Academic journal article Genetics

DPL-1 DP, LIN-35 Rb and EFL-1 E2F Act with the MCD-1 Zinc-Finger Protein to Promote Programmed Cell Death in Caenorhabditis Elegans

Academic journal article Genetics

DPL-1 DP, LIN-35 Rb and EFL-1 E2F Act with the MCD-1 Zinc-Finger Protein to Promote Programmed Cell Death in Caenorhabditis Elegans

Article excerpt

ABSTRACT

The genes egl-1, ced-9, ced-4, and ced-3 play major roles in programmed cell death in Caenorhabditis elegans. To identify genes that have more subtle activities, we sought mutations that confer strong cell-death defects in a genetically sensitized mutant background. Specifically, we screened for mutations that enhance the cell-death defects caused by a partial loss-of-function allele of the ced-3 caspase gene. We identified mutations in two genes not previously known to affect cell death, dpl-1 and mcd-1 (modifier of cell death). dpl-1 encodes the C. elegans homolog of DP, the human E2F-heterodimerization partner. By testing genes known to interact with dpl-1, we identified roles in cell death for four additional genes: efl-1 E2F, lin-35 Rb, lin-37 Mip40, and lin-52 dLin52. mcd-1 encodes a novel protein that contains one zinc finger and that is synthetically required with lin-35 Rb for animal viability. dpl-1 and mcd-1 act with efl-1 E2F and lin-35 Rb to promote programmed cell death and do so by regulating the killing process rather than by affecting the decision between survival and death. We propose that the DPL-1 DP, MCD-1 zinc finger, EFL-1 E2F, LIN-35 Rb, LIN-37 Mip40, and LIN-52 dLin52 proteins act together in transcriptional regulation to promote programmed cell death.

PROGRAMMED cell death is important for many aspects of animal development, including morphogenesis, homeostasis, and neuronal refinement (GLÜCKSMANN 1951; SAUNDERS 1966; JACOBSON et al. 1997). Studies of the mechanisms of programmed cell death in the nematode Caenorhabditis elegans have identified a pathway that is largely conserved in other organisms, including humans (METZSTEIN et al. 1998). Four genes-egl-1, ced-9, ced-4, and ced-3-regulate essentially all somatic programmed cell death and define the core metazoan cell-death execution machinery. EGL-1, which promotes cell death, is a BH3-only protein that binds to and inhibits the CED-9 protein (CONRADT and HORVITZ 1998). CED-9, which inhibits cell death (HENGARTNER et al. 1992), is similar to the human proto-oncoprotein BCL-2 (HENGARTNER and HORVITZ 1994b; YAN et al. 2005) and localizes to mitochondria (CHEN et al. 2000). CED-9 binds CED-4 (SPECTOR et al. 1997), which localizes to mitochondria in a CED-9-dependent manner (CHEN et al. 2000), promotes cell death (ELLIS and HORVITZ 1986), and is similar to the human pro-apoptotic protein APAF-1 (YUAN and HORVITZ 1992; ZOU et al. 1997). The expression of egl-1 or the loss of ced-9 function can trigger cell death and result in a change in the localization of CED-4 frommitochondria to the perinuclear region (CHEN et al. 2000). CED-4 activates CED-3 (SHAHAM and HORVITZ 1996b), which promotes cell death (ELLIS and HORVITZ 1986) and is a defining member of a family of cysteine proteases termed caspases (YUAN et al. 1993). CED-4 can interact directly with the CED-3 procaspase (WU et al. 1997) and facilitate the processing of proCED-3 into active CED-3 (CHINNAIYAN et al. 1997; YANG et al. 1998).

Other C. elegans genes appear to promote cell death more subtly. For example, the gene ced-8 XK affects the timing of programmed cell deaths in C. elegans and has a minor role in cell killing (STANFIELD and HORVITZ 2000). The gene ced-9, which inhibits programmed cell death, also can promote cell death (HENGARTNER and HORVITZ 1994a). The gene cps-6 encodes a mitochondrial endonuclease G protein that likely promotes cell death (PARRISH et al. 2001). The process of the engulfment of dying cells also promotes cell death (HOEPPNER et al. 2001; REDDIEN et al. 2001). Additional genes that affect programmed cell death in C. elegans, such as those encoding proteins that mediate the ability of engulfment to promote cell death, thatmediate the cell-killing activities of ced-8 or ced-9, or that act downstream of CED-3, remain to be identified. We reasoned that genes with subtle contributing roles in programmed cell death might be identified by screening for mutations that further decrease cell death in a genetic background in which cell death is partially impaired. …

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