VDR‐Alien: a novel, DNA‐selective vitamin D₃receptor‐corepressor partnership

Abstract

The vitamin D receptor (VDR) is a transcription factor that transmits incoming 1,25-dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)) signaling via combined contact with coactivator proteins and specific DNA binding sites (VDREs), which ultimately results in activation of transcription. In contrast, the mechanisms of transcriptional repression via the VDR are less well understood. This study documents VDR-dependent transcriptional repression largely via histone deacetylase (HDAC) activity. Direct, ligand-sensitive protein-protein interaction of the VDR with the nuclear receptor corepressor (NCoR) and a novel corepressor, called Alien, was demonstrated to be comparable but independent of the VDR AF-2 trans-activation domain. Functional assays indicated that Alien, but not NCoR, displays selectivity for different VDRE structures for transferring these repressive effects into gene regulatory activities. Moreover, superrepression via Alien was found to be affected only in part by HDAC inhibitors such as trichostatin A. Finally, for a dissociation of VDR-Alien complexes in vitro and in vivo, higher ligand concentrations were needed than for a dissociation of VDR-NCoR complexes. This suggests that Alien and NCoR are using different interfaces for interaction with the VDR and different pathways for mediating superrepression, which in turn characterizes Alien as a representative of a new class of corepressors. Taken together, association of the VDR with corepressor proteins provides a further level of transcriptional regulation, which is emerging as a complex network of protein-protein interaction-mediated control.

Detection and Identification of Transcription Factors as Interaction Partners of Alien in vivo

“…3 Alien was previously characterised as a corepressor for specific members of the nuclear hormone receptors such as the thyroid hormone and vitamin D3 receptor. 4 In line with this, we observed that Alien is capable to repress the transcriptional activity of members of the E2F transcription factor family suggesting a role for Alien as a corepressor also for cell cycle regulated genes. 3 The aim of the present study was to detect in vivo further specific interacting partners of endogenously expressed Alien.…”

Synergistic growth inhibition of prostate cancer cells by 1α,25 Dihydroxyvitamin D3 and its 19-nor-hexafluoride analogs in combination with either sodium butyrate or trichostatin A

“…*P50.05 cancer and PC-3 and DU-145 cells display many alterations that are associated with metastatic androgen-independent cancer, including aberrant p53 function and dysregulation of normal apoptotic responses (Carrol et al, 1993;Ewing et al, 1995;Isaacs et al, 1994;Tamimi et al, 1996;Mackey et al, 1998) and furthermore do not readily undergo apotosis when exposed to 1a,25(OH) 2 D 3 Zhuang and Burnstein, 1998). Interestingly, Carlberg and co-workers have demonstrated that either di erent VDR co-repressors complexes or structurally di erent vitamin D 3 analogs demonstrate VDRE selectivity (Quack and Carlberg, 1999;Nayeri and Carlberg, 1997;Danielsson et al, 1997;Polly et al, 2000). These ®ndings would allow for di erential regulation of genes by 1a,25(OH) 2 D 3 , within the same cell line, and disruption of a speci®c co-factor, such as a co-repressor with associated HDAC activity, would consequently silence a speci®c subset of 1a,25(OH) 2 D 3 -responsive genes.…”

Estrogen receptor corepressors -- a role in human breast cancer?

“…It is likely that cofactors which have been described to repress other NRs, such as Alien (Dressel et al 1999, Polly et al 2000, PSF (polypyrimidine tract-binding protein) (Mathur et al 2001), and SUN-CoR (small unique nuclear receptor corepressor) (Zamir et al 1997), might also modulate ERα activity.…”