Apoptosis - the regulated destruction of a cell - is a complicated process. The decision to die cannot be taken lightly, and the activity of many genes influence a cell's likelihood of activating its self-destruction programme. Once the decision is taken, proper execution of the apoptotic programme requires the coordinated activation and execution of multiple subprogrammes. Here I review the basic components of the death machinery, describe how they interact to regulate apoptosis in a coordinated manner, and discuss the main pathways that are used to activate cell death.

The biochemistry of apoptosis

https://www.cell.com/cell/pdf/0092-8674(93)90509-O.pdf

Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programed cell death

Bcl-2 and related cytoplasmic proteins are key regulators of apoptosis, the cell suicide program critical for development, tissue homeostasis, and protection against pathogens. Those most similar to Bcl-2 promote cell survival by inhibiting adapters needed for activation of the proteases (caspases) that dismantle the cell. More distant relatives instead promote apoptosis, apparently through mechanisms that include displacing the adapters from the pro-survival proteins. Thus, for many but not all apoptotic signals, the balance between these competing activities determines cell fate. Bcl-2 family members are essential for maintenance of major organ systems, and mutations affecting them are implicated in cancer.

https://science.sciencemag.org/content/sci/281/5381/1322.full.pdf

The Bcl-2 Protein Family: Arbiters of Cell Survival

Cell Death: Critical Control Points

BCL-2 family proteins, which have either pro- or anti-apoptotic activities, have been studied intensively for the past decade owing to their importance in the regulation of apoptosis, tumorigenesis and cellular responses to anti-cancer therapy. They control the point of no return for clonogenic cell survival and thereby affect tumorigenesis and host-pathogen interactions and regulate animal development. Recent structural, phylogenetic and biological analyses, however, suggest the need for some reconsideration of the accepted organizational principles of the family and how the family members interact with one another during programmed cell death. Although these insights into interactions among BCL-2 family proteins reveal how these proteins are regulated, a unifying hypothesis for the mechanisms they use to activate caspases remains elusive.

http://dipbsf.uninsubria.it/monti/BFPN%202009/bcl2-1008.pdf

The BCL-2 protein family: opposing activities that mediate cell death

The human homolog, c-ros, of the transforming gene, v-ros, of the avian sarcoma virus, UR2, has been isolated from a human genomic library A single-copy fragment from the human c-ros genomic clone has been used to map the human c-ros homolog (ROS) to human chromosome region 6q16----6q22 by somatic cell hybrid analysis and chromosomal in situ hybridization Thus, the c-ros gene joins the c-myb oncogene, which is distal to the c-ros gene on the long arm of human chromosome 6, as a candidate for involvement in chromosome 6q deletions and rearrangements seen in various malignancies

https://www.pnas.org/content/pnas/83/17/6568.full.pdf

The human c-ros gene (ROS) is located at chromosome region 6q16----6q22.

Chromosome translocations and B cell neoplasia.

LITTLE is known about the biochemical or functional nature of the proteins encoded by the bcl-2 gene, which undergoes chromosomal translocation in approximately 85% of follicular lymphoma, 20% of diffuse large cell lymphoma and 10% of chronic lymphocytic leukaemia of B cells1–5. Translocation of bcl-2 sequences5 from chromosome 18 to the JH segment of the immunoglobulin gene at chromosome band 14q32 in B cells results in deregulated expression of this gene, causing high steady state levels of bcl-2 messenger RNA2. DNA sequence data indicate that bcl-2 encodes two proteins by virtue of alternative splicing, designated as Bcl-2α and Bcl-2β, with relative molecular masses of 26,000 and 22,000 respectively1. Cell fractionation experiments indicate that the bcl-2α gene product is located at the inner surface of the cell membrane, suggesting a possible role in mitogenic signal transduction6. We report here that Bcl-2α has GTP-binding activity and a protein sequence that suggests it belongs to the small molecular weight GTP-binding protein (G protein) family7–16.

The bcl-2 gene encodes a novel G protein

Both the t(14; 18) and the t(11; 14) chromosomal translocations are associated with human B-cell neoplasms Sequence analysis of the regions on chromosomes 18q- and 11q- involved in the joining of chromosomes 14 and 18 and of chromosomes 11 and 14 during their respective translocations indicates the involvement of the DH region There is a deletion of the region between the involved D segment and the JH region, and extranucleotides are present at the joining sites on the 18q- and on the 11q- chromosomes We have previously reported that the joining region on chromosome 14q+ involved in both the t(11; 14) and the t(14; 18) translocations are structurally identical We now report that the joining regions on chromosomes 11q- and 18q- involved in these two different translocations are also identical Thus, these translocations arose by the same mechanisms The deletions of the region between the involved segment and the JH region must likely occur during either a D-J recombination event on the 18q- and 11q- chromosomes following the translocations or, alternatively, during the D-J recombination event that results in the translocation

The reciprocal partners of both the t(14; 18) and the t(11; 14) translocations involved in B-cell neoplasms are rearranged by the same mechanism.

We have shown that the silk fibroin gene from Bombyx mori is faithfully transcribed in an in vitro transcription system of the HeLa cell extract prepared by the method of Manley et al. [Manley, J. L., Fire, A., Cano, A., Sharp, P. A. & Gefter, M. L. (1980) Proc. Natl. Acad. Sci. USA 77, 3855-3859]. Using this system and a series of deletion mutants of fibroin gene, we have assigned the promoter sequence of fibroin gene. The 5' boundary of the promoter is around nucleotide position -29, indicating that most of the T-A-T-A-A-A-A sequence (-30 to -24) is essential for the promoter function, where the transcription initiation point of fibroin gene is assigned as nucleotide position +1 [Tsuda, M., Ohshima, Y. & Suzuki, Y. (1979) Proc. Natl. Acad. Sci. USA 76, 4872-4876]. The 3' boundary is around nucleotide position +6. However, to support the efficient, faithful transcription, some additional (more than 26 but less than 41) nucleotides of nonspecific origin are required at the 5' side of -29. Functions ascribed to the promoter region are discussed.

https://www.pnas.org/content/pnas/78/8/4838.full.pdf

Yoshihide Tsujimoto

Papers

The human c-ros gene (ROS) is located at chromosome region 6q16----6q22.

Chromosome translocations and B cell neoplasia.

The bcl-2 gene encodes a novel G protein

The reciprocal partners of both the t(14; 18) and the t(11; 14) translocations involved in B-cell neoplasms are rearranged by the same mechanism.

Promoter sequence of fibroin gene assigned by in vitro transcription system.