Anti-apoptotic signal

ET-1 also stimulates anti-apoptotic signal cascades in fibroblasts, vascular smooth muscles and endothelial cells (via phosphatidylinositol-3-kinase and Akt/pro-tein kinase B). In prostate and ovarian cancer, upregulation of endothelin synthesis and ETA receptors has been associated with a progression of the disease. The inhibiton of ETA receptors results in a reduced tumour growth. In malignant melanoma, ETB receptors are associated with tumour progression. Endothelins can also stimulate apoptosis in stretch-activated vessels via the ETB receptor, which contrasts the above-mentioned effects. The molecular basis for these differential anti- and pro-apoptotic reactions mediated by endothelins remains elusive. 

Malignant Reed-Sternberg cells overexpress nuclear factor-K B, which is associated with cell proliferation and anti-apoptotic signals. Infections with viral and bacterial pathogens upregulate nuclear factor-K B. Epstein-Barr virus is found in many, but not all, HL tumors. 

The combinatorial approach, which combines a blocker of anti-apoptotic signaling with a stimulator of stress signaling, could prove to be a general approach. 

Concomitant expression of metallothioneins (MTs) and metalloproteinases (MMPs) occurs in skeletal muscle that has experienced an injury (Lecker et al. 2004 Warren et al. 2007). MTs are small (12-14 kDa), ubiquitous, cysteine-rich, zinc-binding proteins which are primarily produced in the liver and released into the circulation (Tapiero and Tew 2003). Upon release into the circulation these proteins play a pivotal role in cellular processes to render protection to all tissues of the body. In skeletal muscle, MTs initiate anti-inflammatory and anti-apoptotic signaling cascades, reduce reactive oxygen species (ROS)-induced cytotoxicity, protect against ROS-induced DNA degradation, and maintain zinc homeostasis... 

As a consequence of caspase activation, a number of key enzymes and structural proteins of the cell are degraded, leading to cell death. The stimuli that induce apoptosis are very diverse and include, e. g., DNA damage, stress conditions, and malfunction of pathways regulating cell proliferation. In the normal situation of a tissue, a finely tuned balance exists between pro-apoptotic signals that activate the apoptotic program and anti-apoptotic signals that suppress apoptosis and promote cell survival. The homeostasis achieved by this balance can be disturbed in favor of apoptosis... 

INTEGRATION OF PRO- AND ANTI-APOPTOTIC SIGNALS BY THE BCL-2 FAMILY OF PROTEINS... 

An example of regulation of Bcl-2 family protein function by posttransla-tional modification is seen with Bad [78-80]. In the presence of an anti-apoptotic signal Bad is phosphorylated by PKA and PKB (Akt) and is then sequestered by 14-3-3 protein within the cytoplasm [81-83]. Dephosphorylation of Bad (perhaps by calcineurin) results in release of Bad from 14-3-3 protein and relocalisation with mitochondria, where it interacts with anti-apoptotic Bcl-2. It then exposes its BH3 domain and inserts into the hydrophobic cleft of Bcl-2 resulting in cytochrome c release. 

Kennedy, S.G. et al.. The PI 3-kinase/Akt signaling pathway delivers an anti-apoptotic signal. Genes Dev., 11,701, 1997. 

For activating pro- and anti-apoptotic signaling, B-cell lymphoma 2 (Bel-2) family proteins are reported to play important roles. Bcl-2 family proteins, Bcl-2, Bcl-xL, and Bcl-w are classified as antiapoptotic proteins, which share four domains BHl, 2, 3, and 4 (Chipuk et al. 2010). Other Bcl-2 family proteins, Bax and Bak, are classified as pro-apoptotic proteins which share multidomain of BHl, 2, and 3 (Chipuk et al. 2010). Also Bid, Bil, Bad, Bim, and Bmf are classified as pro-apoptotic protein, but these proteins share only BH3 domain, thus these are also called BH3-only proteins (Chipuk et al. 2010). 

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