Cell-Nonautonomous Regulation of C. elegans Germ Cell Death by kri-1
Bibliographic record
Abstract
Programmed cell death (or apoptosis) is an evolutionarily conserved, genetically controlled suicide mechanism for cells that, when deregulated, can lead to developmental defects, cancers, and degenerative diseases [1Ellis H.M. Horvitz H.R. Genetic control of programmed cell death in the nematode C. elegans.Cell. 1986; 44: 817-829Abstract Full Text PDF PubMed Scopus (1362) Google Scholar, 2Hipfner D.R. Cohen S.M. Connecting proliferation and apoptosis in development and disease.Nat. Rev. Mol. Cell Biol. 2004; 5: 805-815Crossref PubMed Scopus (173) Google Scholar]. In C. elegans, DNA damage induces germ cell death by signaling through cep-1/p53, ultimately leading to the activation of CED-3/caspase [3Ahmed S. Hodgkin J. MRT-2 checkpoint protein is required for germline immortality and telomere replication in C. elegans.Nature. 2000; 403: 159-164Crossref PubMed Scopus (225) Google Scholar, 4Gartner A. Milstein S. Ahmed S. Hodgkin J. Hengartner M.O. A conserved checkpoint pathway mediates DNA damage-induced apoptosis and cell cycle arrest in C. elegans.Mol. Cell. 2000; 5: 435-443Abstract Full Text Full Text PDF PubMed Scopus (417) Google Scholar, 5Hofmann E.R. Milstein S. Boulton S.J. Ye M. Hofmann J.J. Stergiou L. Gartner A. Vidal M. Hengartner M.O. Caenorhabditis elegans HUS-1 is a DNA damage checkpoint protein required for genome stability and EGL-1-mediated apoptosis.Curr. Biol. 2002; 12: 1908-1918Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar, 6Ahmed S. Alpi A. Hengartner M.O. Gartner A. C. elegans RAD-5/CLK-2 defines a new DNA damage checkpoint protein.Curr. Biol. 2001; 11: 1934-1944Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar, 7Derry W.B. Putzke A.P. Rothman J.H. Caenorhabditis elegans p53: Role in apoptosis, meiosis, and stress resistance.Science. 2001; 294: 591-595Crossref PubMed Scopus (384) Google Scholar, 8Schumacher B. Hofmann K. Boulton S. Gartner A. The C. elegans homolog of the p53 tumor suppressor is required for DNA damage-induced apoptosis.Curr. Biol. 2001; 11: 1722-1727Abstract Full Text Full Text PDF PubMed Scopus (292) Google Scholar, 9Yuan J.Y. Horvitz H.R. The Caenorhabditis elegans genes ced-3 and ced-4 act cell autonomously to cause programmed cell death.Dev. Biol. 1990; 138: 33-41Crossref PubMed Scopus (444) Google Scholar, 10Conradt B. Horvitz H.R. The C. elegans protein EGL-1 is required for programmed cell death and interacts with the Bcl-2-like protein CED-9.Cell. 1998; 93: 519-529Abstract Full Text Full Text PDF PubMed Scopus (514) Google Scholar, 11del Peso L. González V.M. Núñez G. Caenorhabditis elegans EGL-1 disrupts the interaction of CED-9 with CED-4 and promotes CED-3 activation.J. Biol. Chem. 1998; 273: 33495-33500Crossref PubMed Scopus (88) Google Scholar, 12Chen F. Hersh B.M. Conradt B. Zhou Z. Riemer D. Gruenbaum Y. Horvitz H.R. Translocation of C. elegans CED-4 to nuclear membranes during programmed cell death.Science. 2000; 287: 1485-1489Crossref PubMed Scopus (198) Google Scholar, 13Schumacher B. Hanazawa M. Lee M.H. Nayak S. Volkmann K. Hofmann E.R. Hengartner M. Schedl T. Gartner A. Translational repression of C. elegans p53 by GLD-1 regulates DNA damage-induced apoptosis.Cell. 2005; 120: 357-368Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar]. It has been hypothesized that the major regulatory events controlling cell death occur by cell-autonomous mechanisms, that is, within the dying cell. In support of this, genetic studies in C. elegans have shown that the core apoptosis pathway genes ced-4/APAF-1 and ced-3/caspase are required in cells fated to die [9Yuan J.Y. Horvitz H.R. The Caenorhabditis elegans genes ced-3 and ced-4 act cell autonomously to cause programmed cell death.Dev. Biol. 1990; 138: 33-41Crossref PubMed Scopus (444) Google Scholar]. However, it is not known whether the upstream signals that activate apoptosis function in a cell-autonomous manner. Here we show that kri-1, an ortholog of KRIT1/CCM1, which is mutated in the human neurovascular disease cerebral cavernous malformation [14Sahoo T. Johnson E.W. Thomas J.W. Kuehl P.M. Jones T.L. Dokken C.G. Touchman J.W. Gallione C.J. Lee-Lin S.Q. Kosofsky B. et al.Mutations in the gene encoding KRIT1, a Krev-1/rap1a binding protein, cause cerebral cavernous malformations (CCM1).Hum. Mol. Genet. 1999; 8: 2325-2333Crossref PubMed Scopus (305) Google Scholar, 15Laberge-le Couteulx S. Jung H.H. Labauge P. Houtteville J.P. Lescoat C. Cecillon M. Marechal E. Joutel A. Bach J.F. Tournier-Lasserve E. Truncating mutations in CCM1, encoding KRIT1, cause hereditary cavernous angiomas.Nat. Genet. 1999; 23: 189-193Crossref PubMed Scopus (394) Google Scholar], is required to activate DNA damage-dependent cell death independently of cep-1/p53. Interestingly, we find that kri-1 regulates cell death in a cell-nonautonomous manner, revealing a novel regulatory role for nondying cells in eliciting cell death in response to DNA damage.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".