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ABSTRACT: DNA damage, chromosomal abnormalities, oncogene activation, viral infection, substrate detachment and hypoxia can all trigger apoptosis in normal cells. However, cancer cells acquire mutations that allow them to survive these threats that are part and parcel of the transformation process or that may affect the growth and dissemination of the tumor. Eventually, cancer cells accumulate further mutations that make them resistant to apoptosis mediated by standard cytotoxic chemotherapy or radiotherapy. The inhibitor of apoptosis (IAP) family members, defined by the presence of a baculovirus IAP repeat (BIR) protein domain, are key regulators of cytokinesis, apoptosis and signal transduction. Specific IAPs regulate either cell division, caspase activity or survival pathways mediated through binding to their BIR domains, and/or through their ubiquitin-ligase RING domain activity. These protein-protein interactions and post-translational modifications are the subject of intense investigations that shed light on how these proteins contribute to oncogenesis and resistance to therapy. In the past several years, we have seen multiple approaches of IAP antagonism enter the clinic, and the rewards of such strategies are about to reap benefit. Significantly, small molecule pan-IAP antagonists that mimic an endogenous inhibitor of the IAPs, called Smac, have demonstrated an unexpected ability to sensitize cancer cells to tumor necrosis factor-alpha and to promote autocrine or paracrine production of this cytokine by the tumor cell and possibly, other cells too. This review will focus on these and other developmental therapeutics that target the IAPs in cancer.
Oncogene 11/2008; 27(48):6252-75. · 6.37 Impact Factor
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ABSTRACT: The inhibitor of apoptosis protein family has been characterized over the past 5 years, initially in baculovirus and more recently in metazoans. The IAPs are a widely expressed gene family of apoptotic inhibitors from both phylogenic and physiologic points of view. The diversity of triggers against which the IAPs suppress apoptosis is greater than that observed for any other family of apoptotic inhibitors including the bcl-2 family. The central mechanisms of IAP apoptotic suppression appear to be through direct caspase and pro-caspase inhibition (primarily caspase 3 and 7) and modulation of and by the transcription factor NF-kappaB. Although evidence for a direct oncogenic role for the IAPs has yet to be delineated, a number of lines of evidence point towards this class of protein playing a role in oncogenesis. The strongest evidence for IAP involvement in cancer is seen in the IAP called survivin. Although not observed in adult differentiated tissue, survivin is present in most transformed cell lines and cancers tested to date. Survivin has been shown to inhibit caspase directly and apoptosis in general, moreover survivin protein levels correlate inversely with 5 year survival rates in colorectal cancer. Recent data has also implicated survivin in cell cycle control. The second line of evidence for IAP involvement in cancer comes from their emerging role as mediators and regulators of the anti-apoptotic activity of v-Rel and NF-kappaB transcription factor families. The IAPs have been shown to be induced by NF-kappaB or v-Rel in multiple cell lines and conversely, HIAP1 and HIAP2 have been shown to activate NF-kappaB possibly forming a positive feed-back loop. Overall a picture consistent with an IAP role in tumour progression rather than tumour initiation is emerging making the IAPs an attractive therapeutic target.
Oncogene 01/1999; 17(25):3247-59. · 6.37 Impact Factor
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R G Lafrenière,
Z Kibar,
D L Rochefort,
F Y Han,
E A Fon,
M P Dubé,
X Kang, S Baird,
R G Korneluk,
J M Rommens,
G A Rouleau
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ABSTRACT: Several inherited diseases have been mapped to the distal tip of human chromosome 21. In our recent efforts to clone candidate genes for some of these disorders, we have assembled a cosmid and BAC contig spanning 770 kb. We have identified expressed sequences from this contig by means of a cDNA hybrid selection scheme. We present here the isolation, cDNA sequence, genomic organization, and polymorphisms analysis of one such expressed sequence, GT334, which had been identified independently and designated EHOC-1. GT334 is split into 23 exons, and spans an estimated 95 kb of genomic DNA. A pseudogene of the histone H2AZ gene has been identified, and maps within the third intron. We have identified an ORF potentially encoding a protein 1259 amino acids in length, longer than that described in the EHOC-1 gene. The GT334 gene was screened for single base pair changes using single-strand conformation polymorphism (SSCP) analysis and we have identified seven sequence variations within this gene. These polymorphisms can be used as markers in the genetic mapping of other diseases localized to this region.
