The inhibitor of apoptosis protein family and its antagonists in acute leukemias

The Inhibitor of Apoptosis Protein family (IAP) functions as inhibitors of apoptotic pathways, both death receptor- and mitochondrial mediated. We detail the current body of knowledge for the IAP family with regard to their structure and function, their expression in normal and leukemic cells, and their prognostic importance in acute leukemia. Although there is some evidence that IAPs play an important role in the chemoresistance of leukemia cell lines, little is known about their influence on this phenomenon in acute leukemia cells of human origin. IAPs are also explored as a specific target for new antitumor strategies, including antisense oligonucleotides of XIAP (X-chromosome-linked IAP) or survivin and small molecules of polyphenylurea-based XIAP inhibitors. Several proteins negatively regulate the function of the IAP family. One of those antagonists is Smac/DIABLO. Short peptides of Smac were found to enhanced apoptosis, induced by chemo- or immunotherapy, in the leukemic cells in vitro. Moreover, small-molecule agents, resembling Smac/DIABLO in function, were shown to potentiate cytotoxicity of chemotherapy in different malignancies. IAPs, exhibiting downstream influence on both external and intrinsic pathways as well as on some caspase-independent mechanisms of apoptosis, are potentially attractive target for anti-tumor therapy, although their role in the pathology and prognosis of acute leukemia has to be further elucidated.     

Thioamide substitution to probe the hydroxyproline recognition of VHL ligands

Thioamide substitution influences hydrogen bond and n → π¹ interactions involved in the conformational stability of protein secondary structures and oligopeptides. Hydroxyproline is the key recognition element of small molecules targeting the von Hippel-Lindau (VHL) E3 ligase, which are of interest as probes of hypoxia signaling and ligands for PROTAC conjugation. We hypothesized that VHL ligands could be a privileged model system to evaluate the contribution of these interactions to protein:ligand complex formation. Herein we report the synthesis of VHL ligands bearing thioamide substitutions at the central hydroxyproline moiety, and characterize their binding by fluorescence polarization, isothermal titration calorimetry, X-ray crystallography and molecular modeling. In spite of a conserved binding mode, the substitution pattern had a pronounced impact on the ligand affinities. Together the results underscore the role of hydrogen bond and n → π¹ interactions in fine tuning hydroxyproline recognition by VHL.     

Inhibitor of apoptosis proteins and apoptosis

Apoptosis is a physiological cell death process that plays a critical role in development, homeostasis, and immune defense of multicellular animals. Inhibitor of apoptosis proteins (IAPs) constitute a family of proteins that possess between one and three baculovirus IAP repeats. Some of them also have a really interesting new gene finger domain, and can prevent cell death by binding and inhibiting active caspases, but are regulated by IAP antagonists. Some evidence also indicates that IAP can modulate the cell cycle and signal transduction. The three main factors, IAPs, IAP antagonists, and caspases, are involved in regulating the progress of apoptosis in many species. Many studies and assumptions have been focused on the anfractuous interactions between these three main factors to explore their real functional model in order to develop potential anticancer drugs. In this review, we describe the classification, molecular structures, and properties of IAPs and discuss the mechanisms of apoptosis. We also discuss the promising significance of clinical applications of IAPs in the diagnosis and treatment of malignancy.     

Increasing the solubility and degradability of food processing biosolids

Biosolids (BS) from food processing plants are usually put on land or in landfills. They contain nutrients and could be fed to animals, but low digestibility is a limitation. Lab tests were conducted to evaluate treatments that might increase digestibility of BS.

Biosolids were extruded or treated with chemicals and filtered; residues were incubated with proteases. Dry matter disapperance (DMD), measured as weight loss of treated material following filtration, was considered an indicator of digestibility.

The DMD of extruded BS (31–35%) was greater than oven-dried BS (20–27%). Increasing extruder temperature or speed increased DMD by small but significant amounts. Chemical treatment of BS with HCL, AP and NaOH significantly increased DMD to 60–70%; increases were larger than responses to extrusion. Responses were attained differently; on one hand, for HCL and AP treatments, about 50% of the increase in DMD was due to solubilization and 50% due to degradation. On the other hand, NaOH acted almost completely by solubilization. Increased DMD infers that BS should have increased digestibility when fed to animals, but feeding studies are needed for substantiation.     

