PMID- 10359585
OWN - NLM
STAT- MEDLINE
DCOM- 19990708
LR  - 20190508
IS  - 0022-1007 (Print)
IS  - 0022-1007 (Linking)
VI  - 189
IP  - 11
DP  - 1999 Jun 7
TI  - Dephosphorylation targets Bcl-2 for ubiquitin-dependent degradation: a link
      between the apoptosome and the proteasome pathway.
PG  - 1815-22
AB  - Injury of the endothelial cells by the induction of apoptotic cell death may play
      an important role in the pathophysiology of atherosclerosis and the progression
      of inflammatory diseases. Here, we demonstrate an essential role for the
      ubiquitin-dependent proteasome complex in stimulus-induced degradation of the
      antiapoptotic protein Bcl-2. Bcl-2 is specifically degraded after stimulation of 
      human endothelial cells with tumor necrosis factor (TNF)-alpha in a process that 
      is inhibited by specific proteasome inhibitors. In addition, the mutation of the 
      potential ubiquitin-acceptor amino acids of Bcl-2 provides protection against
      TNF-alpha- and staurosporine-induced degradation in vitro and in vivo. Moreover, 
      mimicking phosphorylation of the putative mitogen-activated protein (MAP) kinase 
      sites of the Bcl-2 protein (Thr 56, Thr 74, and Ser 87) abolishes its
      degradation, suggesting a link between the MAP kinase pathway to the proteasome
      pathway. Finally, inhibition of Bcl-2 degradation either by suppressing
      ubiquitin-dependent proteasomal degradation or by mimicking continuous
      phosphorylation of the putative MAP kinase sites in the Bcl-2 protein confers
      resistance against induction of apoptosis. Thus, the degradation of Bcl-2 may
      unleash the inhibitory function of Bcl-2 over the apoptosome and may thereby
      amplify the activation of the caspase cascade.
FAU - Dimmeler, S
AU  - Dimmeler S
AD  - Department of Internal Medicine IV, Division of Molecular Cardiology, University 
      of Frankfurt, 60590 Frankfurt, Germany.
FAU - Breitschopf, K
AU  - Breitschopf K
FAU - Haendeler, J
AU  - Haendeler J
FAU - Zeiher, A M
AU  - Zeiher AM
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Exp Med
JT  - The Journal of experimental medicine
JID - 2985109R
RN  - 0 (Multienzyme Complexes)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (Ubiquitins)
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinases)
RN  - EC 3.4.22.- (Cysteine Endopeptidases)
RN  - EC 3.4.25.1 (Proteasome Endopeptidase Complex)
RN  - H88EPA0A3N (Staurosporine)
SB  - IM
MH  - Apoptosis/drug effects/genetics/*physiology
MH  - Binding Sites
MH  - Calcium-Calmodulin-Dependent Protein Kinases/metabolism
MH  - Cells, Cultured
MH  - Cysteine Endopeptidases/*metabolism
MH  - Endothelium, Vascular/cytology/metabolism
MH  - Genes, bcl-2
MH  - Humans
MH  - Multienzyme Complexes/*metabolism
MH  - Mutation
MH  - Phosphorylation
MH  - Proteasome Endopeptidase Complex
MH  - Proto-Oncogene Proteins c-bcl-2/chemistry/genetics/*metabolism
MH  - Staurosporine/pharmacology
MH  - Transfection
MH  - Tumor Necrosis Factor-alpha/pharmacology
MH  - Ubiquitins/*metabolism
PMC - PMC2193081
EDAT- 1999/06/08 00:00
MHDA- 1999/06/08 00:01
CRDT- 1999/06/08 00:00
PHST- 1999/06/08 00:00 [pubmed]
PHST- 1999/06/08 00:01 [medline]
PHST- 1999/06/08 00:00 [entrez]
AID - 10.1084/jem.189.11.1815 [doi]
PST - ppublish
SO  - J Exp Med. 1999 Jun 7;189(11):1815-22. doi: 10.1084/jem.189.11.1815.