engleski

Bcl-2 family in apoptosis and carcinogenesis

Apoptosis, or programmed cell death, is a cellular suicide program in which individual cells are destroyed while the integrity and architecture of surrounding tissue is preserved. This targeted cell destruction is critical in many physiological contexts including embryogenesis, immune cell maturation and response, tissue homeostasis, and in the cellular response to injury. Apoptosis is also important in several pathological states: excessive or inappropriate apoptosis has been implicated in immunodeficiencies (e.g. AIDS), Alzheimer’ s disease and Parkinson’ s disease, among others, while a failure of cells to die appropriately almost certainly contributes to carcinogenesis. Evasion of the apoptotic program through both down-regulation of apoptotic inducers and inappropriate or excessive induction of survival signals promote tumorigenesis. Thus, a detailed understanding of apoptotic mechanisms and the factors that can compromise them is critical to the design of more potent, specific, and effective cancer therapies. Moreover, selective destruction or preservation of cells through modulation of the apoptotic program promises to impact the treatment of a variety of diseases. Although apoptosis was originally defined on the basis of morphological criteria (chromosomal fragmentation, nuclear pyknosis, plasma membrane blebbing), recent years have seen a rapid expansion in our knowledge of apoptotic mechanisms. Mitochondria, the organelles long thought to act in the singular role of cellular energy generator, are now known to lie at the heart of apoptotic regulation. In organisms where mitochondria do play a critical role in apoptosis, they function primarily as “ storehouses” of apoptotic factors poised for eventual release and action in the cytoplasm. Permeabilization of the mitochondrial membranes allows the escape of cytochrome c, second mitochondria-derived activator of caspase/direct inhibitor of apoptosis protein binding protein with low pI (Smac/Diablo), serine protease Omi/Htr2A, procaspases-2 and -9 (and -3 in some cell types), apoptosis inducing factor (AIF), endonuclease G, hsp10 and hsp60, adenylate kinase 2 (AK2), and a variety of catabolic enzymes. Also liberated are oxidants and reactive oxygen species (ROS) normally confined within the mitochondrion. A number of substances have been shown to promote permeabilization of mitochondrial membranes including small molecules (calcium, nitric oxide, ROS), lipids (ceramide and palmitate) and proteins – most notably those of the Bcl-2 family. The Bcl-2 proto-oncogene was first identified based on its position at the breakpoint of a t(14 ; 18) chromosomal translocation found in certain B cell lymphomas. This event places the Bcl-2 gene under control of the immunoglobulin heavy chain enhancer element, thus greatly up-regulating its transcription and consequently enhancing protein production. Unlike many previously characterized oncogenes, Bcl-2 did not promote cell growth per se, but instead improved cell survival. The connection between Bcl-2 and apoptosis become apparent when the C. elegans Ced-9 gene product, able to negatively regulate developmental apoptotic events in that organism, was found to be a Bcl-2 homologue. Subsequent work has identified homologues of Bcl-2 in many different species. While C. elegans encodes for only two members of the Bcl-2 family Ced-9 and Egl-1, higher eukaryotes possess up to 30 homologues that can be grouped into three categories: 1. Ced-9-like survival factors (Bcl-2, Bcl-xL, Bcl-w, Mcl-1, A1/Bfl-1, NR-13, Boo/Diva/Bcl2-L-10, Bcl-B) ; 2. Egl-like pro-apoptotic proteins (Bik/Nbk, Blk, Hrk/DP5, BNIP3, BimL/Bod, Bad, Bid, Noxa, PUMA/Bbc3, Bmf) ; 3. pro-apoptotic proteins not present in C. elegans (Bax, Bak, Bok/Mtd, Bcl-xS, Drosophila DEBCL). Thus, there are both pro- and anti-apoptotic Bcl-2 proteins, and not surprisingly, Bcl-2 family members can be either tumor suppressor genes or oncogenes. Both Bax and Bak induce cell death in tumors, and Bax mutations have been shown to promote tumorigenesis in large T antigen mouse models of cancer. Moreover, Bax has been shown to be inactivated in colon and hematopoietic malignancies. On the other hand, Bcl-2 and Bcl-xL are both oncogenic owing to their ability to raise the apoptotic threshold, making cells more resistant to stresses that would normally incite apoptotic cell death. Bcl-2 is up-regulated in many tumors, and interfering with Bcl-2 can synergize with chemotherapy and promote regression in some models. The ability to specifically target and inhibit individual genes is the goal of therapeutic modalities currently in development for the treatment of cancer and other diseases.

bcl-2; apoptosis; tumor; antisense ologonucleotides

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