c-Myc primed mitochondria determine cellular sensitivity to TRAIL-induced apoptosis

Research output: Contribution to journalArticleScientificpeer-review

Abstract

Oncogenic c-Myc renders cells sensitive to TRAIL-induced apoptosis, and existing data suggest that c-Myc sensitizes cells to apoptosis by promoting activation of the mitochondrial apoptosis pathway. However, the molecular mechanisms linking the mitochondrial effects of c-Myc to the c-Myc-dependent sensitization to TRAIL have remained unresolved. Here, we show that TRAIL induces a weak activation of procaspase-8 but fails to activate mitochondrial proapoptotic effectors Bax and Bak, cytochrome c release or downstream effector caspase-3 in non-transformed human fibroblasts or mammary epithelial cells. Our data is consistent with the model that activation of oncogenic c-Myc primes mitochondria through a mechanism involving activation of Bak and this priming enables weak TRAIL-induced caspase-8 signals to activate Bax. This results in cytochrome c release, activation of downstream caspases and postmitochondrial death-inducing signaling complex -independent augmentation of caspase-8-Bid activity. In conclusion, c-Myc-dependent priming of the mitochondrial pathway is critical for the capacity of TRAIL- induced caspase-8 signals to activate effector caspases and for the establishment of lethal caspase feedback amplification loop in human cells.
Original languageEnglish
JournalEMBO Journal
Volume26
Pages (from-to)1055-1067
Number of pages13
ISSN0261-4189
DOIs
Publication statusPublished - 2007
MoE publication typeA1 Journal article-refereed

Cite this

@article{5267c45168e84593b1ed2023f45e5021,
title = "c-Myc primed mitochondria determine cellular sensitivity to TRAIL-induced apoptosis",
abstract = "Oncogenic c-Myc renders cells sensitive to TRAIL-induced apoptosis, and existing data suggest that c-Myc sensitizes cells to apoptosis by promoting activation of the mitochondrial apoptosis pathway. However, the molecular mechanisms linking the mitochondrial effects of c-Myc to the c-Myc-dependent sensitization to TRAIL have remained unresolved. Here, we show that TRAIL induces a weak activation of procaspase-8 but fails to activate mitochondrial proapoptotic effectors Bax and Bak, cytochrome c release or downstream effector caspase-3 in non-transformed human fibroblasts or mammary epithelial cells. Our data is consistent with the model that activation of oncogenic c-Myc primes mitochondria through a mechanism involving activation of Bak and this priming enables weak TRAIL-induced caspase-8 signals to activate Bax. This results in cytochrome c release, activation of downstream caspases and postmitochondrial death-inducing signaling complex -independent augmentation of caspase-8-Bid activity. In conclusion, c-Myc-dependent priming of the mitochondrial pathway is critical for the capacity of TRAIL- induced caspase-8 signals to activate effector caspases and for the establishment of lethal caspase feedback amplification loop in human cells.",
author = "Anni Nieminen and Johanna Partanen and Annika Hau and Juha Klefstr{\"o}m",
year = "2007",
doi = "10.1038/sj.emboj.7601551",
language = "English",
volume = "26",
pages = "1055--1067",
journal = "EMBO Journal",
issn = "0261-4189",
publisher = "Wiley",

}

c-Myc primed mitochondria determine cellular sensitivity to TRAIL-induced apoptosis. / Nieminen, Anni; Partanen, Johanna; Hau, Annika; Klefström, Juha.

In: EMBO Journal, Vol. 26, 2007, p. 1055-1067.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - c-Myc primed mitochondria determine cellular sensitivity to TRAIL-induced apoptosis

AU - Nieminen, Anni

AU - Partanen, Johanna

AU - Hau, Annika

AU - Klefström, Juha

PY - 2007

Y1 - 2007

N2 - Oncogenic c-Myc renders cells sensitive to TRAIL-induced apoptosis, and existing data suggest that c-Myc sensitizes cells to apoptosis by promoting activation of the mitochondrial apoptosis pathway. However, the molecular mechanisms linking the mitochondrial effects of c-Myc to the c-Myc-dependent sensitization to TRAIL have remained unresolved. Here, we show that TRAIL induces a weak activation of procaspase-8 but fails to activate mitochondrial proapoptotic effectors Bax and Bak, cytochrome c release or downstream effector caspase-3 in non-transformed human fibroblasts or mammary epithelial cells. Our data is consistent with the model that activation of oncogenic c-Myc primes mitochondria through a mechanism involving activation of Bak and this priming enables weak TRAIL-induced caspase-8 signals to activate Bax. This results in cytochrome c release, activation of downstream caspases and postmitochondrial death-inducing signaling complex -independent augmentation of caspase-8-Bid activity. In conclusion, c-Myc-dependent priming of the mitochondrial pathway is critical for the capacity of TRAIL- induced caspase-8 signals to activate effector caspases and for the establishment of lethal caspase feedback amplification loop in human cells.

AB - Oncogenic c-Myc renders cells sensitive to TRAIL-induced apoptosis, and existing data suggest that c-Myc sensitizes cells to apoptosis by promoting activation of the mitochondrial apoptosis pathway. However, the molecular mechanisms linking the mitochondrial effects of c-Myc to the c-Myc-dependent sensitization to TRAIL have remained unresolved. Here, we show that TRAIL induces a weak activation of procaspase-8 but fails to activate mitochondrial proapoptotic effectors Bax and Bak, cytochrome c release or downstream effector caspase-3 in non-transformed human fibroblasts or mammary epithelial cells. Our data is consistent with the model that activation of oncogenic c-Myc primes mitochondria through a mechanism involving activation of Bak and this priming enables weak TRAIL-induced caspase-8 signals to activate Bax. This results in cytochrome c release, activation of downstream caspases and postmitochondrial death-inducing signaling complex -independent augmentation of caspase-8-Bid activity. In conclusion, c-Myc-dependent priming of the mitochondrial pathway is critical for the capacity of TRAIL- induced caspase-8 signals to activate effector caspases and for the establishment of lethal caspase feedback amplification loop in human cells.

U2 - 10.1038/sj.emboj.7601551

DO - 10.1038/sj.emboj.7601551

M3 - Article

VL - 26

SP - 1055

EP - 1067

JO - EMBO Journal

JF - EMBO Journal

SN - 0261-4189

ER -