Nuclear factor-kappaB-mediated cell survival involves transcriptional silencing of the mitochondrial death gene BNIP3 in ventricular myocytes.
BACKGROUND
A survival role for the transcription factor nuclear factor-kappaB (NF-kappaB) in ventricular myocytes has been reported; however, the underlying mechanism is undefined. In this report we provide new mechanistic evidence that survival signals conferred by NF-kappaB impinge on the hypoxia-inducible death factor BNIP3.


RESULTS
Activation of the NF-kappaB signaling pathway by IKKbeta in ventricular myocytes suppressed mitochondrial permeability transition pore (PTP) opening and cell death provoked by BNIP3. Expression of IKKbeta or p65 NF-kappaB suppressed basal and hypoxia-inducible BNIP3 gene activity. Deletion analysis of the BNIP3 promoter revealed the NF-kappaB elements to be crucial for inhibiting basal and inducible BNIP3 gene activity. Cells derived from p65(-/-)-deficient mice or ventricular myocytes rendered defective for NF-kappaB signaling with a nonphosphorylative IkappaB exhibited increased basal BNIP3 gene expression, mitochondrial PTP, and cell death. Genetic or functional ablation of the BNIP3 gene in NF-kappaB-defective myocytes rescued them from mitochondrial defects and cell death.


CONCLUSIONS
The data provide new compelling evidence that NF-kappaB suppresses mitochondrial defects and cell death of ventricular myocytes through a mechanism that transcriptionally silences the death gene BNIP3. Collectively, our data provide new mechanistic insight into the mode by which NF-kappaB suppresses cell death and identify BNIP3 as a key transcriptional target for NF-kappaB-regulated expression in ventricular myocytes.
Baetz
Delphine
D
Department of Physiology, Institute of Cardiovascular Sciences, St Boniface General Hospital Research Centre, Winnipeg, Manitoba, Canada.
Regula
Kelly M
KM
Ens
Karen
K
Shaw
James
J
Kothari
Shilpa
S
Yurkova
Natalia
N
Kirshenbaum
Lorrie A
LA
D000818:Animals; D002470:Cell Survival; D020868:Gene Silencing; D006352:Heart Ventricles / Q000166:cytology*; D000860:Hypoxia; D051550:I-kappa B Kinase / Q000494:pharmacology; D007473:Ion Channels / Q000032:analysis; D008565:Membrane Proteins / Q000235:genetics*; D008929:Mitochondria, Heart / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D024101:Mitochondrial Proteins; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D016328:NF-kappa B / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic
C505650:BNIP3 protein, rat; D007473:Ion Channels; D008565:Membrane Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D024101:Mitochondrial Proteins; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D051550:I-kappa B Kinase