Survivin complex

Abstract: Apoptosis, also called programmed cell death, is a conserved mechanism inherent to all cells that sentences them to death when they receive the appropriate external stimuli. Inhibitor of apoptosis proteins (IAPs) are a family of regulatory proteins that suppress such cell death. XIAP is the most commonly studied member of the IAP family. It binds to and inhibits Caspases, an important family of apoptotic proteases. In addition, XIAP over-expression has been detected in numerous types of cancer. Smac/DIABLO, a mitochondrial protein that binds to IAPs and promotes Caspase activation, has the opposite action to XIAP and can be considered a key protein in the regulation of IAPs. Survivin, the smallest IAP protein, has received a lot of attention due to its specific expression in many cancer cell lines. It has been shown to interact with Smac/DIABLO, even though the structure of this complex has not yet been reported. We analysed the protein–protein interactions appearing in the Smac/DIABLO–XIAP and Smac/DIABLO–Survivin complexes fully, using molecular dynamics simulations. This information is a first step towards the design of Smac/DIABLO peptidomimetics that could be used as innovative therapeutic agents for the treatment of malignancy. Our results complement the experimental interactions described for the first complex and provide a detailed description for the second. We show that Smac/DIABLO interacts in a similar way with both targets through its amino terminal residues. In addition, we identify a pharmacophore formed by eight stable protein–protein interactions for the XIAP complex and seven stable protein–protein interactions for the Survivin complex, which describe the whole contact surface. This information is used to suggest the binding mode of embelin, the first non-peptidic inhibitor of XIAP, and two of its derivatives. Molecular docking and molecular dynamics simulations were also carried out to describe ligand and receptor flexibility. Finally, an MMGBSA protocol was used to obtain a more quantitative description of the binding in all the complexes studied. Copyright © 2008 John Wiley & Sons, Ltd.

Abstract: Purpose Pterygium is a distinct clinicopathological entity characterized by degenerated and neoplastic-like features. Concerning its rise on normal conjunctiva epithelia, the role of specific gene deregulations including apoptotic/anti-apoptotic factors and significant suppressor genes in signaling transduction pathways is under investigation. In the current study, we co-analyzed p53, survivin and PTEN proteins in pterygia and normal conjunctiva. Methods Using a liquid-based cytology assay, 50 cell specimens were obtained by a smooth scraping on conjunctiva epithelia and fixed accordingly. Among them, 38 were pterygia and the remaining (n=12) normal epithelia (control group). Immunocytochemistry assays were implemented on the corresponding slides by applying ani-p53, survivin, and PTEN antibodies. Digital image analysis was performed for evaluating objectively the corresponding immunostaining intensity levels. Results The majority of the examined pterygia cases overexpressed the markers p53:22/38-57.9%, survivin:30/38-78.9%, and PTEN:25/38-65.7%. Interestingly, overall p53/PTEN co-expression was found to be statistically significant (p=0.022). Conclusions Survivin overexpression leads to an increased anti-apoptotic activity playing a central molecular role in the pathogenesis and progression of pterygia. Furthermore, although p53 expression is observed in these lesions, its impact seems to be low compared to survivin's influence on them. Additionally, the role of PTEN in the process is potentially significant providing a suppressor balance to the p53/ survivin complex.