Inhibitor Of Apoptosis Gene Research Articles

Expression of Apoptosis Inhibitor Genes and Resistance of T Cells to Apoptosis in the Early Acute Phase of Kawasaki Disease

Objective. The acute phase of Kawasaki disease (KD) is characterized by the deregulated production of proinflammatory cytokines and chemokines by PBMC. We studied the activation induced cell death of the peripheral blood T cells and the expression of the apoptosis-related genes during the course of the disease. Methods. Heparinized blood was obtained from 63 patients, 2-4d (Group A, n=25), 5-7d (Group B, n=29), 8-11d (Group C, n=9), 12-14d (Group D, n=9), and >15d (Group E, n=13) after the onset of fever. PBMC were isolated 24h after blood drawing and stained with anti-CD3 antibody and Annexin V followed by the flow cytometry analysis. The expression of the apoptosis-related genes was studied on PBMC obtained during the acute (<6d) and convalescent (>11d) phase of KD by RT-PCR. Results. The percentage of apoptotic T cells was not increased in the early acute phase (Group A, 13.3%), but gradually increased during the subacute phase with the peak value in the Group C (26.2%, p=0.0002 by Fisher's PLSD). After IVGG therapy, the percentage of apoptotic T cells was significantly increased (15.2% vs. 20.2%, p=0.02 by unpaired t test). The expression of the anti-apoptotic protein genes such as FLICE-like inhibitory protein (FLIP), X-linked inhibitor of apoptosis protein (XIAP), and Bcl-XL was significantly elevated during the acute phase compared with the convalescent phase of KD. Conclusion. The enhanced expression of the apoptosis inhibitory proteins during the early acute phase of KD may prevent the induction of activation induced cell death of PBMC and contribute to the sustained production of proinflammatory cytokines during the acute illness.

Spatial distribution of Bax and Bcl-2 in osteocytes after bone fatigue: complementary roles in bone remodeling regulation?

Osteocyte apoptosis appears to play a key role in the mechanism by which osteoclastic resorption activity targets bone for removal, because osteocyte apoptosis occurs in highly specific association with microdamage and subsequent remodeling after fatigue. However, beyond terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP)-biotin nick end labeling (TUNEL) assay, little is known about the mechanisms controlling osteocyte apoptosis in vivo. In the current studies, expression of Bax, a proapoptotic gene product, and Bcl-2, an antiapoptotic gene product, was determined in osteocytes of fatigued rat bone using immunocytochemical staining and compared with TUNEL staining patterns. Bax and Bcl-2 were evident in osteocytes by 6 h after loading. Moreover, Bax and Bcl-2 in osteocytes were expressed differently as a function of distance from microdamage sites. The peak of Bax expression and TUNEL+ staining in osteocytes was observed immediately at the microcrack locus, which is where bone resorption occurs in this system; in contrast, Bcl-2 expression, the antiapoptotic signal, reached its greatest level at some distance (1-2 mm) from microcracks. These data suggest that near sites of microinjury in bone, those osteocytes that do not undergo apoptosis are prevented from doing so by active protection mechanisms. Moreover, the zone of apoptotic osteocytes around microcracks was effectively "walled in" by a surrounding halo of surviving osteocytes actively expressing Bc1-2. Thus, the expression pattern of apoptosis-inhibiting gene products by osteocytes surrounding the apoptotic osteocyte at microdamage sites also may provide important signals in the guidance of resorption processes that occur in association with osteocyte apoptosis after fatigue.

Evolution of inhibitors of apoptosis in baculoviruses and their insect hosts

The phylogenetic relationships of inhibitor of apoptosis (IAP) from insects and insect viruses were reconstructed and compared with the phylogeny of the viruses reconstructed on the basis of DNA polymerase species. The phylogeny supported the hypothesis that there were three IAP genes in the ancestor of the viral genus Nucleopolyhedrovirus (family Baculoviridae), but that there has been differential deletion of IAP genes in different lineages within this genus. An IAP gene from the granulovirus of the lepidopteran species Cydia pomonella (CpGV) was found to be a close relative of IAP genes from species of the insect order Lepidoptera, supporting the origin of this viral gene by capture of a host gene early in the evolution of Lepidoptera. The phylogeny supported the occurrence of least one other independent event of capture of an IAP gene by a virus and suggested the possibility of at least two other such events. Contrary to the prediction that host genes with viral homologues should experience an enhanced rate of amino acid replacement, no acceleration of evolutionary rate was detectable in these lepidopteran genes, which showed particularly low rates of non-synonymous nucleotide substitution in functionally important domains.

