부산대학교 도서관

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.bcp.2006.07.005 Byline: Jonathan D. Turner (a), Andrea B. Schote (a)(b), Joana A. Macedo (a)(b), Laetitia P.L. Pelascini (a), Claude P. Muller (a)(b) Keywords: Glucocorticoid receptor; NR3C1; 5' untranslated region; Alternative exon splicing Abbreviations: ALL, acute lymphoblastic leukaemia; EST, expression sequence tag; GC, glucocorticoid; GR, glucocorticoid receptor; HPA, hypothalamic-pituitary-adrenal; NGFI-A, nerve growth factor inducible protein A; RACE, rapid amplification of complimentary ends; UTR, untranslated region; YY1, Yin Yang 1 Abstract: The CpG island upstream of the GR is highly structured and conserved at least in all the animal species that have been investigated. Sequence alignment of these CpG islands shows inter-species homology ranging from 64 to 99%. This 3.1kb CpG rich region upstream of the GR exon 2 encodes 5' untranslated mRNA regions. These CpG rich regions are organised into multiple first exons and, as we and others have postulated, each with its own promoter region. Alternative mRNA transcript variants are obtained by the splicing of these alternative first exons to a common acceptor site in the second exon of the GR. Exon 2 contains an in-frame stop codon immediately upstream of the ATG start codon to ensure that this 5' heterogeneity remains untranslated, and that the sequence and structure of the GR is unaffected. Tissue specific differential usage of exon 1s has been observed in a range of human tissues, and to a lesser extent in the rat and mouse. The GR expression level is tightly controlled within each tissue or cell type at baseline and upon stimulation. We suggest that no single promoter region may be capable of containing all the necessary promoter elements and yet preserve the necessary proximity to the transcription initiation site to produce such a plethora of responses. Thus we further suggest that alternative first exons each under the control of specific transcription factors control both the tissue specific GR expression and are involved in the tissue specific GR transcriptional response to stimulation. Spreading the necessary promoter elements over multiple promoter regions, each with an associated alternative transcription initiation site would appear to vastly increase the capacity for transcriptional control of GR. Author Affiliation: (a) Institute of Immunology, Laboratoire National de Sante, 20A rue Auguste Lumiere, L-1950 Luxembourg, Grand Duchy of Luxembourg (b) Department of Immunology, Graduate School of Psychobiology, University of Trier, D-54290 Trier, Germany Article History: Received 15 May 2006; Accepted 11 July 2006