Caspase and apoptosis

An effect of YTX as activator of the permeability transition pores of the itmer mitochondrial membrane has been described. These experiments were done over isolated nutochondria in the presence of high calcium concentrations, also in hepatoma cells. These mitochondrial pores are related with caspases and apoptosis (Bianchi et al. 2004). An interaction between YTX and some lydropho-bic derivatives and the glycopholin A, a membrane-integral alfa-helix peptide, has been described (Morietal. 2005). 

Vaux D. Caspases and apoptosis-biology and terminology. Cell Death Differ 1999 6 493-494. 

NO produced by NOS 1 is an important modulator of nervous tissue cell apoptosis. Andoh and colleagues noted that NOSl influences Bcl-2 and other apoptosis regulators, and accounts for some of the neural cell resistance to apoptosis of preconditioning stress (Andoh et al. 2000). Others showed increased NOSl in dorsal root ganglion neurons, as well as an NO inhibition of Bax, caspases, and apoptosis (Thippeswamy et al. 2001). NOSl is found in normal hematopoietic cells, and it influences proliferation and differentiation of these cells (see below) (Enikolopov et al. 1999 Krasnov et al. 2008 Michurina et al. 2004). NOS 1 is expressed in human CLL cells, and NOSl inhibitors induce apoptosis and death in these cells (see below for further discussion of this) (Levesque et al. 2008). 

Mitochondrial permeability transition involves the opening of a larger channel in the inner mitochondrial membrane leading to free radical generation, release of calcium into the cytosol and caspase activation. These alterations in mitochondrial permeability lead eventually to disruption of the respiratory chain and dqDletion of ATP. This in turn leads to release of soluble intramito-chondrial membrane proteins such as cytochrome C and apoptosis-inducing factor, which results in apoptosis. 

Proteasomal inhibition represents a novel strategy in cancer treatment and the small molecule Bortezomid (PS-341, Velcade ) has been approved for the treatment of refractory and relapsed multiple myeloma, a proliferative disease of plasma cells. Bortezomid inhibits an active site in a proteasome subunit and remarkably shows selective cytotoxicity to cancer cells. Although the underlying mechanisms are not completely understood bortezomid apparently induces a cell stress response in these tumor cells followed by caspase-dependent apoptosis. Whether bortezomid is beneficial for the treatment of other proliferative disease is currently being tested in clinical trials. 

Bacellar H, Munoz A et al (1994) Temporal trends in the incidence of HIV-l-related neurologic diseases Multicenter AIDS Cohort Study, 1985-1992. Neurology 44(10) 1892-1900 Banki K, Hutter E et al (1998) Molecular ordering in HIV-induced apoptosis. Oxidative stress, activation of caspases, and cell survival are regulated by transaldolase. . J Biol Chem 273(19) 11944-11953... 

Lee, J.I. et al., Beta-lapachone induces growth inhibition and apoptosis in bladder cancer cells by modulation of Bcl-2 family and activation of caspases, Exp. Oncol., 28, 30, 2006. 

When upstream signaling transduction mechanisms contributing to DON-medi-ated apoptosis were investigated in cloned macrophages, specific inhibition of PKR and Hck additively suppressed DON-induced caspase-3 activity and apoptosis as well as p38, ERK, and JNK phosphorylation.59 Inhibition of PKR and Hck also inhibits DON-induced binding and enzyme activity of p53. 

Byrd, J., Kitada, S., Flinn, L, Aron, J., Pearson, M., Lucas, D., and Reed, J.C., The mechanism of tumor cell clearance by rituximab leukemia evidence of caspase activation and apoptosis induction. Blood, 99, 1038-1043, 2002. 

Monney, L., Ohvier, R., Otter, 1., Jansen, B., Poirier, GG., and Bomer, C., 1998, Role ofan acidic compartment in tumor-necrosis-factor-a-induced production of ceramide, activation of caspase-3 and apoptosis. Eur. J. Biochem. 251 295-303 Morrison, H., Jemstrom, B., Nordenskjdld, M., Thor, H., and Orrenius, S., 1984, Induction of DNA damage by menadione (2-methyl-l,4-naphthoquinone) in primary cultures of rat hepatocytes. Biochem. Pharmacol. 33 1763-1769 Neuzil, J., Svensson, 1., Weber, T, Weber, C., and Brunk, U.T., 1999, alpha-tocopheryl succinate-induced apoptosis in Jurkat T cells involves caspase-3 activation, and both lysosomal and mitochondrial destabilisation. FEES Lett. 445 295-300 Ngo, E.O., Nutter, L.M., Sura, T., and Gutierrez, P. L., 1998, Induction ofp53 by the... 

Wesselborg, S., Engels, I.H., Rossmann, E., Los, M. and Schulze-Osthoff, K., 1999, Anticancer drugs induce caspase-8/FLICE activation and apoptosis in the absence of CD95 receptor/ligand interaction. Blood, 93 3053-3063. 

Figure 3. The many ways to lose a HAT. Decreased amounts of functional CBP protein and subsequent CBP s loss of function has been observed in different contexts of neurological disorders and neuronal apoptosis. RTS (Rubinstein-Taybi Syndrome) results from a mutation on one cbp gene allele. In several cases of polyQ diseases, CBP can be sequestred by the mutated polyQ proteins, forming aggregates in the cytoplasm or the nucleus. CBP proteasomal degradation was also shown to be favored by polyQ proteins. CBP is a caspase-6 substrate in cerebellar granule neurons (CGN) deprived of potassium modeling caspase-dependent apoptosis. Finally, cbp gene repression has been observed in oxidative stress-induced death of a motomeuronal cell line. The mechanisms by which CBP levels are reduced in motomeurons of ALS mice is still unknown...

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