Molecular ordering of the cell death pathway. Bcl-2 and Bcl-xL function upstream of the CED-3-like apoptotic proteases.
Genetic analyses of Caenorhabditis elegans has identified three genes that function in the regulation of nematode cell death. Mammalian homologs of two of these genes, ced-9 and ced-3, have been identified and comprise proteins belonging to the Bcl-2 and ICE families, respectively. To date, it is unclear where the negative regulators, ced-9 and bcl-2, function relative to the death effectors, ced-3 and the mammalian ced-3 homologs, respectively. Here, the molecular order of the cell death pathway is defined. Our results establish that Bcl-2 and Bcl-xL function upstream of two members of the ICE/CED-3 family of cysteine proteases, Yama (CPP32/apopain) and ICE-LAP3 (Mch3).
Chinnaiyan
A M
AM
Department of Pathology, University of Michigan Medical School, Ann Arbor 48109, USA.
Orth
K
K
O'Rourke
K
K
Duan
H
H
Poirier
G G
GG
Dixit
V M
VM
D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies; D017209:Apoptosis / Q000235:genetics*; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins; D020169:Caspases; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation; D017238:Genes, Helminth; D015801:Helminth Proteins / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D015151:Immunoblotting; D008322:Mammals; D008954:Models, Biological; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2; D011519:Proto-Oncogenes; D051020:bcl-X Protein
D000906:Antibodies; C494811:BCL2L1 protein, human; D029742:Caenorhabditis elegans Proteins; D015801:Helminth Proteins; D010455:Peptides; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D011505:Protein-Tyrosine Kinases; D020169:Caspases; D003546:Cysteine Endopeptidases; C089223:ced-3 protein, C elegans