Activation of cancer-specific gene expression by the survivin promoter.

Survivin, a member of the IAP (inhibitor of apoptosis) gene family, appears to be overexpressed in common cancers but not in corresponding normal adult tissues. To investigate whether the survivin promoter controls cancer cell-specific gene expression, we determined whether the survivin gene promoter could regulate reporter gene expression in cancer cell lines and xenografts. Survivin protein levels were determined in human and murine cancer cell lines and in normal tissues of adult C57BL/6 mice by Western blot analysis. A reporter construct in which a portion of the survivin gene promoter was used to drive transcription of a human secreted alkaline phosphatase (SEAP) gene was transiently transfected into cancer cells, and promoter activity was extrapolated from SEAP activity. A2780 human ovarian cancer cells were transfected with this construct, and stable transfectants were injected into the intrabursal ovarian space of immunodeficient mice. Tumor growth was monitored, and plasma SEAP levels were used as a measure of survivin promoter activity in vivo. Survivin protein was detected in all cancer cell lines examined but not in most normal adult mouse tissues. After transfection, the survivin promoter was more active in all cancer cell lines than in normal ovarian surface epithelial cells or mouse 3T3 cells. After 0.8 x 10(6) stable transfectant cells were injected into the intrabursal cavity of mouse ovaries, plasma SEAP activity was detected within 24 hours, and the activity increased with time and tumor growth. Transfection experiments indicate that survivin protein expression in cancer tissue appears to be regulated, at least in part, transcriptionally. Thus, the survivin promoter may be useful in controlling gene expression in cancer cells.

Cloning and characterization of the rat homologues of the Inhibitor of Apoptosis protein 1, 2, and 3 genes.

BackgroundInhibitor of Apoptosis (IAP) proteins are key intrinsic regulators of apoptosis induced by a variety of triggers. We isolated the rat Inhibitor of Apoptosis genes 1, 2 and 3 and characterized their tissue distribution and expression.ResultsRat iap-1 encodes a protein of 67.1 kDa with 73 % and 89.2 % homology to human and mouse iap-1 respectively. Rat iap-2 encodes a protein of 66.7 kDa with 81.6 % and 89.3 % homology to human and mouse iap-2 respectively. Rat iap-3 encodes a protein of 56.1 kDa with 89.5 % and 93.1 % homology to human and mouse iap-3 respectively. We have generated rabbit polyclonal antibodies against all three rat IAP genes. Northern and Western blot analysis detected rat IAP transcripts and proteins in majority of the tissues examined. In addition, a shorter, alternatively spliced transcript corresponding to iap-2 was found in testes.ConclusionsWe have identified three rat homologues of the IAP genes. The elevated expression of rat iap-1 and iap2 in testes suggests that these two genes play an important antiapoptotic role in spermatogenesis.

Regulation of renal tubular cell apoptosis and proliferation after ischemic injury to a solitary kidney

The time course and regulation of apoptosis and cellular regeneration after 30 minutes of acute ischemic injury to a single kidney was elucidated in rats at five time points over 20 weeks. The fraction of apoptotic cells was most prominent at 1 day after the insult in the distal tubule (8% ± 4% vs 0% ± 0%, acute renal failure [ARF] vs sham, respectively) and was still elevated at 7 days (2% ± 2% vs 0% ± 0%). At that time, the whole kidney mRNA expression of the apoptosis inhibitory genes bcl-xL and bcl-2, as well as that of the apoptosis promotor bax, was significantly reduced. Immunohistochemistry of kidney specimen showed suppression of bcl-2 in the distal tubule but up-regulation in the proximal tubule, whereas bax protein was more strongly expressed in the distal tubule. Cellular proliferation started at day 1 and continued over the following 20 weeks, leading to severe tubular dilation and kidney failure. These data indicate that differential regulation of bcl-2 family members contributes to the early apoptotic clearance of lethally injured tubular epithelial cells after ischemic injury to a solitary kidney. (J Lab Clin Med 2001;138:343-51)

Up-regulation by IGF-I of proliferating cell nuclear antigen and Bcl-2 protein expression in human uterine leiomyoma cells.

