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c-Myc potentiates the mitochondrial pathway of apoptosis by acting upstream of apoptosis signal-regulating kinase 1 (Ask1) in the p38 signalling cascade.
Biochem J. 2003 Jun 01; 372(Pt 2):631-41.BJ

Abstract

Cell transformation by growth-promoting oncoproteins renders cells extremely sensitive to apoptosis through an unknown mechanism affecting the mitochondrial pathway of apoptosis. We have shown previously that sensitization to apoptosis also correlated with the activation of the stress-activated protein kinase p38. In the present study, we investigated the role of p38 in c-Myc-dependent apoptosis induced by the anticancer agent cisplatin. Cisplatin treatment of Rat1 cells with deregulated expression of c-Myc resulted in nuclear fragmentation that was accompanied in all cells by the activation of Bax and the translocation of cytochrome c from the mitochondria to the cytoplasm. None of these features of apoptosis was induced in control Rat-1 cells. p38 was also activated by cisplatin only in cells with deregulated expression of c-Myc, but, in contrast with all features of apoptosis, this activation was not affected by Bcl-2. Remarkably, overexpression of an interfering mutant of the p38alpha isoform, but not p38beta, blocked cisplatin-induced Bax activation or cytochrome c release and nuclear fragmentation. Analysis of the kinase cascade upstream of p38 revealed a c-Myc-dependent activation by cisplatin of mitogen-activated protein kinase kinase (MKK) 3/6 and apoptosis signal-regulating kinase 1 (Ask1). Inhibition of Ask1 blocked p38 activation by cisplatin and all features of apoptosis. Several of these data were confirmed using other DNA-damaging agents. The findings indicated that c-Myc potentiation of the mitochondrial pathway of apoptosis results, at least in part, from a sensitization of Ask1 activation, allowing DNA-damaging agents to induce in cascade Ask1, p38alpha and Bax.

Authors+Show Affiliations

Centre de recherche en cancérologie de l'Université Laval, L'Hôtel-Dieu de Québec, 9 rue McMahon, Québec, Canada G1R 2J6.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12646044

Citation

Desbiens, Katia M., et al. "C-Myc Potentiates the Mitochondrial Pathway of Apoptosis By Acting Upstream of Apoptosis Signal-regulating Kinase 1 (Ask1) in the P38 Signalling Cascade." The Biochemical Journal, vol. 372, no. Pt 2, 2003, pp. 631-41.
Desbiens KM, Deschesnes RG, Labrie MM, et al. C-Myc potentiates the mitochondrial pathway of apoptosis by acting upstream of apoptosis signal-regulating kinase 1 (Ask1) in the p38 signalling cascade. Biochem J. 2003;372(Pt 2):631-41.
Desbiens, K. M., Deschesnes, R. G., Labrie, M. M., Desfossés, Y., Lambert, H., Landry, J., & Bellmann, K. (2003). C-Myc potentiates the mitochondrial pathway of apoptosis by acting upstream of apoptosis signal-regulating kinase 1 (Ask1) in the p38 signalling cascade. The Biochemical Journal, 372(Pt 2), 631-41.
Desbiens KM, et al. C-Myc Potentiates the Mitochondrial Pathway of Apoptosis By Acting Upstream of Apoptosis Signal-regulating Kinase 1 (Ask1) in the P38 Signalling Cascade. Biochem J. 2003 Jun 1;372(Pt 2):631-41. PubMed PMID: 12646044.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - c-Myc potentiates the mitochondrial pathway of apoptosis by acting upstream of apoptosis signal-regulating kinase 1 (Ask1) in the p38 signalling cascade. AU - Desbiens,Katia M, AU - Deschesnes,Réna G, AU - Labrie,Mireille M, AU - Desfossés,Yan, AU - Lambert,Herman, AU - Landry,Jacques, AU - Bellmann,Kerstin, PY - 2003/03/19/accepted PY - 2003/02/24/revised PY - 2002/10/07/received PY - 2003/3/21/pubmed PY - 2003/7/23/medline PY - 2003/3/21/entrez SP - 631 EP - 41 JF - The Biochemical journal JO - Biochem J VL - 372 IS - Pt 2 N2 - Cell transformation by growth-promoting oncoproteins renders cells extremely sensitive to apoptosis through an unknown mechanism affecting the mitochondrial pathway of apoptosis. We have shown previously that sensitization to apoptosis also correlated with the activation of the stress-activated protein kinase p38. In the present study, we investigated the role of p38 in c-Myc-dependent apoptosis induced by the anticancer agent cisplatin. Cisplatin treatment of Rat1 cells with deregulated expression of c-Myc resulted in nuclear fragmentation that was accompanied in all cells by the activation of Bax and the translocation of cytochrome c from the mitochondria to the cytoplasm. None of these features of apoptosis was induced in control Rat-1 cells. p38 was also activated by cisplatin only in cells with deregulated expression of c-Myc, but, in contrast with all features of apoptosis, this activation was not affected by Bcl-2. Remarkably, overexpression of an interfering mutant of the p38alpha isoform, but not p38beta, blocked cisplatin-induced Bax activation or cytochrome c release and nuclear fragmentation. Analysis of the kinase cascade upstream of p38 revealed a c-Myc-dependent activation by cisplatin of mitogen-activated protein kinase kinase (MKK) 3/6 and apoptosis signal-regulating kinase 1 (Ask1). Inhibition of Ask1 blocked p38 activation by cisplatin and all features of apoptosis. Several of these data were confirmed using other DNA-damaging agents. The findings indicated that c-Myc potentiation of the mitochondrial pathway of apoptosis results, at least in part, from a sensitization of Ask1 activation, allowing DNA-damaging agents to induce in cascade Ask1, p38alpha and Bax. SN - 0264-6021 UR - https://www.unboundmedicine.com/medline/citation/12646044/c_Myc_potentiates_the_mitochondrial_pathway_of_apoptosis_by_acting_upstream_of_apoptosis_signal_regulating_kinase_1__Ask1__in_the_p38_signalling_cascade_ L2 - https://portlandpress.com/biochemj/article-lookup/doi/10.1042/BJ20021565 DB - PRIME DP - Unbound Medicine ER -