PMID- 23395931
OWN - NLM
STAT- MEDLINE
DCOM- 20130509
LR  - 20211203
IS  - 1941-3297 (Electronic)
IS  - 1941-3289 (Linking)
VI  - 6
IP  - 2
DP  - 2013 Mar
TI  - Bidirectional regulation of nuclear factor-kappaB and mammalian target of rapamycin 
      signaling functionally links Bnip3 gene repression and cell survival of 
      ventricular myocytes.
PG  - 335-43
LID - 10.1161/CIRCHEARTFAILURE.112.000061 [doi]
AB  - BACKGROUND: Tumor necrosis factor-alpha and other proinflammatory cytokines activate 
      the canonical nuclear factor (NF)-kappaB pathway through the kinase IKKbeta. Previously, 
      we established that IKKbeta is also critical for Akt-mediated NF-kappaB activation in 
      ventricular myocytes. Akt activates the kinase mammalian target of rapamycin 
      (mTOR), which mediates important processes such as cardiac hypertrophy. However, 
      whether mTOR regulates cardiac myocyte cell survival is unknown. METHODS AND 
      RESULTS: Herein, we demonstrate bidirectional regulation between NF-kappaB signaling 
      and mTOR, the balance which determines ventricular myocyte survival. 
      Overexpression of IKKbeta resulted in mTOR activation and conversely overexpression 
      of mTOR lead to NF-kappaB activation. Loss of function approaches demonstrated that 
      endogenous levels of IKKbeta and mTOR also signal through this pathway. NF-kappaB 
      activation by mTOR was mediated by phosphorylation of the NF-kappaB p65 subunit 
      increasing p65 nuclear translocation and activation of gene transcription. This 
      circuit was also important for NF-kappaB activation by the canonical tumor necrosis 
      factor-alpha pathway. Our previous work has shown that NF-kappaB signaling suppresses 
      transcription of the death gene Bnip3 resulting in ventricular myocyte survival. 
      Inhibition of mTOR with rapamycin decreased NF-kappaB activation resulting in 
      increased Bnip3 expression and cell death. Conversely, mTOR overexpression 
      suppressed Bnip3 levels and cell death of ventricular myocytes in response to 
      hypoxia. CONCLUSIONS: To our knowledge, these data provide the first evidence for 
      a bidirectional link between NF-kappaB signaling and mTOR that is critical in the 
      regulation of Bnip3 expression and cardiac myocyte death. Hence, modulation of 
      this axis may be cardioprotective during ischemia.
FAU - Dhingra, Rimpy
AU  - Dhingra R
AD  - Departments of Physiology, The Institute of Cardiovascular Sciences, St. Boniface 
      Hospital Research Centre, University of Manitoba, Winnipeg, Manitoba, Canada.
FAU - Gang, Hongying
AU  - Gang H
FAU - Wang, Yan
AU  - Wang Y
FAU - Biala, Agnieszka K
AU  - Biala AK
FAU - Aviv, Yaron
AU  - Aviv Y
FAU - Margulets, Victoria
AU  - Margulets V
FAU - Tee, Andrew
AU  - Tee A
FAU - Kirshenbaum, Lorrie A
AU  - Kirshenbaum LA
LA  - eng
GR  - Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130208
PL  - United States
TA  - Circ Heart Fail
JT  - Circulation. Heart failure
JID - 101479941
RN  - 0 (BNIP3 protein, rat)
RN  - 0 (Membrane Proteins)
RN  - 0 (Mitochondrial Proteins)
RN  - 0 (NF-kappa B)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Rela protein, rat)
RN  - 0 (Transcription Factor RelA)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 2.7.1.1 (mTOR protein, rat)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.10 (I-kappa B Kinase)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Animals, Newborn
MH  - Cell Hypoxia
MH  - Cell Survival
MH  - Cells, Cultured
MH  - Enzyme Activation
MH  - Gene Expression Regulation
MH  - I-kappa B Kinase/genetics/metabolism
MH  - Membrane Proteins/genetics/*metabolism
MH  - Mitochondrial Proteins
MH  - Myocytes, Cardiac/drug effects/*enzymology/pathology
MH  - NF-kappa B/genetics/*metabolism
MH  - Phosphorylation
MH  - Promoter Regions, Genetic
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Proto-Oncogene Proteins/genetics/*metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - RNA Interference
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - *Signal Transduction/drug effects
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/genetics/*metabolism
MH  - Transcription Factor RelA/metabolism
MH  - Transcription, Genetic
MH  - Transfection
MH  - Tumor Necrosis Factor-alpha/metabolism
EDAT- 2013/02/12 06:00
MHDA- 2013/05/10 06:00
CRDT- 2013/02/12 06:00
PHST- 2013/02/12 06:00 [entrez]
PHST- 2013/02/12 06:00 [pubmed]
PHST- 2013/05/10 06:00 [medline]
AID - CIRCHEARTFAILURE.112.000061 [pii]
AID - 10.1161/CIRCHEARTFAILURE.112.000061 [doi]
PST - ppublish
SO  - Circ Heart Fail. 2013 Mar;6(2):335-43. doi: 10.1161/CIRCHEARTFAILURE.112.000061. 
      Epub 2013 Feb 8.