IGF-I has been reported to play a role in regulating proliferation of human leiomyoma cells. There is, however, little evidence to suggest that IGF-I inhibits apoptosis in the leiomyoma cells. The present study was conducted to elucidate whether IGF-I affects apoptosis and Bcl-2 protein expression, an apoptosis-inhibiting gene product, in cultured leiomyoma cells. In addition, we examined the effect of IGF-I on proliferating cell nuclear antigen (PCNA) expression in cultured leiomyoma cells. Isolated human leiomyoma cells were subcultured in phenol red-free DMEM supplemented with 10% FBS for 120 h and then stepped down to serum-free conditions for an additional 72 h in the absence or presence of graded concentrations of IGF-I (1.0, 10, and 100 ng/ml). The effects of IGF-I on Bcl-2 protein and PCNA expression in cultured leiomyoma cells were assessed by Western immunoblot analysis and immunocytochemical staining, whereas the effects of IGF-I on the cell viability and apoptosis of the cultured cells were determined by 3-(4,5-dimethylatriazol-2-yl)-2,5diphenyltetrasodium bromide (MTT) assay and terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick end labeling assay, respectively. Immunocytochemical staining demonstrated that IGF-I treatment resulted in the increase in PCNA labeling index in cultured leiomyoma cells in a dose-dependent manner. Immunoblot analysis of proteins extracted from the cultured leiomyoma cells revealed that the addition of IGF-I (10 and 100 ng/ml) significantly increased the expression of 35-kDa immunoreactive PCNA and 26-kDa Bcl-2 protein, compared with those in control cultures. Cell survival and proliferation of cultured leiomyoma cells, assessed by MTT assay, was significantly augmented by IGF-I treatment, compared with those of control cultures. Terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick end labeling assay showed that the apoptosis-positive rate of leiomyoma cells treated with IGF-I was significantly decreased, compared with that in control cultures. The present results suggest that IGF-I plays crucial roles in leiomyoma cell growth, not only in promoting the proliferative potential by up-regulation of PCNA expression but also in down-regulating apoptosis by up-regulation of Bcl-2 protein expression in leiomyoma cells.

Identification of apoptosis-inhibiting gene in Leucania separata nuclear polyhedrosis virus.

A novel gene lsp40 from leucania separata nuclear polyhedrosis virus (LsNPV) which was homologous to the p35 gene from Autographa californica Nuclear Polyhedrosis Virus (AcNPV) was localized in the EcoRV-5.5 kb fragment of LsNPV genome DNA and was sequenced. The open reading frame (ORF) of lsp40 was 906 bp long and encoded an approximately 40 kDa peptide consisting of 302 amino acid residues. The Isp40 shares 80.4% and 70.4% identity of nucleotide and amino acid sequence, respectively, to the AcNPV-p35 gene. The identity in promoters of both genes was as high as 100%. It was found that there were two TATA and GC boxes, three ACGT motifs for initiation of early gene transcription and one typical TTAAG core sequence for initiation of late gene transcription at both gene's 5' end, and two AATAAA tail signals at 3' end. The Isp40 started to express 2 hours after being transfected into the Ls cells to produce an approximately 40 kDa protein. The expression of the lsp40 gene might also inhibit the apoptosis of the Ls cells induced by removing serum. The expression of lsp40 in Vero cells delayed the apoptosis of the Vero cells induced by poliovirus infection. The lsp40 gene rescued vAcAnh (a kind of AcNPV p35-deletion mutant) in the Sf9 cells resulting in inhibition of the apoptosis and production of polyhedra. All these data suggested that the lsp40 gene was a homologous and functional gene similar to AcNPV p35 gene.

Expression of the antiapoptosis gene, AAC-11, as a prognosis marker in non-small cell lung cancer

Inhibition of programmed cell death (apoptosis) is associated with increased tumor aggressiveness. We hypothesized that a novel apoptosis inhibitor gene, antiapoptosis clone 11 (AAC-11), may be expressed in tumors of patients with non-small cell lung cancer (NSCLC) and affect their clinical outcome. Expression of AAC-11 messenger RNA was evaluated by reverse transcription polymerase chain reaction (RT-PCR) in 94 non-small cell lung carcinomas and adjacent histologically normal lung samples. The data was analyzed in reference to clinicopathological and survival data. AAC-11 transcripts were detected in 12 (12.7%) of the tumor samples, although five of paired normal lung samples showed very weak expression. There was no relationship between AAC-11 gene expression and age, gender, N or T-status. AAC-11 was preferentially expressed in squamous cell carcinoma (26.9% of squamous cell carcinoma vs. 7% of adenocarcinoma). The NSCLC patients with AAC-11 expression had significantly poor survival than the patients without AAC-11 expression ( P=0.0360). Although the AAC-11 gene was not expressed in a majority of NSCLC tumors, we suggest that AAC-11 may predict poor survival.

