Related F-box proteins control cell death in Caenorhabditis elegans and human lymphoma

Cell death is a common metazoan cell fate, and its inactivation is central to human malignancy. In Caenorhabditis elegans, apoptotic cell death occurs via the activation of the caspase CED-3 following binding of the EGL-1/BH3-only protein to the antiapoptotic CED-9/ BCL2 protein. Here we report a major alternative mechanism for caspase activation in vivo involving the F-box protein DRE-1. DRE-1 functions in parallel to EGL-1, requires CED-9 for activity, and binds to CED-9, suggesting that DRE-1 promotes apoptosis by inactivating CED-9. FBXO10, a human protein related to DRE-1, binds BCL2 and promotes its degradation, thereby initiating cell death. Moreover, some human diffuse large B-cell lymphomas have inactivating mutations in FBXO10 or express FBXO10 at low levels. Our results suggest that DRE-1/FBXO10 is a conserved regulator of apoptosis. Fil: Chiorazzi, Michael. The Rockefeller University. Laboratory of Developmental Genetics; Estados Unidos de América; Fil: Rui, Lixin. National Cancer Institute. Center for Cancer Research. Metabolism Branch; Estados Unidos de América; Fil: Yang, Yandan. National Cancer Institute. Center for Cancer Research. Metabolism Branch; Estados Unidos de América; Fil: Ceribelli, Michelle. National Cancer Institute. Center for Cancer Research. Metabolism Branch; Estados Unidos de América; Fil: Tishbi, Nima. The Rockefeller University. Laboratory of Developmental Genetics; Estados Unidos de América; Fil: Maurer. Carine W.. The Rockefeller University. Laboratory of Developmental Genetics; Estados Unidos de América; Fil: Ranuncolo, Stella Maris. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología; Argentina; National Cancer Institute. Center for Cancer Research. Metabolism Branch; Estados Unidos de América; Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina; Fil: Zhao, Hong. National Cancer Institute. Center for Cancer Research. Metabolism Branch; Estados Unidos de América; Fil: Xu, Weihong. National Cancer Institute. Center for Cancer Research. Metabolism Branch; Estados Unidos de América; Fil: Chan, Wing-Chung C.. University of Nebraska. Department of Pathology and Microbiology; Estados Unidos de América; Fil: Jaffe, Elaine S.. National Cancer Institute. Center for Cancer Research. Laboratory of Pathology; Estados Unidos de América; Fil: Gascoyne, Randy D.. British Columbia Cancer Agency; Canadá; Fil: Campo, Elias. Universidad de Barcelona. Hospital Clínico; España; Fil: Rossenwald, Andreas. University of Wurzburg. Department of Pathology; Alemania; Fil: Ott, German. Robert-Bosch-Krankenhaus and Dr. Margarete Fischer-Bosch Institute for Clinical Pharmacology. Department of Clinical Pathology; Alemania; Fil: Delabie, Jan. Oslo University Hospital. Pathology Clinic; Noruega; Fil: Rimsza, Lisa M.. University of Arizona. Department of Pathology; Estados Unidos de América; Southwest Oncology Group; Estados Unidos de América; Fil: Shaham, Shai. The Rockefeller University. Laboratory of Developmental Genetics; Estados Unidos de América; Fil: Staudt, Louis M.. National Cancer Institute. Center for Cancer Research. Metabolism Branch; Estados Unidos de América