Involvement of c-myc in the resistance of non-obese diabetic mice to glucocorticoid-induced apoptosis.
Non-obese diabetic (NOD) mice spontaneously develop insulin-dependent diabetes mellitus (IDDM) as a consequence of autoimmune aggression of beta cells of the endocrine pancreas by T cells. T lymphocytes of NOD mice are resistant to apoptosis induced by glucocorticoids, or by starving or DNA-damaging treatments, a feature that was interpreted as being linked to escape of autoreactive T cells from thymic negative selection. c-myc is one of the gene targets of glucocorticoids (GC), its expression being down-regulated by the activated GC-GC receptor complex. We investigated here whether expression of Myc protein, in response to dexamethasone stimulation, was the same in NOD mice and in non-autoimmune strains, namely NON, BALB/c and C57Bl.6. We found a consistent increase in the levels of Myc protein after GC-treatment of lymphocytes of NOD mice, a finding that was in contrast to the down-regulation of c-myc that we observed in lymphocytes from mice not prone to diabetes. We also report that, rather than a absolute resistance to GC-induced cell death, NOD mice display a delayed apoptotic response to GC. We propose that the resistance of NOD mice lymphocytes to GC-induced apoptosis is because of inhibition of the repressive action of GC-GR complexes at the level of c-myc transcription. This deficient action of GC-GR results in increased production of nuclear Myc protein, peculiar to NOD mice cells, following their treatment with GC.
Martins
T C
TC
Institute for Molecular and Cellular Biology, University of Porto, Portugal.
Aguas
A P
AP
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000473:pathology; D016259:Genes, myc; D008214:Lymphocytes / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis
D016271:Proto-Oncogene Proteins c-myc; D003907:Dexamethasone