segment, the late proximal tubules, whereas b 0,+ AT expression is highest in the S1 segment, the early proximal tubules, so that the presence of an unknown partner of rBAT in the S3 segment has been proposed. In this study, by means of coimmunoprecipitation followed by mass spectrometry, we have found that a membrane protein AGT1/SLC7A13 is the second partner of rBAT. AGT1 is localized in the apical membrane of the S3 segment, where it forms a heterodimer with rBAT. Depletion of rBAT in mice eliminates the expression of AGT1 in the renal apical membrane. We have reconstituted the purified AGT1-rBAT heterodimer into proteoliposomes and showed that AGT1 transports cystine, aspartate, and glutamate. In the apical membrane of the S3 segment, AGT1 is suggested to locate itself in close proximity to sodium-dependent acidic amino acid transporter EAAC1 for efficient functional coupling. EAAC1 is proposed to take up aspartate and glutamate released into luminal fluid by AGT1 due to its countertransport so that preventing the urinary loss of aspartate and glutamate. Taken all together, AGT1 is the long-postulated second cystine transporter in the S3 segment of proximal tubules and a possible candidate to be involved in isolated cystinuria.amino acid transporter | cystine reabsorption | cystinuria | kidney T he heteromeric amino acid transporter (HAT) family is one of the major amino acid transporter families responsible for cellular uptake and epithelial transport (1-3). HATs form heterodimers composed of a 12 membrane spanning light chain (SLC7) that catalyzes transport functions and a single membrane spanning heavy chain (SLC3) essential for plasma membrane localization and stabilization of the light chains. Two heavy chains, SLC3A1/ rBAT and SLC3A2/4F2hc/CD98hc, covalently bound to light chains via a disulfide bridge have been identified so far (4-6). 4F2hc interacts with most of the light chains in HATs whereas rBAT has been known to form a heterodimer only with b 0,+ AT/ SLC7A9. Because the rBAT-b 0,+ AT complex is presented on the apical membrane of proximal tubules in the kidney and involved in the reabsorption of cystine and dibasic amino acids, the mutations of either rBAT or b 0,+ AT cause cystinuria, a disorder of renal reabsorption of cystine and dibasic amino acids leading to serious renal lithiasis due to low solubility of cystine (7).An unsolved paradox on rBAT and b 0,+ AT has been the discrepancy between the distribution of rBAT and that of b 0,+ AT (5,(8)(9)(10). rBAT is the most abundant in the S3 segmen...

show abstract

Section: Discussionmentioning

confidence: 99%

Novel cystine transporter in renal proximal tubule identified as a missing partner of cystinuria-related plasma membrane protein rBAT/SLC3A1

Nagamori

Wiriyasermkul

Guarch

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…All the compounds were dissolved in DMSO (Acros Organics). Cells were harvested in Passive Lysis buffer (Promega) and the luciferase and b-galactosidase measurements were done according to the protocol described previously (19).…”

Section: Androgen Receptor Transactivation Assaymentioning

confidence: 99%

The Effect of F877L and T878A Mutations on Androgen Receptor Response to Enzalutamide

Prekovic

Royen

Voet

et al. 2016

Molecular Cancer Therapeutics

Self Cite

View full text Add to dashboard Cite

Treatment-induced mutations in the ligand-binding domain of the androgen receptor (AR) are known to change antagonists into agonists. Recently, the F877L mutation has been described to convert enzalutamide into an agonist. This mutation was seen to co-occur in the endogenous AR allele of LNCaP cells, next to the T878A mutation. Here, we studied the effects of enzalutamide on the F877L and T878A mutants, as well as the double-mutant AR (F877L/T878A). Molecular modeling revealed favorable structural changes in the double-mutant AR that lead to a decrease in steric clashes for enzalutamide. Ligand-binding assays confirmed that the F877L mutation leads to an increase in relative binding affinity for enzalutamide, but only the combination with the T878A mutation resulted in a strong agonistic activity. This correlated with changes in coregulator recruitment and chromatin interactions. Our data show that enzalutamide is only a very weak partial agonist of the AR F877L, and a strong partial agonist of the double-mutant AR.

show abstract

“…The AR is a ligand-dependent transcription factor that is activated when androgens are present (Helsen et al 2012a). In response to androgen binding, it can initiate expression of genes that contain response elements, which are recognized by the AR (Denayer et al 2010). Indeed, in prostate cells, the AR controls the balance between cell differentiation and proliferation.…”

Section: Ar-targeted Therapiesmentioning

confidence: 99%

Androgen receptor antagonists for prostate cancer therapy

Helsen¹,

Broeck²,

Voet³

et al. 2014

Endocrine-Related Cancer

Self Cite

125

View full text Add to dashboard Cite

Androgen deprivation is the mainstay therapy for metastatic prostate cancer (PCa). Another way of suppressing androgen receptor (AR) signaling is via AR antagonists or antiandrogens. Despite being frequently prescribed in clinical practice, there is conflicting evidence concerning the role of AR antagonists in the management of PCa. In the castration-resistant settings of PCa, docetaxel has been the only treatment option for decades. With recent evidence that castration-resistant PCa is far from AR-independent, there has been an increasing interest in developing new AR antagonists. This review gives a concise overview of the clinically available antiandrogens and the experimental AR antagonists that tackle androgen action with a different approach.

show abstract

The Rules of DNA Recognition by the Androgen Receptor

Cited by 127 publications

References 53 publications

Novel cystine transporter in renal proximal tubule identified as a missing partner of cystinuria-related plasma membrane protein rBAT/SLC3A1

Novel cystine transporter in renal proximal tubule identified as a missing partner of cystinuria-related plasma membrane protein rBAT/SLC3A1

The Effect of F877L and T878A Mutations on Androgen Receptor Response to Enzalutamide

Androgen receptor antagonists for prostate cancer therapy

Contact Info

Product

Resources

About