PMID- 10400650
OWN - NLM
STAT- MEDLINE
DCOM- 19990819
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 274
IP  - 29
DP  - 1999 Jul 16
TI  - Ceramide induces Bcl2 dephosphorylation via a mechanism involving mitochondrial
      PP2A.
PG  - 20296-300
AB  - Phosphorylation of Bcl2 at serine 70 is required for its potent anti-apoptotic
      function. We have recently shown that Bcl2 phosphorylation is a dynamic process
      that involves the protein kinase C alpha and protein phosphatase 2A (PP2A)
      (Ruvolo, P. P., Deng, X., Carr, B. K., and May, W. S. (1998) J. Biol. Chem. 273, 
      25436-25442; and Deng, X., Ito, T., Carr, B. K., Mumby, M. C., and May, W. S.
      (1998) J. Biol. Chem. 273, 34157-34163). The potent apoptotic agent ceramide can 
      activate a PP2A, suggesting that one potential component of the ceramide-induced 
      death signal may involve the inactivation of Bcl2. Results indicate that
      C2-ceramide but not inactive C2-dihydroceramide, was found to specifically
      activate a mitochondrial PP2A, which rapidly and completely induced Bcl2
      dephosphorylation and correlated closely with ceramide-induced cell death. Using 
      a genetic approach, the gain-of-function S70E Bcl2 mutation, which mimics
      phosphorylation, fails to undergo apoptosis even with the addition of high doses 
      of ceramide (IC50 > 50 microM). In contrast, cells overexpressing exogenous
      wild-type Bcl2 were sensitive to ceramide at dosages where PP2A is fully active
      and Bcl2 would be expected to be dephosphorylated (IC50 = 14 microM). These
      findings indicate that in cells expressing functional Bcl2, the mechanism of
      death action for ceramide may involve, at least in part, a mitochondrial PP2A
      that dephosphorylates and inactivates Bcl2.
FAU - Ruvolo, P P
AU  - Ruvolo PP
AD  - Sealy Center for Oncology and Hematology and Department of Internal Medicine, The
      University of Texas Medical Branch, Galveston, Texas 77555-1048, USA.
FAU - Deng, X
AU  - Deng X
FAU - Ito, T
AU  - Ito T
FAU - Carr, B K
AU  - Carr BK
FAU - May, W S
AU  - May WS
LA  - eng
GR  - CA44649/CA/NCI NIH HHS/United States
GR  - CA47993/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Ceramides)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - EC 3.1.3.16 (Phosphoprotein Phosphatases)
RN  - EC 3.1.3.16 (Protein Phosphatase 2)
SB  - IM
MH  - Animals
MH  - Ceramides/*pharmacology
MH  - Humans
MH  - Mice
MH  - Mitochondria/*enzymology
MH  - Phosphoprotein Phosphatases/*metabolism
MH  - Phosphorylation
MH  - Protein Phosphatase 2
MH  - Proto-Oncogene Proteins c-bcl-2/*metabolism
MH  - Tumor Cells, Cultured
EDAT- 1999/07/10 00:00
MHDA- 1999/07/10 00:01
CRDT- 1999/07/10 00:00
PHST- 1999/07/10 00:00 [pubmed]
PHST- 1999/07/10 00:01 [medline]
PHST- 1999/07/10 00:00 [entrez]
AID - 10.1074/jbc.274.29.20296 [doi]
AID - S0021-9258(19)72651-9 [pii]
PST - ppublish
SO  - J Biol Chem. 1999 Jul 16;274(29):20296-300. doi: 10.1074/jbc.274.29.20296.