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C/EBPalpha redirects androgen receptor signaling through a unique bimodal interaction.

ABSTRACT: Nuclear expression of CCAAT enhancer binding protein-alpha (C/EBPalpha), which supports tissue differentiation through several antiproliferative protein-protein interactions, augurs terminal differentiation of prostate epithelial cells. C/EBPalpha is also a tumor suppressor, but in many tumors its antiproliferative interactions may be attenuated by de-phosphorylation. C/EBPalpha acts as a corepressor of the classical androgen response element (ARE)-mediated gene activation by the androgen receptor (AR), but this is paradoxical as the genotropic actions of AR are crucial not only for the growth of the prostate but also for its maintenance and function. We show that DNA-bound C/EPBalpha recruits AR to activate transcription. C/EBPalpha-dependent trans-activation by AR also overrode suppression of AREs by C/EBPalpha elsewhere in a promoter. This mechanism was remarkable in that its androgen dependence was apparently for nuclear translocation of AR; it was otherwise androgen independent, flutamide insensitive and tolerant to disruption of AR dimerization. Gene response profiles and global chromatin associations in situ supported the direct bimodal regulation of AR transcriptional signaling by C/EBPalpha. This unique mechanism explains the functional coordination between AR and C/EPBalpha in the prostate and also shows that hormone-refractory AR signaling in prostate cancer could occur through receptor tethering.

SUBMITTER: Zhang J

PROVIDER: S-EPMC3836216 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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C/EBPalpha redirects androgen receptor signaling through a unique bimodal interaction.

Zhang J J Gonit M M Salazar M D MD Shatnawi A A Shemshedini L L Trumbly R R Ratnam M M

Oncogene 20091109 5

Nuclear expression of CCAAT enhancer binding protein-alpha (C/EBPalpha), which supports tissue differentiation through several antiproliferative protein-protein interactions, augurs terminal differentiation of prostate epithelial cells. C/EBPalpha is also a tumor suppressor, but in many tumors its antiproliferative interactions may be attenuated by de-phosphorylation. C/EBPalpha acts as a corepressor of the classical androgen response element (ARE)-mediated gene activation by the androgen recept ...[more]

PMID: 19901962

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Project description:Fluorosed maturation stage enamel is hypomineralized in part due to a delay in the removal of matrix proteins to inhibit final crystal growth. The delay in protein removal is likely related to reduced expression of kallikrein-related peptidase 4 (KLK4), resulting in a reduced matrix proteinase activity that found in fluorosed enamel. Klk4 transcription is known to be regulated in other cell types by androgen receptor (AR) and progesterone receptors (PR). In this study, we determined the possible role of fluoride in down-regulation of KLK4 expression through changes in AR and PR. Immunohistochemical localization showed that both AR and PR nuclear translocation was suppressed in fluoride exposed mice. However, when AR signaling was silenced in mouse ameloblast-lineage cells (ALCs), expression of both Pgr and Klk4 were increased. Similar to the effect from AR silencing, fluoride also upregulated Pgr in ALCs, but downregulated Klk4. This finding suggests that though suppression of AR transactivation by fluoride increases Prg expression, inhibition of PR transactivation by fluoride has a much greater effect, ultimately resulting in downregulation of Klk4 expression. These findings indicate that in ameloblasts, PR has a dominant role in regulating Klk4 expression. We found that when AR was retained in the cytoplasm in the presence of fluoride, that co-localized with heat shock protein 90 (HSP90), a well-known chaperone for steroid hormone receptors. HSP90 also known to regulate TGF-β signaling. Consistent with the effect of fluoride on AR and HSP90, we found evidence of reduced TGF-β signaling activity in fluorosed ameloblasts as reduced immunolocalization of TGFB1 and TGFBR-2 and a significant increase in Cyclin D1 mRNA expression, which also possibly contributes to the reduced AR signaling activity. In vitro, when serum was removed from the media, aluminum was required for fluoride to inhibit the dissociation of HSP90 from AR. In conclusion, fluoride related downregulation of Klk4 is associated with reduced nuclear translocation of AR and PR, and also reduced TGF-β signaling activity, all of which are regulated by HSP90. We suggest that a common mechanism by which fluoride affects AR, PR, and TGF-β signaling is through inhibiting ATP-dependent conformational cycling of HSP90.

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C/EBPalpha redirects androgen receptor signaling through a unique bimodal interaction.

Publications

C/EBPalpha redirects androgen receptor signaling through a unique bimodal interaction.

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