ced-4 and Proto-Oncogene tfg-1 Antagonistically Regulate Cell Size and Apoptosis in C. elegans

BACKGROUND Cell-size-control systems, coupled with apoptotic- and cell-proliferation-regulatory mechanisms, determine the overall dimensions of organs and organisms, and their dysregulation can lead to tumor formation. The interrelationship between cell-growth-regulatory mechanisms and apoptosis during normal development and cancer is not understood. The TRK-fused gene (TFG) promotes tumorigenesis when present in chromosomal rearrangements from various human-cancer types by unknown mechanisms. Apaf1/CED-4 is essential for apoptosis but has not been shown to function in cell-growth control. RESULTS We found that loss of TFG-1, the TFG ortholog in Caenorhabditis elegans, results in supernumerary apoptotic corpses, whereas its overexpression is sufficient to inhibit developmentally programmed cell death. TFG-1 is also required for cells and nuclei to grow to normal size. Furthermore, we found that CED-4 is required for cell-growth inhibition in animals lacking TFG-1. However, caspases, the downstream effectors of CED-4-mediated apoptosis, are not required in TFG-1- or CED-4-regulated cell-size control. CED-4 acts to inhibit cell growth by antagonizing the effects of other conserved cell-size-regulating proteins, including cAMP response element binding (CREB) protein, translation-initiation factor eIF2B, and the nucleolar p53-interacting protein nucleostemin. CONCLUSIONS These findings show that TFG-1 suppresses apoptosis and is essential for normal cell-size control, suggesting that abnormalities in the cell-growth-promoting and apoptosis-inhibiting functions of TFG might be responsible for its action in tumorigenesis. Also, they reveal that CED-4 plays a pivotal role in activating apoptosis and restricting cell and nuclear size, thereby determining the appropriate overall size of an animal. Thus, these findings reveal links between the control mechanisms for apoptosis and cell growth.