Expression, regulation, and function of inhibitor of apoptosis family genes in rat mesangial cells

The inhibitor of apoptosis (IAP) family of proteins regulates programmed cell death triggered by various stimuli. The purpose of this investigation was to examine the expression, regulation, and function of IAP genes in cultured rat mesangial cells. Basal and inducible expression of c-IAP1, c-IAP2, XIAP, and TIAP mRNAs was examined in mesangial cells, isolated glomeruli, and other cell lines under unstimulated and tumor necrosis factor-alpha (TNF-alpha)-stimulated conditions. To examine a role of nuclear factor-kappa B (NF-kappa B) in the regulation of IAPs, expression of IAPs in NF-kappa B-inactive mesangial cells was compared with that in wild-type cells. To investigate roles of IAPs in mesangial cell apoptosis, NF-kappa B--inactive cells were stably supertransfected with c-IAP1 or c-IAP2, and the susceptibility of these cells to TNF-alpha--induced apoptosis was evaluated quantitatively. Substantial, constitutive expression of c-IAP2, XIAP, and TIAP was observed in serum-deprived rat mesangial cells and c-IAP2 and XIAP in isolated normal rat glomeruli. In response to TNF-alpha, expression of c-IAP1 and c-IAP2 was induced in HeLa cells and ECV304 endothelial cells, but not in mesangial cells. In contrast to previous reports on other cell types, the expression of IAPs in rat mesangial cells was independent of NF-kappa B; that is, expression levels of IAPs in NF-kappa B--inactive cells were same as those in NF-kappa B--active cells under both unstimulated and TNF-alpha--stimulated conditions. Even without the induction of IAPs, NF-kappa B--active mesangial cells were more resistant to TNF-alpha--induced apoptosis than NF-kappa B--inactive cells. Interestingly, overexpression of either c-IAP1 or c-IAP2 completely compensated for the lack of resistance to apoptosis in NF-kappa B--inactive cells. IAPs are constitutively expressed in cultured rat mesangial cells and isolated normal rat glomeruli. IAPs can contribute to the survival of rat mesangial cells, but unexpectedly, these molecules are not involved in the TNF-alpha--induced, NF-kappa B--dependent cytoprotection in this cell type.

Two splicing variants of a new inhibitor of apoptosis gene with different biological properties and tissue distribution pattern

Using homology searches, we identified a novel human inhibitor of apoptosis (IAP) gene. This gene has two splicing variants that contain open reading frames of 298 and 280 amino acids and both contained a single copy of baculovirus IAP repeat (BIR) and RING domain. We refer here to the longer and shorter variants as Livin α and β, respectively. Semiquantitative reverse transcriptase-polymerase chain reaction demonstrated a tissue-specific and non-correlated expression pattern in both adult and fetal tissues. Both mRNA variants were detected in various transformed cell lines. Despite their very close similarity, the two isoforms have different antiapoptotic properties. Both isoforms have a significant antiapoptotic activity in the Jurkat T cell line after triggering apoptosis via tumor necrosis factor and CD95 receptors. The Livin α but not β protects cells from apoptosis induced by staurosporine, but in contrast, apoptosis initiated by etoposide was blocked only by the β isoform. This difference in biological activities may indicate the presence of critical amino acids outside the BIR and RING domains. These functional and tissue distribution differences of Livin α and β suggest that Livin may play a complex role in the regulation of apoptosis.

The expression of Survivin, an inhibitor of apoptosis gene, in esophageal cancer

The expression of Survivin, an inhibitor of apoptosis gene, in esophageal cancer

The expression of Survivin, an inhibitor of apoptosis gene, in esophageal cancer

The expression of Survivin, an inhibitor of apoptosis gene, in esophageal cancer

Helicobacter pylori associated gastric B cell MALT lymphoma: predictive factors for regression

See article on page 297 Experimental data have extended the knowledge of the mere association of gastric mucosa associated lymphoid tissue (MALT) lymphoma and infection with Helicobacter pylori. The acquisition...

