Uncoupling of apoptosis and Jun/AP-1 activity in human promonocytic cells treated with DNA-damaging and stress-inducing agents.
Earlier studies have indicated that Jun/AP-1 activity is associated with, and probably required for apoptosis induction by DNA-damaging and stress-inducing agents in human myeloid cells. To investigate this possibility, we examined the capacity of continuous treatments with etoposide (10 microM) and camptothecin (0.4 microM), and pulse treatments with X-rays (20 Gy), heat (2 h at 42.5 C) and cadmium chloride (2 h at 200 microM) followed by recovery, to provoke apoptosis and to simulate c-jun and c-fos expression and AP-1 binding in U-937 human promonocytic cells. All these treatments generated apoptosis with similar efficacy (50-60% apoptotic cells at 6 h of treatment or recovery). However, the capacity to increase c-jun and c-fos mRNA levels and to stimulate AP-1 binding was very different, ranging from more than a twelve-fold increase in the case of cadmium, to almost no increase in the case of heat-shock and etoposide. When the cells were pre-conditioned with a soft heat shock (1 h at 42 degrees C) the cadmium-provoked apoptosis was greatly inhibited, but the stimulation of AP-1 binding was not affected. The administration of cAMP-increasing agents also reduced the etoposide- and cadmium-provoked apoptosis. However, cAMP greatly stimulated c-jun and c-fos expression and AP-1 binding when applied together with etoposide (which itself was ineffective), and potentiated the cadmium-induced AP-1 binding. Conversely, retinoic acid abrogated the cadmium-provoked stimulation of AP-1 binding and transactivation capacity, and greatly inhibited the stimulation of binding caused by camptothecin and X-rays. However, retinoic acid did not inhibit the induction of apoptosis by these agents. These results indicate that Jun/AP-1 activity is not necessarily coupled with apoptosis, nor required for apoptosis induction by DNA-damaging and stress-inducing agents in human promonocytic cells.
Galán
A
A
Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid/Spain.
Garcia-Bermejo
L
L
Vilaboa
N E
NE
de Blas
E
E
Aller
P
P
D017209:Apoptosis; D019256:Cadmium Chloride / Q000494:pharmacology; D002166:Camptothecin / Q000494:pharmacology; D005576:Colforsin / Q000378:metabolism / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004249:DNA Damage; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D015870:Gene Expression; D006361:Heating; D006801:Humans; D009000:Monocytes; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics*; D013806:Theophylline / Q000378:metabolism / Q000494:pharmacology; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014212:Tretinoin / Q000378:metabolism / Q000494:pharmacology; D020298:U937 Cells; D014475:Uncoupling Agents
D004791:Enzyme Inhibitors; D016755:Proto-Oncogene Proteins c-jun; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D018808:Transcription Factor AP-1; D014475:Uncoupling Agents; D005576:Colforsin; D014212:Tretinoin; D005047:Etoposide; D013806:Theophylline; D000242:Cyclic AMP; D019256:Cadmium Chloride; D002166:Camptothecin