Degradation of constitutive transcription factors during apoptosis in rat thymocytes.
Dexamethasone (Dex) accelerates the rate of apoptosis in thymocytes by a process thought to require gene expression. Among the genes implicated in the regulation of this phenomenon are the immediate early genes such as c-fos and c-jun, whose expression is modulated by a complement of preexisting transcription factors. We have analyzed the DNA-binding activity of these constitutive transcription factors during Dex-induced apoptosis in thymocytes to assess their functionality. We observed a progressive loss of the DNA-binding proteins in parallel with the appearance of the characteristic morphological and biochemical features of apoptosis. At the same time we have found a general increase in the nuclear proteolytic activity concomitant with a significant loss of the nuclear nonhistone chromosomal proteins. Indeed, cotreatment of thymocytes with the nonspecific serine protease inhibitor phenylmethylsulphonyl fluoride was able to partially protect the stability of the DNA-binding proteins and alter the expression of the c-fos and c-jun genes but did not inhibit apoptosis. Our results suggest that the action of a protease(s) is responsible for the degradation of constitutive transcription factors during Dex-induced apoptosis, rendering the death pathway irreversible.
de Belle
I
I
Institute for Biological Sciences, National Research Council of Canada, Ottawa, ON.
Testolin
L
L
Pandey
S
S
Carson
C
C
Walker
P R
PR
Armato
U
U
Sikorska
M
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001483:Base Sequence; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D018076:DNA, Complementary; D003907:Dexamethasone / Q000494:pharmacology; D015870:Gene Expression; D016762:Genes, fos; D016758:Genes, jun; D008297:Male; D008969:Molecular Sequence Data; D051381:Rats; D017207:Rats, Sprague-Dawley; D013950:Thymus Gland / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018808:Transcription Factor AP-1 / Q000378:metabolism*
D017362:Cyclic AMP Response Element-Binding Protein; D018076:DNA, Complementary; D018808:Transcription Factor AP-1; D003907:Dexamethasone