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Regulation of the antiproliferative gene BTG2 by hypoxia and cobalt



Regulation of the antiproliferative gene BTG2 by hypoxia and cobalt



FASEB Journal 17(4-5): Abstract No. 59-11



B-cell translocation gene (BTG2/TIS21/PC3) was initially identified in PC12 cells as an immediate early gene that is stimulated by nerve growth factor (NGF). It belongs to a large family of antiproliferative genes and is a target of the p53 tumor suppressor protein. We identified BTG2 as a hypoxia-responsive gene in PC12 cells by subtractive suppression hybridization (SSH). We confirmed its upregulation by cDNA microarray analysis of clones from the SSH library. In this study, we show that in PC12 cells, BTG2 is induced in response to moderate hypoxia (5% O2) and cobalt in addition to NGF. Hypoxia-induced BTG2 expression is time-and dose dependent, and requires activity from the L-type Ca2+ channel and PKA. Upregulation of BTG2 by hypoxia is independent of the growth factor-responsive p42/p44 MAPK, p38 kinase, and PI3 kinase/Akt signaling pathways. Cobalt stimulation of BTG2 gene expression is also dependent on PKA. In contrast, NGF-induced BTG2 expression is independent of L-type Ca2+ channel activity and PKA. BTG2 has been reported to be induced by apoptosis in both PC12 cells and in primary sympathetic neurons. However, it is unclear whether it functions to promote cell death or cell survival. We are currently investigating the functionality of BTG2 in regulation of cell survival during hypoxia. This work was supported by NIH grants HL33831, HL59945, and DK58811.

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