Anti-apoptotic proteins

Moreover, a recent study also revealed that ROS generation led to the activation of caspase-2 during p-carotene-induced apoptosis in the human leukemic T cell line Molt 4. The apoptosis progressed by simultaneous activation of caspase-8 and caspase-9, and a cross talk between these initiator caspases was mediated by the pro-apoptotic protein Bid. Inhibition of caspases 2, 8, 9, and 3 independently suppressed the caspase cascade. The cleavage of the anti-apoptotic protein BclXL was found to be another important event during P-carotene-induced apoptosis, suggesting the presence of an extensive feedback amplification loop in P-carotene-induced apoptosis (Prasad et al., 2006). 

HSC and progenitor cells after radiation exposure have the self-renewal capacity needed for leukemia induction. This was shown at low, intermediate and high dose intervals. Cells in patients as compared to controls more often expressed anti-apoptotic protein Bcl-2 and less often demonstrated expression of Fas receptor (fig. 6-7). Cells in patients with low CD8-h counts were simultaneously Fas negative and Bcl-2 positive in 4 out of 19 studied patients. We assume that cells over-expressing anti-apoptotic protein Bcl-2 and demonstrating low Fas expression could lack apoptotic response to environmental factors. 

Esophagus (cells of BE, a pre-neoplastic lesion) Increased resistance to DOC-induced apoptosis in BE cells compared to control cells. Increased expression of anti-apoptotic proteins Bc1-xl, and Mcl-l 47,126... 

Bile-duct epithelial cells (in pre-neoplastic bile-duct inflammatory disease) Strongly increased expression of anti-apoptotic protein Mcl-l 49... 

Pancreas (pre-malignant ductal lesions) In a mouse model of pancreatic cancer there is increased expression of the anti-apoptotic protein Bc1-Xl and decreased expression of pro-apoptotic Bax protein 51... 

Colon [biopsies from colonic mucosa (nontumour tissue) of patients with colon cancer] Increased resistance to DOC-induced apoptosis of colonic epithelial cells of cancer patients or increased expression of anti-apoptotic protein Bc1-xl. 1,27,28,52,127... 

In a transgenic mouse model of ductal pancreatic adenocarcinoma, the development of ductal carcinoma is preceded by trans-differentiation of acinar cells to ductal-like cells.The anti-apoptotic protein Bc1-Xl is highly expressed... 

Although taxanes bind to p-tubulin promoting microtubule polymerization and stabilization of the spindle complex, they serve to cause a sustained mitotic block at the metaphase/anaphase boundary. This block will occur at a lower concentration than that which is required to increase the microtubule mass (10). However, it is not completely clear how this interaction with microtubules translates into cell death. Morphologic features and the characteristic DNA fragmentation patterns seen in the setting of apoptosis have been documented in tumor cells after therapy with taxanes (10). These observations are accompanied by the phosphorylation of Bcl-2, an anti-apoptotic protein, changing the cellular balance between Bax and Bcl-2 to a status that favors apoptosis (11). 

Bcl-2 and related cytoplasmic proteins are key regulators of apoptosis [26], Anti-apoptotic proteins such as Bcl-2 and Bc1-Xl prevent apoptosis in response to numerous stimuli. During the apoptotic process, cytochrome c is released from mitochondria, but the release can be inhibited by the presence of Bcl-2 on the organelles [27]. The released cytochrome c forms an essential part of die apoptosome, which is composed of cytochrome c, Apaf-1, and procaspase-9 [28]. The complex formation results in activation of caspase-9, which leads to the stimulation of caspase-3. Bcl-XL has recently been reported to bind to Apaf-1 [29], It may inhibit the association of Apaf-1 with procaspase-9 and thereby prevent caspase activation. 

While increasing the antioxidant potential of fl cells appears to prevent cell death, the overexpression of proteins imparting islet cell resistance to immune based destruction through interference with the apoptotic pathway, also appears to be quite promising. Increased levels of Bcl-2 (Liu et al., 1996 Bilbao et al., 1999 Rabinovitch et al., 1999), Bcl-xL (Fujita et al., 2000) and anti-apoptotic protein A20 (Grey et al., 1999) were all shown to protect P cells from apoptosis. 

In the absence of a death signal, most of the pro- and anti-apoptotic members are located in separate subcellular compartments. Anti-apoptotic proteins are inserted in intracellular membranes, mainly the mitochondrial membrane, while some proapoptotic members are located in the cytoplasm or cytoskeleton in an inactive form. They are activated and translocated by apoptotic stimuli to their place of action to perform their functions (Gross et al., 1999). 

Zhou Q, Krebs JF, Snipas SJ, Price A, Alnemri ES, Tomaselli KJ, Salvesen GS (1998), Interaction of the baculovirus anti-apoptotic protein p35 with caspases. Specificity, kinetics, and characterization of the caspase/35 complex, Biochemistry 37 10757-10765. 

---