Nuclear Coactivator-62 kDa/Ski-interacting Protein Is a Nuclear Matrix-associated Coactivator That May Couple Vitamin D Receptor-mediated Transcription and RNA Splicing

The vitamin D receptor (VDR) and its ligand 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] are required for normal keratinocyte differentiation. Both the epidermis and the hair follicle are disrupted in VDR-null mice. Hairless (Hr), a presumptive transcription factor with no known ligand, when mutated, disrupts hair follicle cycling similar to the effects of VDR mutations. Hr, like VDR, is found in the nuclei of keratinocytes in both epidermis and hair follicle. To investigate the potential interaction between Hr and VDR on keratinocyte differentiation, we examined the effect of Hr expression on vitamin D-responsive genes in normal human keratinocytes. Inhibition of Hr expression in keratinocytes potentiated the induction of vitamin D-responsive genes, including involucrin, transglutaminase, phospholipase C-γ1, and 25-hydroxyvitamin D-24-hydroxylase (24-hydroxylase) by 1,25(OH)2D3. Overexpression of Hr in human keratinocytes suppressed the induction of these vitamin D-responsive genes by 1,25(OH)2D3. Coimmunoprecipitation, DNA mobility shift assays, and chromatin immunoprecipitation revealed that Hr binds to VDR in human keratinocytes. Hr binding to the VDR was eliminated by 1,25(OH)2D3, which recruited the coactivator vitamin D receptor-interacting protein 205 (DRIP205) to the VDR/vitamin D response element complex. These data indicate that Hr functions as a corepressor of VDR to block 1,25(OH)2D3 action on keratinocytes.

Download Full-text

Binding of Liganded Vitamin D Receptor to the Vitamin D Receptor Interacting Protein Coactivator Complex Induces Interaction with RNA Polymerase II Holoenzyme

Journal of Biological Chemistry ◽

10.1074/jbc.275.15.10719 ◽

2000 ◽

Vol 275 (15) ◽

pp. 10719-10722 ◽

Cited By ~ 42

Author(s):

Natsuko Chiba ◽

Zalman Suldan ◽

Leonard P. Freedman ◽

Jeffrey D. Parvin

Keyword(s):

Vitamin D ◽

Rna Polymerase ◽

Rna Polymerase Ii ◽

Vitamin D Receptor ◽

Interacting Protein ◽

Rna Polymerase Ii Holoenzyme ◽

Coactivator Complex

Download Full-text

Polyamines Modulate the Interaction between Nuclear Receptors and Vitamin D Receptor-Interacting Protein 205

Molecular Endocrinology ◽

10.1210/mend.16.7.0883 ◽

2002 ◽

Vol 16 (7) ◽

pp. 1502-1510 ◽

Cited By ~ 15

Author(s):

Yutaka Maeda ◽

Christophe Rachez ◽

Leo Hawel ◽

Craig V. Byus ◽

Leonard P. Freedman ◽

...

Keyword(s):

Vitamin D ◽

Ligand Binding ◽

Nuclear Receptors ◽

Vitamin D Receptor ◽

Binding Domain ◽

Ligand Binding Domain ◽

Full Length ◽

Dependent Manner ◽

Interacting Protein

Abstract Nuclear receptors (NR) activate transcription by interacting with several different coactivator complexes, primarily via LXXLL motifs (NR boxes) of the coactivator that bind a common region in the ligand binding domain of nuclear receptors (activation function-2, AF–2) in a ligand-dependent fashion. However, how nuclear receptors distinguish between different sets of coactivators remains a mystery, as does the mechanism by which orphan receptors such as hepatocyte nuclear factor 4α (HNF4α) activate transcription. In this study, we show that HNF4α interacts with a complex containing vitamin D receptor (VDR)-interacting proteins (DRIPs) in the absence of exogenously added ligand. However, whereas a full-length DRIP205 construct enhanced the activation by HNF4α in vivo, it did not interact well with the HNF4α ligand binding domain in vitro. In investigating this discrepancy, we found that the polyamine spermine significantly enhanced the interaction between HNF4α and full-length DRIP205 in an AF-2, NR-box-dependent manner. Spermine also enhanced the interaction of DRIP205 with the VDR even in the presence of its ligand, but decreased the interaction of both HNF4α and VDR with the p160 coactivator glucocorticoid receptor interacting protein 1 (GR1P1). We also found that GR1P1 and DRIP205 synergistically activated HNF4α-mediated transcription and that a specific inhibitor of polyamine biosynthesis, α-difluoromethylornithine (DFMO), decreased the ability of HNF4α to activate transcription in vivo. These results lead us to propose a model in which polyamines may facilitate the switch between different coactivator complexes binding to NRs.

Download Full-text