Apoptosis protection by Mcl-1 and Bcl-2 modulation of inositol 1,4,5-trisphosphate receptor-dependent Ca2+ signaling.
Members of the Bcl-2 protein family play a central role in the regulation of apoptosis. An interaction between anti-apoptotic Bcl-x(L) and the endoplasmic reticulum (ER)-localized inositol trisphosphate receptor Ca(2+) release channel (InsP(3)R) enables Bcl-x(L) to be fully efficacious as an anti-apoptotic mediator (White, C., Li, C., Yang, J., Petrenko, N. B., Madesh, M., Thompson, C. B., and Foskett, J. K. (2005) Nat. Cell Biol. 7, 1021-1028). Physiologically, Bcl-x(L) binds to the InsP(3)R to enhance its gating and Ca(2+) signaling. Here we have discovered that structurally related proteins Bcl-2 and Mcl-1 function similarly. Bcl-2, Mcl-1 and Bcl-x(L) bind with comparable affinity to the carboxyl termini of all three mammalian InsP(3)R isoforms with important functional consequences. Stable expression of Bcl-2 or Mcl-1 lowered ER Ca(2+) content and enhanced the rate of InsP(3)-mediated Ca(2+) release in response to submaximal InsP(3) stimulation in permeabilized wild-type DT40 cells but not in cells lacking InsP(3)R. In addition, expression of either Bcl-2 or Mcl-1 enhanced spontaneous InsP(3)R-dependent Ca(2+) oscillations and spiking in intact cells in the absence of agonist stimulation. Bcl-2- and Mcl-1-mediated protection from apoptosis induced by staurosporine or etoposide was enhanced in cells expressing InsP(3)R, demonstrating that their interactions with InsP(3)R enable Bcl-2 and Mcl-1 to be fully efficacious anti-apoptotic mediators. Our data suggest a molecular mechanism that is shared by several anti-apoptotic Bcl-2 proteins that provides apoptosis resistance by direct interactions at the ER with the InsP(3)R that impinges on cellular Ca(2+) homeostasis.
Eckenrode
Emily F
EF
Department of Physiology and Biophysics, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois 60064, USA.
Yang
Jun
J
Velmurugan
Gopal V
GV
Foskett
J Kevin
JK
White
Carl
C
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001683:Biological Clocks / Q000187:drug effects / Q000502:physiology; D019556:COS Cells; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D002522:Chlorocebus aethiops; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics / Q000378:metabolism*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D019311:Staurosporine / Q000494:pharmacology; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
C494811:BCL2L1 protein, human; C494813:Bcl2l1 protein, rat; D004791:Enzyme Inhibitors; D053496:Inositol 1,4,5-Trisphosphate Receptors; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D019311:Staurosporine; D002118:Calcium