CRM1-mediated nuclear export determines the cytoplasmic localization of the antiapoptotic protein Survivin

Survivin is a member of the inhibitor of apoptosis (IAP) family of negative regulators of programmed cell death that is frequently overexpressed in human tumors. Survivin is not only involved in the regulation of apoptosis, but is also known to play a role in the control of cell cycle progression at the G2/M phase. Survivin is a predominantly cytoplasmic protein expressed in a cell cycle-dependent manner, but the mechanism(s) that determine its nuclear-cytoplasmic localization have not been described. In this study, we report that Survivin is a nuclear shuttling protein that is actively exported from the nucleus via the CRM1-dependent pathway. Nuclear export of Survivin is independent of the export of other shuttling proteins that control the G2/M phase transition, such as cyclin B1 and cdc25. The carboxy-terminal domain of Survivin is both necessary and sufficient for its nuclear export, although this region does not contain a functional leucine-rich nuclear export signal. Differences in the amino acid sequence of this region determine the dramatically different localization of Survivin (in the cytoplasm) and its splicing variant Survivin-DeltaEx3 (in the nucleus). The carboxy-terminal end of Survivin-DeltaEx3 contains a bipartite nuclear localization signal, not present in Survivin, which mediates its strong nuclear accumulation. These data suggest that active transport between the nucleus and cytoplasm may constitute an important regulatory mechanism for Survivin function.     

IAPs regulate the plasticity of cell migration by directly targeting Rac1 for degradation

Inhibitors of apoptosis proteins (IAPs) are a highly conserved class of multifunctional proteins. Rac1 is a well-studied Rho GTPase that controls numerous basic cellular processes. While the regulation of nucleotide binding to Rac1 is well understood, the molecular mechanisms controlling Rac1 degradation are not known. Here, we demonstrate X-linked IAP (XIAP) and cellular IAP1 (c-IAP1) directly bind to Rac1 in a nucleotide-independent manner to promote its polyubiquitination at Lys147 and proteasomal degradation. These IAPs are also required for degradation of Rac1 upon CNF1 toxin treatment or RhoGDI depletion. Consistently, downregulation of XIAP or c-IAP1 by various strategies led to an increase in Rac1 protein levels in primary and tumour cells, leading to an elongated morphology and enhanced cell migration. Further, XIAP counteracts Rac1-dependent cellular polarization in the developing zebrafish hindbrain and promotes the delamination of neurons from the normal tissue architecture. These observations unveil an evolutionarily conserved role of IAPs in controlling Rac1 stability thereby regulating the plasticity of cell migration and morphogenesis.     

凋亡抑制蛋白IAP及其调控

调亡过程中关键参与者是caspase家族的多种成员,它们在凋亡过程中要受到严格调控。凋亡抑制蛋白IAP通过抑制caspase的活性从而参与对凋亡的调控,所以IAP的结构特征及其调控机制具有重要意义。     

Life and death decisions: the role of the IAPs in modulating programmed cell death

Multicellular organisms have evolved elaborate signal transduction pathways for maintaining homeostasis through the control of cell proliferation and death. The recent surge of interest in the regulation of programmed cell death has led to the rapid identification of many proteins involved in controlling and executing apoptosis. The inhibitors of apoptosis proteins (IAPs) constitute a family of highly conserved death suppressing proteins that were first identified in baculoviruses, and that has recently expanded to include at least two homologues in Drosophila melanogaster and four in rodents and humans. In this article we review the current state of IAP research. Two of the IAPs, HIAP-1 and HIAP-2, have been placed within the TNFα induced cell death pathway which involves two receptors for TNFα and multiple, overlapping signal transduction proteins. A third, X-linked gene termed XIAP, is ubiquitously expressed and appears to have a broad range of suppressor activity to a variety of apoptotic triggers. The fourth member, NAIP, has been identified as the protein product of a candidate gene for the inherited neuromuscular disorder, spinal muscular atrophy (SMA). The neuroprotective activity of NAIP in an in vivo model of cerebral ischemia has also been demonstrated. This revised version was published online in November 2006 with corrections to the Cover Date.