https://www.cell.com/cell/pdf/S0092-8674(00)80434-1.pdf

Cytochrome c and dATP-Dependent Formation of Apaf-1/Caspase-9 Complex Initiates an Apoptotic Protease Cascade

Cell Death: Critical Control Points

Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition.

https://www.univie.ac.at/ibmz/student/results/apoptosis1.pdf

Apaf-1, a Human Protein Homologous to C. elegans CED-4, Participates in Cytochrome c–Dependent Activation of Caspase-3

Apoptosis is a morphologically distinct form of programmed cell death that plays a major role during development, homeostasis, and in many diseases including cancer, acquired immunodeficiency syndrome, and neurodegenerative disorders. Apoptosis occurs through the activation of a cell-intrinsic suicide program. The basic machinery to carry out apoptosis appears to be present in essentially all mammalian cells at all times, but the activation of the suicide program is regulated by many different signals that originate from both the intracellular and the extracellular milieu. Genetic studies in the nematode Caenorhabditis elegans and in the fruit fly Drosophila melanogaster have led to the isolation of genes that are specifically required for the induction of programmed cell death. At least some components of the apoptotic program have been conserved among worms, insects, and vertebrates.

https://science.sciencemag.org/content/sci/267/5203/1445.full.pdf

Mechanisms and genes of cellular suicide

Mutations in the gene ced-4 block almost all of the programmed cell deaths that normally occur during Caenorhabditis elegans development. We have cloned the ced-4 gene using a ced-4 mutation caused by the insertion of the transposon Tc4. When microinjected into a ced-4 animal, a 4.4 kb DNA fragment derived from the wild-type strain and corresponding to the region of the Tc4 insertion in the mutant ced-4(n1416) rescues the Ced-4 mutant phenotype. The ced-4 gene encodes a 2.2 kb RNA transcript. This mRNA is expressed primarily during embryogenesis, when most programmed cell deaths occur. The Ced-4 protein, as deduced from cDNA and genomic DNA clones, is 549 amino acids in length. Two regions of the putative Ced-4 protein product show some similarity to known calcium-binding domains.

The Caenorhabditis elegans cell death gene ced-4 encodes a novel protein and is expressed during the period of extensive programmed cell death

The cysteine-rich LIM motif is highly conserved between invertebrates and mammals. This motif shows similarity both to proteins that bind zinc and to ferredoxins, which contain iron-sulfur clusters. Two tandem copies of the LIM motif are found in a number of presumptive transcription factors, including the protein product of the Caenorhabditis elegans cell-lineage gene lin-11. To investigate the possible metal-binding properties of the LIM region of the lin-11 protein, we expressed and purified a 151-amino acid peptide containing the tandem LIM motifs. The purified peptide binds both zinc (two atoms per protein molecule) and iron (as a redox-active iron-sulfur cluster, with four atoms of iron and four atoms of inorganic sulfide per protein molecule). These observations suggest that the LIM motif is a metallodomain that might function in a redox-sensitive regulation of transcription.

The LIM region of a presumptive Caenorhabditis elegans transcription factor is an iron-sulfur- and zinc-containing metallodomain.

We have identified and characterized a family of transposable elements in the nematode Caenorhabditis elegans. The Tc4 transposable element family is present at about 20 copies per haploid genome in the C. elegans Bristol and Bergerac strains. Although Tc4 transposition events have not been observed in these wild-type strains, we have identified Tc4 transposition events in the mut-2 mutant strain TR679, in which the elements Tc1 and Tc3 also transpose at a higher frequency than in the wild type. We determined the sequence of one Tc4 element. This 1.6-kilobase element contains almost perfect inverted terminal repeats of 774 base pairs (bp) with a 57-bp unique internal sequence. Tc4 is a fold-back element, but its long inverted terminal repeats, unlike those of the fold-back elements of other organisms, do not consist of multiple short repeats. In the two cases studied, Tc4 insertion resulted in duplication of a TNA trinucleotide target site. The family of Tc4 elements differs from other C. elegans transposable element families in structure, degree of structural heterogeneity, and target-site specificity.

H. R. Horvitz

Papers

The Caenorhabditis elegans cell death gene ced-4 encodes a novel protein and is expressed during the period of extensive programmed cell death

The LIM region of a presumptive Caenorhabditis elegans transcription factor is an iron-sulfur- and zinc-containing metallodomain.

Tc4, a Caenorhabditis elegans transposable element with an unusual fold-back structure.