Structure and functional regulation of the CD38 promoter
- Mount Sinai Bone Program and Department of Medicine, Mount Sinai School of Medicine, NY (United States)
CD38 has multiple roles in biology, including T lymphocyte signaling, neutrophil migration, neurotransmission, cell proliferation, apoptosis, and bone remodeling. To study the transcriptional control of the CD38 gene, we cloned a putative 1.8 kb promoter fragment from a rabbit genomic DNA library. Primer extension analysis indicated two transcription start sites consistent with the absence of a TATA box. Sequence analysis revealed several AP-1, AP-4, myo-D, GATA, and SP-1 sequences. MC3T3.E1 (osteoblast) or RAW-C3 (osteoclast precursor macrophage) cells were then transfected with the CD38 promoter or its deletion fragments ligated to the luciferase reporter gene. Except for the shortest 41 bp fragment, all fragments showed significant luciferase activity. There was a marked stimulation of basal activity in the 93 bp fragment that contained a GC box and SP-1 site. Furthermore, there were significant differences in the activity of the fragments in MC3T3.E1 and RAW-C3 cells. Intracellular Ca{sup 2+} elevations by ionomycin (10 {mu}M) in MC3T3.E1 cells inhibited promoter activity, except in the short 41 bp. In contrast, cAMP elevation by exposure to forskolin (100 {mu}M) inhibited activation of all fragments, except the 0.6 and 1.2 kb fragments. Finally, TNF-{alpha} stimulated promoter activity in RAW-C3 cells transfected with the 93 bp and 1.0 kb fragments, consistent with the stimulation of CD38 mRNA by TNF-{alpha}. Physiologically, therefore, modulation of the expression of the NAD{sup +}-sensing enzyme, CD38, by Ca{sup 2+}, cAMP, and cytokines, such as TNF-{alpha} may contribute to coupling the intense metabolic activity of osteoclasts and osteoblasts to their respective bone-resorbing and bone-forming functions.
- OSTI ID:
- 20798844
- Journal Information:
- Biochemical and Biophysical Research Communications, Vol. 341, Issue 3; Other Information: DOI: 10.1016/j.bbrc.2006.01.033; PII: S0006-291X(06)00107-0; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
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