C. elegans orthologs of components of the RB tumor suppressor complex have distinct pro-apoptotic functions.
To obtain insight into the role of the retinoblastoma susceptibility gene (Rb; also known as Rb1) in apoptosis, we analyzed Caenorhabditis elegans mutants lacking a functional lin-35 RB gene. We found that the loss of lin-35 function results in a decrease in constitutive germ cell apoptosis. We present evidence that lin-35 promotes germ cell apoptosis by repressing the expression of ced-9, an anti-apoptotic C. elegans gene that is orthologous to the human proto-oncogene BCL2. Furthermore, we show that the genes dpl-1 DP, efl-1 E2F and efl-2 E2F also promote constitutive germ cell apoptosis. However, in contrast to lin-35, dpl-1 (and probably also efl-1 and efl-2) promotes germ cell apoptosis by inducing the expression of the pro-apoptotic genes ced-4 and ced-3, which encode an APAF1-like adaptor protein and a pro-caspase, respectively. Based on these results, we propose that C. elegans orthologs of components of the RB tumor suppressor complex have distinct pro-apoptotic functions in the germ line and that the transcriptional regulation of components of the central apoptosis machinery is a critical determinant of constitutive germ cell apoptosis in C. elegans. Finally, we demonstrate that lin-35, dpl-1 and efl-2, but not efl-1, function either downstream of or in parallel to cep-1 p53 (also known as TP53) and egl-1 BH3-only to cause DNA damage-induced germ cell apoptosis. Our results have implications for the general mechanisms through which RB-like proteins control gene expression, the role of RB-, DP- and E2F-like proteins in apoptosis, and the regulation of apoptosis.
Schertel
Claus
C
Dartmouth Medical School, Department of Genetics, Norris Cotton Cancer Center, 7400 Remsen, Hanover, NH 03755, USA.
Conradt
Barbara
B
D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000502:physiology*; D017173:Caenorhabditis elegans / Q000033:anatomy & histology / Q000196:embryology / Q000235:genetics* / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D050684:E2F Transcription Factors / Q000235:genetics / Q000378:metabolism; D005854:Germ Cells / Q000166:cytology / Q000502:physiology*; D006801:Humans; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D029742:Caenorhabditis elegans Proteins; D002135:Calcium-Binding Proteins; C089224:Ced-4 protein, C elegans; C087233:Ced-9 protein, C elegans; D050684:E2F Transcription Factors; C000715470:MAS1 protein, human; D020033:Protein Isoforms; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D016160:Retinoblastoma Protein; D014157:Transcription Factors; C433249:dpl-1 protein, C elegans; C493765:efl-1 protein, C elegans