PMID- 8022822
OWN - NLM
STAT- MEDLINE
DCOM- 19940801
LR  - 20191210
IS  - 0027-8424 (Print)
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Linking)
VI  - 91
IP  - 14
DP  - 1994 Jul 5
TI  - Evidence that BCL-2 represses apoptosis by regulating endoplasmic 
      reticulum-associated Ca2+ fluxes.
PG  - 6569-73
AB  - BCL-2 is a 26-kDa integral membrane protein that represses apoptosis by an 
      unknown mechanism. Recent findings indicate that Ca2+ release from the 
      endoplasmic reticulum (ER) mediates apoptosis in mouse lymphoma cells. In view of 
      growing evidence that BCL-2 localizes to the ER, as well as mitochondria and the 
      perinuclear membrane, we investigated the possibility that BCL-2 represses 
      apoptosis by regulating Ca2+ fluxes through the ER membrane. A cDNA encoding 
      BCL-2 was introduced into WEHI7.2 cells and two subclones, W.Hb12 and W.Hb13, 
      which express high and low levels of BCL-2 mRNA and protein, respectively, were 
      isolated. WEHI7.2 cells underwent apoptosis in response to treatment with the 
      glucocorticoid hormone dexamethasone, whereas W.Hb12 and W.Hb13 cells were 
      protected from apoptosis, revealing a direct relationship between the level of 
      BCL-2 expression and the degree of protection. Significantly, BCL-2 also blocked 
      induction of apoptosis by thapsigargin (TG), a highly specific inhibitor of the 
      ER-associated Ca2+ pump. TG completely inhibited ER Ca2+ pumping in both WEHI7.2 
      and W.Hb12 cells, but the release of Ca2+ into the cytosol after inhibition of ER 
      Ca2+ pumping was significantly less in W.Hb12 cells than in WEHI7.2 cells, 
      indicating that BCL-2 reduces Ca2+ efflux through the ER membrane. By reducing ER 
      Ca2+ efflux, BCL-2 interfered with a signal for "capacitative" entry of 
      extracellular Ca2+, preventing a sustained increase of cytosolic Ca2+ in 
      TG-treated cells. These findings suggest that BCL-2 either directly or indirectly 
      regulates the flux of Ca2+ across the ER membrane, thereby abrogating Ca2+ 
      signaling of apoptosis.
FAU - Lam, M
AU  - Lam M
AD  - Department of Medicine, Case Western Reserve University, Cleveland, OH 44106.
FAU - Dubyak, G
AU  - Dubyak G
FAU - Chen, L
AU  - Chen L
FAU - Nunez, G
AU  - Nunez G
FAU - Miesfeld, R L
AU  - Miesfeld RL
FAU - Distelhorst, C W
AU  - Distelhorst CW
LA  - eng
GR  - CA42755/CA/NCI NIH HHS/United States
GR  - GM36387/GM/NIGMS NIH HHS/United States
GR  - GM40738/GM/NIGMS NIH HHS/United States
PT  - Comparative Study
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  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - 0 (RNA, Messenger)
RN  - 0 (Terpenes)
RN  - 67526-95-8 (Thapsigargin)
RN  - 7S5I7G3JQL (Dexamethasone)
RN  - EC 3.6.1.- (GTP-Binding Proteins)
RN  - EC 7.2.2.10 (Calcium-Transporting ATPases)
RN  - KOO5CM684H (Digitonin)
RN  - SY7Q814VUP (Calcium)
SB  - IM
GS  - Bcl-2
GS  - ced-3
GS  - ced-4
GS  - ced-9
MH  - Apoptosis/*physiology
MH  - Calcium/*metabolism
MH  - Calcium-Transporting ATPases/antagonists & inhibitors/*metabolism
MH  - Cell Line
MH  - Cell Membrane Permeability
MH  - Cell Survival/drug effects
MH  - Clone Cells
MH  - Dexamethasone/pharmacology
MH  - Digitonin
MH  - Endoplasmic Reticulum/*metabolism
MH  - GTP-Binding Proteins/metabolism
MH  - Humans
MH  - Kinetics
MH  - Proto-Oncogene Proteins/biosynthesis/*metabolism
MH  - Proto-Oncogene Proteins c-bcl-2
MH  - *Proto-Oncogenes
MH  - RNA, Messenger/*biosynthesis
MH  - Terpenes/pharmacology
MH  - Thapsigargin
MH  - Time Factors
MH  - Transfection
PMC - PMC44244
EDAT- 1994/07/05 00:00
MHDA- 1994/07/05 00:01
PMCR- 1995/01/05
CRDT- 1994/07/05 00:00
PHST- 1994/07/05 00:00 [pubmed]
PHST- 1994/07/05 00:01 [medline]
PHST- 1994/07/05 00:00 [entrez]
PHST- 1995/01/05 00:00 [pmc-release]
AID - 10.1073/pnas.91.14.6569 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6569-73. doi: 
      10.1073/pnas.91.14.6569.