c-Myc Functionally Cooperates with Bax To Induce Apoptosis

Juin, Philippe; Hunt, Abigail E.; Littlewood, Trevor D.; Griffiths, Beatrice; Swigart, Lamorna Brown; Korsmeyer, Stanley J.; Evan, Gérard I.

doi:10.1128/mcb.22.17.6158-6169.2002

Cited by 131 publications

(135 citation statements)

References 59 publications

Supporting

Mentioning

125

Contrasting

Unclassified

Order By: Relevance

“…This action appears to be mediated by either the activation or the change in expression of Bcl-2 protein members and results in the facilitated release of cytochrome c from the mitochondria [17,18,32,35,36]. In the present study, we now report that p38, and more precisely p38α, is an essential mediator of cisplatin-induced activation of Bax at the mitochondria in c-Myc-transformed cells.…”

Section: Discussionmentioning

confidence: 50%

c-Myc potentiates the mitochondrial pathway of apoptosis by acting upstream of apoptosis signal-regulating kinase 1 (Ask1) in the p38 signalling cascade

Desbiens

Deschesnes

Labrie

et al. 2003

Biochemical Journal

View full text Add to dashboard Cite

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 p38α isoform, but not p38β, 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, p38α and Bax.

show abstract

Section: Discussionmentioning

confidence: 50%

c-Myc potentiates the mitochondrial pathway of apoptosis by acting upstream of apoptosis signal-regulating kinase 1 (Ask1) in the p38 signalling cascade

Desbiens

Deschesnes

Labrie

et al. 2003

Biochemical Journal

View full text Add to dashboard Cite

show abstract

“…C-myc has also been shown to sensitize tumor cells to various apoptotic stimuli (Juin et al, 2002). One of these pathways involves the permeabilization of the cellular and mitochondrial membranes, and the release of cytochrome C. Therefore, c-Myc must act to potentiate the ability of an additional factor to induce permeabilization and cytochrome C release.…”

Section: Discussionmentioning

confidence: 99%

Functional analysis of the host defense peptide Human Beta Defensin-1: New insight into its potential role in cancer

Bullard

Gibson

Bose

et al. 2008

Molecular Immunology

View full text Add to dashboard Cite

Although it is known that innate immunity is key for protecting the body against foreign agents such as bacteria, little is known about elements of the innate immune system that have anti-tumor activity. Human Beta Defensin-1 (hBD-1), an important component of the innate immune response, is lost at high frequencies in malignant prostatic tissue, while high levels of expression are maintained in adjacent benign regions. In prostate carcinoma, frequent genetic alterations occur in the 8p22-23 region and several studies indicate there may be multiple tumor suppressor genes present within this region. The high incidence of loss of hBD-1 expression in prostate cancer, along with its chromosomal location of 8p23.2, raised the possibility that it may play a role in tumor suppression. To gain insight as to its function in prostate cancer, hBD-1 was cloned and ectopically expressed in four prostate cancer cell lines. Induction of hBD-1 expression resulted in a decrease in cellular growth in DU145 and PC3 cells. However, hBD-1 has no effect on the growth of androgen receptor (AR) positive LNCaP prostate cancer cells, but was again growth suppressive to PC3 cells with ectopic AR expression (PC3/AR+). hBD-1 also caused rapid induction of cytolysis and caspase-mediated apoptosis in DU145 and PC3 prostate cancer cells. Although the regulation of hBD-1 was not addressed in this study, our preliminary data demonstrated that the pathways involoved may include cMYC and/or PAX2. Data presented here are the first to provide evidence of its potential role in prostate cancer cell death.

show abstract

“…c-myc is an oncogene that immortalizes cells and stimulates their proliferation, actively contributing to tumor progression when over-expressed or deregulated (Garte, 1993). Moreover, as an independent function, c-myc also induces apoptosis by promoting strictly Bax-dependent mitochondria damage (Juin et al, 2002): c-myc does not modify Bax protein abundance or localization, but promotes Bax activation once Bax is already inserted in the mitochondrial membrane (Cao et al, 2008).…”

Section: Multistep Bax Activationmentioning

confidence: 99%

Multistep and multitask Bax activation

Ghibelli

Diederich

2010

Mitochondrion

View full text Add to dashboard Cite

Bax is a pro-apoptotic protein allowing apoptosis to occur through the intrinsic, damage-induced pathway, and amplifying that one occurring via the extrinsic, receptor mediated pathway. Bax is present in viable cells and activated by pro-apoptotic stimuli. Activation implies structural changes, consisting of exposure of the N terminus and hydrophobic domains; changes in localization, consisting in migration from cytosol to mitochondria and endoplasmic reticulum membranes; changes in the aggregation status, from monomer to dimer and multimer. Bax has multiple critical domains, namely the N terminus exposed after activation; two hydrophobic stretches exposed for membrane anchorage; two reactive cysteines allowing multimerization; the BH3 domain for interactions with the Bcl-2 family members; alpha helix 1 for t-Bid interaction. Bax has also multiple functions: it releases different mitochondrial factors such as cytochrome c, SMAC/diablo; it regulates mitochondrial fission, the mitochondrial permeability transition pore; it promotes Ca 2+ leakage through ER membrane. Altogether, Bax activation is a complex multi-step phenomenon. Here, we analyze these events as logically separable or alternative steps, attempting to assess their role, timing and reciprocal relation.

show abstract

c-Myc Functionally Cooperates with Bax To Induce Apoptosis

Cited by 131 publications

References 59 publications

c-Myc potentiates the mitochondrial pathway of apoptosis by acting upstream of apoptosis signal-regulating kinase 1 (Ask1) in the p38 signalling cascade

c-Myc potentiates the mitochondrial pathway of apoptosis by acting upstream of apoptosis signal-regulating kinase 1 (Ask1) in the p38 signalling cascade

Functional analysis of the host defense peptide Human Beta Defensin-1: New insight into its potential role in cancer

Multistep and multitask Bax activation

Contact Info

Product

Resources

About