Gene 11/1997; 198(1-2):313-21. · 2.34 Impact Factor
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R G Lafrenière,
D L Rochefort,
Z Kibar,
E A Fon,
F Han,
J Cochius,
X Kang, S Baird,
R G Korneluk,
E Andermann,
J M Rommens,
G A Rouleau
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ABSTRACT: As part of efforts to identify candidate genes for disorders mapped to 21q22.3, we have constructed a 405-kb cosmid contig encompassing five tightly linked markers mapping to this region. A subset of these cosmids was used to identify cDNA fragments by the method of hybrid selection. We present here the cDNA sequence of one such gene (GT335) mapping to this region. The gene is expressed as a 1.7-kb transcript predominantly in heart and skeletal muscle, potentially displays alternate splicing, and is predicted to encode a protein 268 amino acids in length. GT335 spans an estimated 13 kb of genomic DNA and is split into seven exons. Five of the six introns conform to the GT . . . AG consensus for intronic splice junctions; the sixth contains nonconventional (AT . . . AC) intronic junctions. We screened this gene for single-basepair mutations using single-strand conformation polymorphism and sequence analysis of both cDNA and genomic DNA from a number of unrelated individuals and have identified several sequence variations, two of which cause conservative amino acid substitutions. This gene is well conserved evolutionarily, with homologs identified in zebrafish and Escherichia coli, suggesting that it plays an important role in basic cellular metabolism.
Genomics 01/1997; 38(3):264-72. · 3.02 Impact Factor
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C M Phelan,
C Larsson, S Baird,
P A Futreal,
M H Ruttledge,
K Morgan,
P Tonin,
H Hung,
R G Korneluk,
M N Pollak,
S A Narod
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ABSTRACT: The mammary-derived growth inhibitor (MDGI) gene is a candidate tumor suppressor gene for human breast cancer. It has been shown to reduce the tumorigenicity of breast cancer cell lines in nude mice, and loss of expression of this gene has been shown in primary breast tumors. Furthermore, the human MDGI gene has been mapped to human chromosome 1p32-p35, a common region of deletion in sporadic breast tumors. We have determined the genomic structure of the human MDGI gene from a cosmid clone mapping to chromosome 1p32-p35 and have more finely mapped the MDGI gene relative to chromosome 1p microsatellite markers. The gene covers approximately 8 kb of genomic DNA and is divided into four exons. In an attempt to identify possible inactivating mutations in the MDGI gene in human breast cancer, we have sequenced all four exons and their surrounding splice junctions in 30 sporadic breast tumors. Ten of these tumors showed loss of heterozygosity (LOH) in the 1p32-p35 region, with 5 tumors showing LOH in the subregion containing the MDGI gene. No mutations were found in this analysis. A polymorphism was identified in exon 2 in the constitutional DNA of 1/30 cases in this study, which resulted in the conversion of a lysine to an arginine residue at codon 53. This variant was present in the constitutional DNA of a further 3/26 women with sporadic breast cancer and 2/90 control individuals (P = 0.20). Despite experimental evidence that MDGI has tumor suppressor activity, our data suggest that mutations in the coding region are uncommon in human breast tumorigenesis.
Genomics 06/1996; 34(1):63-8. · 3.02 Impact Factor
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P Liston,
N Roy,
K Tamai,
C Lefebvre, S Baird,
G Cherton-Horvat,
R Farahani,
M McLean,
J E Ikeda,
A MacKenzie,
R G Korneluk
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ABSTRACT: Dysregulation of apoptosis can result in inappropriate suppression of cell death, as occurs in the development of some cancers, or in failure to control the extent of cell death, as is believed to occur in acquired immunodeficiency and certain neurodegenerative disorders, such as spinal muscular atrophy (SMA). Recently, we isolated a candidate gene, encoding neuronal apoptosis inhibitor protein (NAIP), for SMA. This gene is homologous to two baculovirus inhibitor of apoptosis proteins (Cp-IAP and Op-IAP) and is partly deleted in individuals with type I SMA. A second SMA candidate gene encoding survival motor neuron (SMN), which is contiguous with the NAIP locus on 5q13.1, was also reported. Here we demonstrate a NAIP-mediated inhibition of apoptosis induced by a variety of signals, and have identified three additional human complementary DNAs and a Drosophila melanogaster sequence that are also homologous to the baculovirus IAPs. The four open reading frames (ORFs) possess three baculoviral inhibition of apoptosis protein repeat (BIR) domains and a carboxy-terminal RING zinc-finger. The human iap genes have a distinct but overlapping pattern of expression in fetal and adult tissues. These proteins significantly increase the number of known apoptotic suppressors.