Activation of Gadd34 by diverse apoptotic signals and suppression of its growth inhibitory effects by apoptotic inhibitors.

DNA damage has many cellular consequences including, in some cases, apoptosis. Expression of Gadd34 was shown to be increased by ionizing radiation only in cells that undergo rapid apoptosis following this treatment. The effects of various other apoptosis-inducing agents as well as apoptosis-inhibiting genes on regulation of Gadd34 were investigated. In many cell types, agents which have been reported to lead to increased intracellular ceramide levels led to an increase in Gadd34 transcript levels. These included TNFalpha, the ceramide analog C-2 ceramide, dimethyl sphingosine and anti-Fas antibody as well as ionizing radiation. Induction of Gadd34 by ionizing radiation was coincident with the onset of apoptosis and increased as apoptosis progressed. In a short-term transfection assay, more than 30% of Gadd34-transfected cells exhibited nuclear fragmentation by 48 hours. Apoptosis, as well as induction of Gadd34 by apoptotic stimuli, was attenuated by the apoptosis inhibitors, Bcl-2, cowpox virus CrmA and herpes simplex virus ICP34.5. Thus, activation of Gadd34 is a downstream event in apoptotic signaling pathways and may directly contribute to the apoptotic process.

The inhibitors of apoptosis of Epiphyas postvittana nucleopolyhedrovirus.

In this study, four inhibitor of apoptosis genes (iaps) in the genome of Epiphyas postvittana nucleopolyhedrovirus (EppoMNPV) that are homologous to iap-1, iap-2, iap-3 and iap-4 genes of other baculoviruses have been identified. All four iap genes were sequenced and the iap-1 and iap-2 genes were shown to be functional inhibitors of apoptosis. The iap-1, iap-2 and iap-3 genes contain two baculovirus apoptosis inhibitor repeat motifs and a C(3)HC(4) RING finger-like motif. The activity of the iap genes was tested by transient expression in Spodoptera frugiperda (Sf-21) cells treated with the apoptosis-inducing agents actinomycin D, cycloheximide, anisomycin, tumour necrosis factor-alpha and UV light. The iap-2 gene prevented apoptosis induced by all agents tested, indicating activity towards a conserved component(s) of multiple apoptotic pathways. However, the iap-2 gene was unable to function in the absence of a gene immediately upstream of iap-2 that has homology to the orf69 gene of Autographa californica MNPV. The use of a CMV promoter rescued the apoptosis inhibition activity of the iap-2 gene, indicating that the upstream orf69 homologue is associated with expression of iap-2. The iap-1 gene was able to delay the onset of apoptosis caused by all of the induction agents tested but, unlike iap-2, was unable to prevent the development of an apoptotic response upon prolonged exposure of cells to the apoptosis induction agents. No anti-apoptotic activity was observed for the iap-3 and iap-4 genes of EppoMNPV.

Effects of progesterone on uterine leiomyoma growth and apoptosis

Uterine leiomyomas appear during the reproductive years and regress after menopause, indicating the ovarian steroid-dependent growth potential. Recently we have found that the use of levonorgestrel-releasing intrauterine system (IUS) is effective in the long-term contraception and management of menorrhagic women with uterine myomas because of a striking reduction in menorrhagia. These clinical experiences prompted us to characterize the effects of progestin on the proliferation and apoptosis of leiomyoma cells cultured in vitro. As epidermal growth factor (EGF) has been shown to mediate estrogen action and play a crucial role in regulating leiomyoma growth, we also investigated the effects of sex steroids on EGF and EGF receptor (EGF-R) expression in leiomyoma cells. In cultures of leiomyoma cells, the addition of either E 2 (10 ng/ml) or P 4 (100 ng/ml) resulted in an increase in proliferating cell nuclear antigen (PCNA) expression in the cells; whereas in cultures of normal myometrial cells, the addition of E 2 augmented PCNA expression in the cells, but P 4 did not. Immunoblot analysis revealed that leiomyoma cells contained immunoreactive EGF and that P 4 treatment resulted in an increase in EGF expression in the cells. In contrast, E 2 treatment augmented EGF-R expression in cultured leiomyoma cells, but P 4 did not. These results indicate that P 4 up-regulates the expression of PCNA and EGF in leiomyoma cells, whereas E 2 up-regulates the expression of PCNA and EGF-R in those cells. It is, therefore, conceivable that P 4 and E 2 act in combination to stimulate the proliferative potential of leiomyoma cells through the induction of EGF and EGF-R expression. We also found that Bcl-2 protein, an apoptosis-inhibiting gene product, was abundantly expressed in leiomyoma relative to that in normal myometrium, suggesting that the abundant expression of Bcl-2 protein in leiomyoma cells may be one of the molecular bases for the enhanced growth of leiomyoma relative to that of normal myometrium in the uterus. Furthermore, Bcl-2 protein expression in leiomyoma cells was up-regulated by P 4, but down-regulated by E 2. Therefore, it seems likely that P 4 may also participate in leiomyoma growth through the induction of Bcl-2 protein in leiomyoma cells.

