In addition to this complex biology, survivin has generated considerable interest as a `cancer gene' ( Altieri, 2003). With respect to the inability of survivin to suppress caspase activity, this turned out to be the rule rather than the exception, as most, perhaps all IAP family members except XIAP, are not physiologic antagonists of caspases in vivo ( Eckelman et al., 2006). In addition, survivin functions as a cell death inhibitor: this second pathway is operative in both interphase and mitotic cells, relies on intermolecular cooperation with other cofactor molecules ( Dohi et al., 2007) and is evolutionarily conserved in certain model organisms, for instance flies ( Jones et al., 2000) and yeast ( Walter et al., 2006). This pathway, at least some of its aspects, is highly evolutionarily conserved among various model organisms ( Altieri, 2006 Lens et al., 2006). Indeed, survivin is an essential mitotic gene, localized to multiple aspects of the mitotic apparatus, and indispensable for several steps in cell division. This controversy has been solved over the years with the realization that survivin is a bona fide multifunctional protein. Similarly, survivin knockdown in worms, a model organism extensively used to study apoptosis, did not uncover defects in cell death, rather a phenotype of aberrant mitosis ( Speliotes et al., 2000). However, it was confusing that survivin did not appear to function as a direct caspase inhibitor ( Verdecia et al., 2000), which was thought of as the main mechanism of IAP-mediated cytoprotection ( Salvesen and Duckett, 2002). Overexpression of survivin in various cellular systems was clearly associated with inhibition of cell death, and, conversely, targeting survivin function and/or expression, especially in tumor cells, caused spontaneous cell death and enhanced the effect of other apoptotic stimuli ( Altieri, 2003). Soon after its discovery, there was uncertainty as to the true function(s) of survivin in mammalian cells. Most likely, orthologs of survivin are found in lower organisms, such as yeast, worms and flies, underscoring the evolutionary conservation of this pathway in cellular homeostasis. Survivin ( Uren et al., 2000) and BRUCE ( Ren et al., 2005), another single-baculovirus IAP repeat IAP protein, are the only two essential members of this gene family, in that their homozygous deletion in mice results in early embryonic lethality, and is incompatible with tissue viability ( Okada et al., 2004). These post-translational mechanisms have been largely implicated in survivin protein stability, and in controlling protein trafficking among various subcellular compartments. One example involves stimulation with insulin growth factor-1, which results in stabilization and rapid translation of a pool of survivin mRNA, in a pathway dependent on the mammalian target of rapamycin ( Vaira et al., 2007 Oh et al., 2008).Ī newly generated survivin protein is post-translationally regulated by degradative ( Zhao et al., 2000) and non-degradative cycles ( Vong et al., 2005) of ubiquitylation and de-ubiquitylation, as well as multiple phosphorylation events by kinases, including Cdk1 ( O'Connor et al., 2002), Aurora B ( Wheatley et al., 2007) and protein kinase A ( Dohi et al., 2007). There are also mechanisms of post-transcriptional modulation of survivin levels, especially in tumor cells. Examples of survivin gene expression independent of cell cycle periodicity have also been described, especially in response to growth factor and cytokine stimulation ( Aoki et al., 2003). Located at the tip of chromosome 17 in humans (17q25), a single survivin gene is extensively alternatively spliced to generate several protein isoforms ( Sampath and Pelus, 2007), and is transcriptionally controlled in a sharp cell cycle-dependent manner, with peak expression at mitosis ( Altieri, 2006 Lens et al., 2006). The regulation of the survivin gene is complex, involving multiple pathways of transcriptional and post-transcriptional control. Survivin is a structural homodimer, containing a single baculovirus IAP repeat, which is the hallmark of all IAPs, and a -COOH terminus coiled coil ( Verdecia et al., 2000), with no other identifiable protein domain(s) ( Srinivasula and Ashwell, 2008). Since the cloning of the survivin gene in 1997, there has been mounting interest in the biology and functions of this pathway in several areas of biomedical research, and peer-reviewed publications dealing with various facets of survivin biology have continued to appear at an exponential rate. Survivin is the smallest member of the inhibitor of apoptosis (IAP) gene family in mammalian cells ( Srinivasula and Ashwell, 2008).
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