Bcl-x(L) complements Saccharomyces cerevisiae genes that facilitate the switch from glycolytic to oxidative metabolism.
All eukaryotic organisms have mechanisms to adapt to changing metabolic conditions. The mammalian cell survival gene Bcl-x(L) enables cells to adapt to changes in cellular metabolism. To identify genes whose function can be substituted by Bcl-x(L) in a unicellular eukaryote, a genetic screen was performed using the yeast Saccharomyces cerevisiae. S. cerevisiae grows by anaerobic glycolysis when glucose is available, switching to oxidative phosphorylation when carbohydrate in the media becomes limiting (diauxic shift). Given that Bcl-x(L) appears to facilitate the switch from glycolytic to oxidative metabolism in mammalian cells, a library of yeast mutants was tested for the ability to efficiently undergo diauxic shift in the presence and absence of Bcl-x(L). Several mutants were identified that have a defect in growth when switched from a fermentable to a nonfermentable carbon source that is corrected by the expression of Bcl-x(L). These genes include the mitochondrial chaperonin TCM62, as well as previously uncharacterized genes. One of these uncharacterized genes, SVF1, promotes cell survival in mammalian cells in response to multiple apoptotic stimuli. The finding that TCM62 and the analogous human prohibitin gene also inhibit mammalian cell death following growth factor withdrawal implicates mitochondrial chaperones as regulators of apoptosis. Further characterization of the genes identified in this screen may enhance our understanding of Bcl-x(L) function in mammalian cells, and of cell survival pathways in general.
Vander Heiden
Matthew G
MG
Department of Medicine, The University of Chicago, Chicago, Illinois 60637, USA.
Choy
John S
JS
VanderWeele
David J
DJ
Brace
Jennifer L
JL
Harris
Marian H
MH
Bauer
Daniel E
DE
Prange
Bryan
B
Kron
Stephen J
SJ
Thompson
Craig B
CB
Rudin
Charles M
CM
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002244:Carbon / Q000378:metabolism; D002460:Cell Line; D005285:Fermentation / Q000502:physiology; D005800:Genes, Fungal; D006019:Glycolysis / Q000502:physiology*; D006801:Humans; D007377:Interleukin-3 / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D010085:Oxidative Phosphorylation; D000091402:Prohibitins; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D013696:Temperature; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D007377:Interleukin-3; D018832:Molecular Chaperones; D000091402:Prohibitins; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; C116028:TCM62 protein, S cerevisiae; D051020:bcl-X Protein; D002244:Carbon