Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Exposure of pulmonary airways to environmental toxins and allergens may cause proliferation of airway epithelial cells and mucous cell metaplasia (MCM); however, it is unclear to what extent proliferating cells differentiate into mucus-storing cells and contribute to MCM. Our previous studies demonstrated that Bcl-2, an inhibitor of apoptosis with cell cycle regulatory functions, is expressed in metaplastic mucous cells. The purpose of the present study was to investigate the number of metaplastic mucous cells that are derived from proliferating epithelial cells and whether Bcl-2 has a role in cell cycle entry in these cells. Rats were intratracheally instilled with 100 microg of LPS from Pseudomonas aeruginosa in 500 microl of saline, and proliferating airway cells were labeled with bromodeoxyuridine (BrdU) by implanting a subcutaneous osmotic pump 24 h before instillation. The volume of stored mucosubstance and the number of mucous cells were increased 10- and 3-fold, respectively, from 24-48 h after instillation. The number of total epithelial cells per millimeter of basal lamina increased, and the number of serous cells per millimeter of basal lamina decreased during this time. Approximately 50% of Alcian blue-periodic acid Schiff-stained mucous cells were labeled with BrdU at 48 h after instillation, suggesting that one-half of the secretory cells were derived from proliferating cells. Furthermore, 50% of the Bcl-2-positive mucous cells were BrdU negative and therefore derived from nonproliferating, preexisting cells. Our findings demonstrate that preexisting and proliferating cells differentiate into mucous cells and compose LPS-induced metaplasia and that Bcl-2 does not have cell cycle regulatory function in these cells.
Am J Physiol Lung Cell Mol Physiol 2004 Feb
PMID:DNA synthesis and Bcl-2 expression during development of mucous cell metaplasia in airway epithelium of rats exposed to LPS. 1452 29

The X-linked inhibitor of apoptosis (XIAP) is a member of a novel family of inhibitors of apoptosis. Since suppression of apoptosis is fundamentally important for carcinogenesis and tumor growth, we investigated the expression and function of XIAP in human hepatocellular carcinomas (HCCs). XIAP was expressed constitutively in HCC cell lines. Fourteen out of 20 (70%) HCC tissues demonstrated moderate or strong cytoplasmic staining for XIAP, whereas non-tumor parts showed negative or weak staining for XIAP by immunohistochemistry. In addition, XIAP expression was inversely correlated with apoptosis, but not with proliferation in HCC tissues. These results indicated that XIAP is a principal inhibitor of apoptosis overexpressed in human HCCs and that XIAP may be a potential target for gene therapy of human HCCs.
Int J Mol Med 2003 Nov
PMID:Overexpression of X-linked inhibitor of apoptosis in human hepatocellular carcinoma. 1453 97

The mitochondrial release of cytochrome c and Smac/DIABLO has been implicated in the activation of apoptosis in response to cell stress. Smac promotes cytochrome c-induced activation of caspases by sequestering the inhibitor of apoptosis protein (IAP) family of potent caspase suppressors. Differential release from mitochondria of cytochrome c and Smac can occur, but the underlying mechanism and physiological significance of this are unclear. Here we show that the mechanism by which fibroblast growth factor 2 (FGF-2) protects small cell lung cancer (SCLC) cells from etoposide-induced cell death involves inhibition of Smac release but not of cytochrome c release. This process is MEK dependent and correlates with an increased expression of XIAP and cellular IAP-1, mediated principally through translational regulation. Exogenous expression of XIAP is sufficient to inhibit caspase 9 activation, Smac release, and cell death induced by etoposide. Prevention of the FGF-2-promoted increase in levels of functional IAPs by RNA interference or the cell-permeant Smac amino-terminal peptide blocked FGF-2-induced protection. FGF-2 can thus protect SCLC cells from chemotherapeutic drugs by modulating IAP levels via posttranscriptional regulation, providing a mechanism for postmitochondrial survival signaling by the MEK/mitogen-activated protein kinase pathway.
Mol Cell Biol 2003 Nov
PMID:Fibroblast growth factor 2-mediated translational control of IAPs blocks mitochondrial release of Smac/DIABLO and apoptosis in small cell lung cancer cells. 1456 6