Gene therapy for cancer by mutant HSV deleted apoptosis-inhibited gene

A mutant HSV (mtHSV) deleted icp34.5, an apoptosis-inhibiting gene was constructed. It is supposed that the mtHSV can replicate in p53-deficient cells selectively and lead to oncolysis targetedly. Mice tumor model harboring sarcoma cell line s-180 was developed and the mtHSV was injected into the tumors. We found that the mean volume and weight of tumors of early therapeutic group(ETG) were reduced 49.29% and 38.31% of that of control tumors. In the mid-term group (MTG), the redutcion rate were 26.9% and 24.52% respectively.

AAC-11 Overexpression Induces Invasion and Protects Cervical Cancer Cells from Apoptosis

To identify the genes involved in cervical carcinogenesis, we applied the mRNA differential display (DD) method to analyze normal cervical tissue, cervical cancer, metastatic lymph node, and cervical cancer cell line. We cloned a 491-bp cDNA fragment, CC231, which was present in metastatic tissue and cervical cancer cell line, but absent in normal cervical and cervical cancer tissues. The 491 bp cDNA fragment has 98% homology to the previously published sequence, AAC-11 (antiapoptosis clone 11). The levels of AAC-11 mRNA expressions in nine normal cervical and nine primary cervical cancer tissues were low. Its expression was higher in three metastatic tissues and five cervical cancer cell lines (HeLa, CaSki, SiHa, CUMC-3, and CUMC-6). Invasion of matrigel and adhesion to laminin by AAC-11 transfected CUMC-6 cells were increased by approximately 2-fold and 4-fold, respectively. Northern blot analysis showed that matrix metalloproteinase (MMP)-2 and membrane type 1 MMP (MT1-MMP) genes were found to be expressed in high levels in AAC-11-transfected cancer cells. But MMP-2 and MT1-MMP were not expressed in cells transfected with vector alone or wild-type cells. AAC-11-transfected cells expressed an elevated level of MMP-2 protein as assessed by immunoblotting. On the contrary, tissue inhibitor of MMP (TIMP-2) expression was detectable in cells transfected with vector alone or wild-type cells, respectively. Its expression was undetectable in AAC-11 transfected cells. In cervical cancer cells transfected with AAC-11, the expression of β-catenin was up-regulated. These suggest that overexpressions of MMP-2 and MT1-MMP, loss of TIMP-2 expression, and up-regulation of β-catenin by AAC-11 transfection may contribute to the development of cervical cancer invasion. AAC-11 gene transfection increased cervical cancer cell colonization. The effect of AAC-11 on cultured cervical cancer cells was associated with antiapoptotic process. Approximately 50% of the AAC-11 transfected cells in serum-free medium died after 2 weeks, compared to 1 week for vector alone or wild-type cells. These results suggest that AAC-11 may serve as a candidate metastasis-related and apoptosis-inhibiting gene in human cervical cancer.

The hippocampal neurons of neuronal apoptosis inhibitory protein 1 (NAIP1)-deleted mice display increased vulnerability to kainic acid-induced injury.

The neuronal apoptosis inhibitory protein (NAIP) is a member of a novel family of inhibitor of apoptosis (IAP) proteins. The IAP genes are highly conserved from baculovirus to metazoans and suppress apoptosis induced by a variety of triggers both in vitro and in vivo. Here we describe the generation and characterization of mice with the targeted deletion of NAIP1. We demonstrate that the NAIP1-deleted mice develop normally. However, the survival of pyramidal neurons in the hippocampus after kainic acid-induced limbic seizures is greatly reduced in the NAIP1 knock-out animals. Thus, although NAIP1 is not necessary for normal development of murine central nervous system, the endogenous NAIP1 is required for neuronal survival in pathological conditions.