A neuronal-specific differentiation protein that directly modulates retinoid receptor transcriptional activation

Henry, Spencer, Theodosiou Maria, Lou Dingyuan, Noonan

Description

The specificity of a nuclear receptor's ability to modulate gene expression resides in its ability to bind a specific lipophilic ligand, associate with specific dimerization partners and bind specific DNA sequences in the promoter regions of genes. This sequence of events appears to be the basis for targeting an additional regulatory complex composed of a variety of protein and RNA components that deliver signals for facilitation or inhibition of the RNA polymerase complex. Characterization of the tissue and cell-specific components of these coregulatory complexes appear to be integral to our understanding of nuclear receptor regulation of transcription. Results A novel yeast screen sensitive to retinoid-X receptor (RXR) transcriptional activation resulted in the isolation of the rat homologue of the mouse NPDC-1 gene. NPDC-1 has been shown to be involved in the control of neural cell proliferation and differentiation, possibly through interactions with the cell cycle promoting transcription factor E2F-1. Although the amino acid sequence of NPDC-1 is highly conserved between mouse, rat and human homologues, their tissue specific expression was seen to vary. A potential for direct protein:protein interaction between NPDC-1, RXR and retinoic acid receptor beta (RARβ) was observed in vitro and NPDC-1 facilitated RXR homodimer and RAR-RXR heterodimer DNA binding in vitro. Expression of NPDC-1 was also observed to repress transcription mediated by retinoid receptors as well as by several other nuclear receptor family members, although not in a universal manner. Conclusions These results suggest that NPDC-1, through direct interaction with retinoid receptors, functions to enhance the transcription complex formation and DNA binding function of retinoid receptors, but ultimately repress retinoid receptor-mediated gene expression. As with NPDC-1, retinoids and their receptors have been implicated in brain development and these data provide a point of convergence for NPDC-1 and retinoid mediation of neuronal differentiation.

Informations

• Publié par: biomed
• Publié le: 01 janvier 2003
• Nombre de lectures: 9
• Langue: English

Extrait

Pga e 1fo1  ( 9 apegum nr bet nor foaticnoitrup esops)

Abstract Background: The specificity of a nuclear receptor's abil ity to modulate gene expression resides in its ability to bind a specific lipophilic ligand, associate with specific dimerization partners and bind specific DNA sequences in the promoter regions of genes. This sequence of events appears to be the basis for targeting an additional regulatory complex compos ed of a variety of protein and RNA components that deliver signals for facilitation or inhibition of the RNA polymerase complex. Characterization of the tissue and cell-specific components of these coregulatory complexes appear to be integral to our understanding of nuclear receptor regulation of transcription. Results: A novel yeast screen sensitiv e to retinoid-X receptor (R XR) transcriptional activation resulted in the isolation of the rat homologu e of the mouse NPDC-1 gene. NPDC-1 has been shown to be involved in the control of neural cell proliferation and differentiation, possibly through interactions with the cell cycle promoting tran scription factor E2F-1. Although the amino acid sequence of NPDC-1 is highly conserved between mouse, rat an d human homologues, their tissue specific expression was seen to vary. A potential for direct pr otein:protein interaction between NPDC-1, RXR and retinoic acid receptor beta (RAR β ) was observed in vitro and NPDC-1 facilitated RXR homodimer and RAR-RXR hetero dimer DNA binding in vitro. Expression of NPDC-1 was also observed to repress transcriptio n mediated by retinoid receptors as well as by several other nuclear receptor family memb ers, although not in a universal manner. Conclusions: These results suggest that NPDC-1, th rough direct interaction with retinoid receptors, functions to enhance the transcriptio n complex formation and DNA binding function of retinoid receptors, but ultimate ly repress retinoid receptor-med iated gene expression. As with NPDC-1, retinoids and their receptors have been implicated in brain development and these data provide a point of convergence for NPDC-1 and re tinoid mediation of neuronal differentiation.

Published: 10 September 2003 Received: 20 May 2003 Nuclear Receptor 2003, 1 :7 Accepted: 10 September 2003 This article is available from: http:/ /www.nuclear-receptor.com/content/1/1/7 © 2003 Henry II et al; licensee BioMed Centra l Ltd. This is an Open Ac cess article: verbatim copyin g and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.

Background all-trans retinoic acid (atRA) regulates gene expression by Retinoids are a class of compounds that demonstrate a complexing with members of the steroid/hormone family profound effect on cellular differentiation and prolifera- of nuclear receptors. Two groups of nuclear receptors have tion [1–4]. The physiologically active retinoid metabolite, been shown to mediate retinoid signaling. The three

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Research Open Access A neuronal-specific differentiatio n protein that directly modulates retinoid receptor transcriptional activation Kenneth W Henry II, Michael L Spencer, Maria Theodosiou, Dingyuan Lou and Daniel J Noonan*

Address: Department of Molecula r and Cellular Biochemistry, University of Kentucky, 800 Ro se Street, Lexington, KY 40536, USA Email: Kenneth W Henry II - khenry@sequenom .com; Michael L Spencer - [e-mail]; Maria Theodosiou - [e-mail]; Dingyuan Lou - [e-mail]; Daniel J Noonan* - [e-mail] * Corresponding author

Nuclear Receptor