Activation of C. elegans cell death protein CED-9 by an amino-acid substitution in a domain conserved in Bcl-2.
The Caenorhabditis elegans gene ced-9 and the human proto-oncogene bcl-2, both of which protect cells from programmed cell death, are members of the same gene family. ced-9 and bcl-2 were discovered because of the effects of dominant gain-of-function mutations. Such bcl-2 mutations, which are commonly found in follicular lymphoma, are translocations that result in over-expression of a normal Bcl-2 protein in B cells. Here we report that, by contrast, the ced-9(n1950) gain-of-function mutation affects the open reading frame of ced-9 and results in a glycine-to-glutamate substitution in a region highly conserved among all ced-9/bcl-2 family members. We conclude that this glycine has an important function in ced-9 regulation, and we suggest that alteration of this glycine in other members of the ced-9/bcl-2 family might lead to oncogenic activation. We also present genetic evidence suggesting that the CED-9 protein might exist in two distinct forms that have opposite effects on cell death.
Hengartner
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Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge 02139.
Horvitz
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D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins; D017173:Caenorhabditis elegans / Q000737:chemistry / Q000235:genetics*; D029742:Caenorhabditis elegans Proteins; D017124:Conserved Sequence; D005786:Gene Expression Regulation / Q000235:genetics; D017238:Genes, Helminth / Q000235:genetics; D005971:Glutamates; D018698:Glutamic Acid; D005998:Glycine / Q000502:physiology; D015801:Helminth Proteins / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D016366:Open Reading Frames / Q000235:genetics; D017354:Point Mutation; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2
D051017:Apoptosis Regulatory Proteins; D029742:Caenorhabditis elegans Proteins; C087233:Ced-9 protein, C elegans; D005971:Glutamates; D015801:Helminth Proteins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D018698:Glutamic Acid; D005998:Glycine