Nature 02/1996; 379(6563):349-53. · 36.28 Impact Factor
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ABSTRACT: We present the cloning and sequencing of the human gene for a novel G-protein coupled receptor (GPR4), from the critical myotonic dystrophy (DM) region on chromosome 19q13.3. The homologous porcine gene was isolated and sequenced as well. The genes of both species are intronless and contain an open reading frame encoding a protein of 362 amino acids. In human, two isoforms of GPR4 are expressed, differing in their 3' untranslated region due to the use of alternate polyadenylation signals and measuring approximately 2.8 and 1.8 kb, respectively. Northern blot analysis showed that GPR4 is widely expressed, with higher levels in kidney, heart, and especially lung, where it is at least fivefold greater than in other tissues. Sequence analysis suggests that GPR4 is a peptide receptor and shares strongest homologies with purinergic receptors and receptors for angiotensin II, platelet activating factor, thrombin, and bradykinin.
Genomics 12/1995; 30(1):84-8. · 3.02 Impact Factor
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ABSTRACT: The spinal muscular atrophies (SMAs), characterized by spinal cord motor neuron depletion, are among the most common autosomal recessive disorders. One model of SMA pathogenesis invokes an inappropriate persistence of normally occurring motor neuron apoptosis. Consistent with this hypothesis, the novel gene for neuronal apoptosis inhibitory protein (NAIP) has been mapped to the SMA region of chromosome 5q13.1 and is homologous with baculoviral apoptosis inhibitor proteins. The two first coding exons of this gene are deleted in approximately 67% of type I SMA chromosomes compared with 2% of non-SMA chromosomes. Furthermore, RT-PCR analysis reveals internally deleted and mutated forms of the NAIP transcript in type I SMA individuals and not in unaffected individuals. These findings suggest that mutations in the NAIP locus may lead to a failure of a normally occurring inhibition of motor neuron apoptosis resulting in or contributing to the SMA phenotype.
Cell 02/1995; 80(1):167-78. · 32.40 Impact Factor
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ABSTRACT: Analyses of linkage disequilibrium (LD) between markers of known location and disease phenotypes often provide valuable information in efforts to clone the causative genes. However, there exist a number of factors which may attenuate a consistent inverse relationship between physical distance and LD for a given pairing of a genetic marker and a human disease gene. Chief among these is the effect of the general population frequency of an allele which demonstrates LD with a disease gene. Possibly as a result of this, a number of methods of calculating LD has been proposed. We have calculated seven such LD parameters for twelve physically mapped RFLP`s from a 1.3 Mb DM gene containing region of 19q13.3 using 107 DM and 213 non-DM chromosomes. Correlation of the DM-marker physical distance with LD for the 12 loci reveals the Yule coefficient and Dij{prime} parameter to give the most consistent relationship. The D{prime} parameter shown to have a relative allele frequency independence gave only a weak correlation. A similar analysis is being carried out on published cystic fibrosis genetic and physical mapping data. The parameters identified in this study may be the most appropriate for future LD based localizations of disease genes.
The American Journal of Human Genetics 08/1994; 55(Suppl.3). · 10.60 Impact Factor
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ABSTRACT: The mutation underlying myotonic dystrophy (DM) has been identified as an expansion of a polymorphic CTG-repeat in a gene encoding protein kinase activity. Brain and heart transcripts of the DM-kinase (DMR-B15) gene are subject to alternative RNA splicing in both human and mouse. The unstable [CTG]5-30 motif is found uniquely in humans, although the flanking nucleotides are also present in mouse. Characterization of the DM region of both species reveals another active gene (DMR-N9) in close proximity to the kinase gene. DMR-N9 transcripts, mainly expressed in brain and testis, possess a single, large open reading frame, but the function of its protein product is unknown. Clinical manifestation of DM may be caused by the expanded CTG-repeat compromising the (alternative) expression of DM-kinase or DMR-N9 proteins.
Nature Genetics 08/1992; 1(4):261-6. · 35.53 Impact Factor