The release of mitochondrial proapoptotic proteins into the cytosol is the key event in apoptosis signaling, leading to the activation of caspases. Once in the cytosol, cytochrome c triggers the formation of a caspase-activating protein complex called the apoptosome, whereas Smac/Diablo and Omi/htra2 antagonize the caspase inhibitory effect of inhibitor of apoptosis proteins (IAPs). Here, we identify diarylurea compounds as effective inhibitors of the cytochrome c-induced formation of the active, approximately 700-kDa apoptosome complex and caspase activation. Using diarylureas to inhibit the formation of the apoptosome complex, we demonstrated that cytochrome c, rather than IAP antagonists, is the major mitochondrial caspase activation factor in tumor cells treated with tumor necrosis factor. Thus, we have identified a novel class of compounds that inhibits apoptosis by blocking the activation of the initiator caspase 9 by directly inhibiting the formation of the apoptosome complex. This mechanism of action is different from that employed by the widely used tetrapeptide inhibitors of caspases or known endogenous apoptosis inhibitors, such as Bcl-2 and IAPs. Thus, these compounds provide a novel specific tool to investigate the role of the apoptosome in mitochondrion-dependent death paradigms.
Mol Cell Biol 2003 Nov
PMID:Diarylurea compounds inhibit caspase activation by preventing the formation of the active 700-kilodalton apoptosome complex. 1456 26

C-phycocyanin, which is a major biliprotein of the blue-green algae, has been shown to possess cyclooxygenase-2 inhibitory activity. We have studied the effect of phycocyanin on a rat histiocytic tumor line. AK-5 cells are induced into apoptotic death program when treated with phycocyanin, which involves the activation of caspase-3. Phycocyanin-mediated apoptotic death is induced through the generation of reactive oxygen radicals. Free radical scavengers inhibited phycocyanin-induced apoptotic death in AK-5 cells. Bcl-2, an inhibitor of apoptosis, is shown to regulate ROS generation. Bcl-2 gene-transfected AK-5 cells are resistant to phycocyanin-induced death. Overexpression of Bcl-2 inhibited the production of ROS in phycocyanin-treated AK-5 cells. Thus, our observations demonstrate phycocyanin-induced apoptotic death in AK-5 cells, which is inhibited by Bcl-2 expression through the regulation of free radical generation. Phycocyanin, a natural product, could therefore be a possible chemotherapeutic agent through its apoptotic activity against tumor cells.
Mol Cancer Ther 2003 Nov
PMID:Phycocyanin-mediated apoptosis in AK-5 tumor cells involves down-regulation of Bcl-2 and generation of ROS. 1461 90

The anti-CD20 monoclonal antibody rituximab (Rituxan, IDEC-C2B8) has shown promising results in the clinical treatment of a subset of patients with low grade or follicular non-Hodgkin's lymphoma (NHL). However, chemotherapy- and rituximab-refractory NHL patients may benefit from a regimen in which rituximab acts as a sensitizing agent. This study examined the apoptotic signaling mediated by rituximab on rituximab- and paclitaxel-resistant CD20(+) NHL B cell lines (Ramos, Raji, Daudi, and 2F7). Treatment with either rituximab (20 micro g/ml) or paclitaxel (0.1-1000 nM) inhibited viable cell recovery of NHL lines. Neither rituximab nor paclitaxel induced significant apoptosis, although the combination treatment resulted in synergy in apoptosis. Rituximab selectively down-regulated Bcl-xL and induced apoptosis protease activating factor 1 (Apaf-1) expressions in Ramos cells. Paclitaxel down-regulated the expression of Bcl-xL and inhibitor of apoptosis proteins (c-IAP-1) and up-regulated the expression of Bad and Apaf-1. The combination treatment resulted in the formation of truncated Bid, cytosolic accumulation of cytochrome c and second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low PI, activation of caspase-9, caspase-7, caspase-3, and cleavage of poly(ADP-ribose) polymerase. The findings identify two potential novel intracellular targets of rituximab-mediated signaling in Ramos NHL cells (i.e., Bcl-xL and Apaf-1). Further, the findings show that both rituximab and paclitaxel selectively modify the expression pattern of proteins involved in the apoptosis signal transduction pathway and, through functional complementation, the combination results in synergy in apoptosis. The potential therapeutic significance of these findings is discussed.
Mol Cancer Ther 2003 Nov
PMID:Rituximab (anti-CD20) selectively modifies Bcl-xL and apoptosis protease activating factor-1 (Apaf-1) expression and sensitizes human non-Hodgkin's lymphoma B cell lines to paclitaxel-induced apoptosis. 1461 92

Survivin is a member of the inhibitor of apoptosis protein (IAP) family that has been implicated in both apoptosis inhibition and cell cycle control. Recently, Survivin has attracted growing attention because of its tumor-specific expression and potential applications in tumor therapy. However, its inhibitory mechanism and subcellular localization remain controversial. Here, we report a novel Survivin mutant Surv-D53A, which displays a function opposite to Survivin and a distinctive subcellular distribution compared with its wild-type counterpart. Surv-D53A was shown to induce apoptosis in a p53-independent manner, indicating that tumor suppressor p53 is not involved in its apoptosis pathway. Surv-D53A was shown to markedly sensitize apoptosis induced by TRAIL, doxorubicin, and RIP3. We also demonstrated that similar to wild-type Survivin, Surv-D53A was localized in cytoplasm in interphase and to midbody at telophase. However, it fails to colocalize in chromosomes with Aurora-B in metaphase as wt-Survivin. Surv-D53A mutant is less stable than wt-Survivin and is degraded more rapidly by ubiquitin-proteasome pathway. Additionally, we found that Surv-D53A interacts with wt-Survivin to form heterodimer or with itself to form mutant homodimer, which may account for the loss of its antiapoptotic function. Finally, unlike Survivin*Survivin, neither Surv-D53A*Survivin nor Surv-D53A*Surv-D53A is able to bind to Smac/DIABLO, which may explain the underlying mechanism for its abolishment of antiapoptotic activity of Survivin.
Mol Biol Cell 2004 Mar
PMID:A single amino acid change (Asp 53 --> Ala53) converts Survivin from anti-apoptotic to pro-apoptotic. 1469 67

The Drosophila melanogaster inhibitor of apoptosis protein DIAP1 suppresses apoptosis in part through inhibition of the effector caspase DrICE. The pro-death proteins Reaper, Hid and Grim (RHG) induce apoptosis by antagonizing DIAP1 function. However, the underlying molecular mechanisms remain unknown. Here we demonstrate that DIAP1 directly inhibits the catalytic activity of DrICE through its BIR1 domain and this inhibition is countered effectively by the RHG proteins. Inhibition of DrICE by DIAP1 occurs only after the cleavage of its N-terminal 20 amino acids and involves a conserved surface groove on BIR1. Crystal structures of BIR1 bound to the RHG peptides show that the RHG proteins use their N-terminal IAP-binding motifs to bind to the same surface groove, hence relieving DIAP1-mediated inhibition of DrICE. These studies define novel molecular mechanisms for the inhibition and activation of a representative D. melanogaster effector caspase.
Nat Struct Mol Biol 2004 May
PMID:Molecular mechanisms of DrICE inhibition by DIAP1 and removal of inhibition by Reaper, Hid and Grim. 1511 36

Members of the inhibitor of apoptosis protein (IAP) family, including survivin, have been reported to be expressed in many tumors. However, their expression in esophageal cancer has not been clarified completely. We investigated the expression of mRNA for IAP family proteins in samples from esophageal cancers and their adjacent normal mucosa tissues by real-time quantitative RT-PCR. The survivin expression in esophageal cancer was significantly higher than that in normal mucosa (P < 0.05). Other IAP family proteins including cIAP1, cIAP2, NAIP and XIAP tended to show stronger expression in cancer tissue than normal mucosa, although the differences were not significant. As to the histological type of tumor, poorly differentiated squamous cell carcinomas exhibited significantly higher level of expression than well-differentiated carcinomas (P < 0.05). The proportion of apoptotic cells of cancer tissue inversely correlated with the intensity of survivin expression (P < 0.05). Immunohistochemical staining demonstrated cytoplasmic as well as nuclear expression of survivin in esophageal cancer, and further, in situ hybridization analysis demonstrated cytoplasmic expression of mRNA for survivin. The results suggest that the expression of IAP family proteins, especially survivin, may be associated with the biological character of esophageal cancer, such as apoptosis.
Exp Mol Pathol 2004 Jun
PMID:Expression of IAP family proteins in esophageal cancer. 1512 8

The inhibitor of apoptosis protein BIRC-5/survivin plays roles in both apoptosis and the regulation of chromosome-segregation/cytokinesis during mitosis. As the population dynamics of male germ cells are regulated by both proliferation (mitosis and meiosis) and apoptotic culling, we hypothesized that BIRC-5/survivin could be central to the regulation of spermatogenesis. We have analyzed BIRC-5/survivin expression throughout the seminiferous epithelial cycle of the rat. BIRC-5/survivin RNA and protein exhibit rhythms of expression throughout the seminiferous epithelial cycle. The highest levels of expression were found, by immunohistochemistry and in situ hybridization, to occur during the long first meiotic prophase of spermatocytes. Cytoplasmic abundance declined at metaphase and reappeared at anaphase. Some BIRC-5/survivin expression was also found to occur in interstitial Leydig cells. BIRC-5/survivin protein levels were up-regulated in vitro by the paracrine, Stem-Cell Factor, that is known to regulate both proliferation and apoptosis of germ cells and Leydig cells.
Mol Cell Endocrinol 2004 Apr 15
PMID:Survivin expression in rat testis is upregulated by stem-cell factor. 1513 May 21


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