Doom, a Product of the <i>Drosophila mod</i>(<i>mdg4</i>) Gene, Induces Apoptosis and Binds to Baculovirus Inhibitor-of-Apoptosis Proteins

Harvey, Alex J.; Bidwai, Ashok P.; Miller, Lois K.

doi:10.1128/mcb.17.5.2835

Cited by 88 publications

(71 citation statements)

References 46 publications

(54 reference statements)

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“…Uninfected and baculovirus-infected insect cell cultures contain proteins that affect apoptosis (44)(45)(46)(47)(48)(49). Because unpurified exogenous APC was used in some of our experiments, these baculovirus-encoded and insect cellrelated proteins are present in both the control Sf 9 cell lysates and those containing APC.…”

Section: Protein Expression and Purificationmentioning

confidence: 99%

The APC Tumor Suppressor Promotes Transcription-Independent Apoptosis In vitro

Steigerwald

Behbehani

Combs

et al. 2005

Molecular Cancer Research

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The APC tumor suppressor is found in nonproliferating epithelial cells of the colonic crypts and is mutated in most colorectal tumors. To understand the function of APC in normal epithelium and how its loss leads to tumor formation, we tested whether APC is a mediator of apoptosis using an in vitro assay that monitors caspase-3-mediated cleavage of lamin B protein or a colorimetric substrate in a cell-free Xenopus egg extract. Recombinant APC protein accelerates apoptosis-associated caspase activity independently of ongoing transcription and protein synthesis. Conversely, the addition of mutant APC and immunodepletion of Xenopus APC decelerates apoptosis-associated caspase activity. Acceleration of apoptosis by APC is abolished by the caspase-8 inhibitor Z-IETD-FMK, demonstrating that caspase-8 is an essential component of APC-mediated apoptosis. These results suggest that the induction of apoptosis may be one role of APC in tumor suppression and that this mechanism is independent of h h-catenin-mediated effects on transcription. (Mol Cancer Res 2005; 3(2):78 -89)

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Section: Protein Expression and Purificationmentioning

confidence: 99%

The APC Tumor Suppressor Promotes Transcription-Independent Apoptosis In vitro

Steigerwald

Behbehani

Combs

et al. 2005

Molecular Cancer Research

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“…Similarly, a dierential display analysis of porcine aortic endothelial cells revealed an inducible porcine IAP with 73.9% amino acid homology to HIAP1 (Stehlik et al, 1998b). Speci®cally, LPS, TNFa Wang et al, 1998Deveraux et al, 1998Takahashi et al, 1998Rothe et al, 1995Uren et al, 1996;Roy et al, 1997;Hawkins et al, 1998Rothe et al, 1995Uren et al, 1996;Shu et al, 1996;Duckett et al, 1998;Roy et al, 1997;Hawkins et al, 1998Chu et al, 1997Wang et al, 1998; **Tanner (personal communication) Sanna et al, 1998 McCarthy andVucic et al, 1997a, 1998Hay et al, 1995Vucic et al, 1997aVucic et al, ,b, 1998Seshagiri and Miller, 1997Harvey et al, 1997aHarvey et al, 1997a,b Oeda et al, 1998 Crook et al, 1993Clem and Miller, 1994McLachlin and Miller, 1997Clem and Miller, 1994Clem and Miller, 1994 continued and IL-Ib were found to upregulate this gene and this induction was suppressed by IkB suggesting a direct role for NF-kB stimulation of these cells. A more detailed discussion of the role of NF-kB in IAP function is given in part B.…”

Section: Non-caspase Inhibitory Mechanisms Of the Iapsmentioning

confidence: 99%

The inhibitors of apoptosis (IAPs) and their emerging role in cancer

LaCasse¹,

et al. 1998

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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-kB. 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 dierentiated 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-kB transcription factor families. The IAPs have been shown to be induced by NF-kB or v-Rel in multiple cell lines and conversely, HIAP1 and HIAP2 have been shown to activate NF-kB 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.Keywords: inhibitor of apoptosis; IAP; programmed cell death; BIR; RING ®nger; CARD; NAIP; survivin; NF-kB; caspase Part A. The IAP familyThe ®rst Inhibitor of Apoptosis (IAP) proteins were identi®ed in 1993 and 1994 in the baculoviruses Cydia pomonella granulosis virus (CpGV) and Orgyia pseudotsugata nuclear polyhedrosis virus (OpMNPV) by the laboratory of Lois Miller (Crook et al., 1993;Birnbaum et al., 1994). The Miller lab utilized an assay in which infection by a mutant strain of a third baculovirus, Autographa californica nuclear polyhedrosis virus (AcMNPV) results in an unconstrained host lepidopteran SF-21 cell apoptosis. (The natural host cell apoptotic response to viral infection is usually eectively suppressed by the infecting baculovirus). Employing this assay, the CpGV and OpMNPV genomes were screened for loci which would suppress this cell death, resulting in the identi®cation of founding members of a new class of anti-apoptotic genes encoding Cp-IAP and Op-IAP, two proteins which share both homology and the ability to block apoptosis by a wide number of apoptotic triggers (Tables 1, 2 and 5). BIR and RING Zn ®nger domainsThere exists in the baculoviral IAPs two de®ning motifs. The ®rst of these is the B...

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“…Sequence analysis of a large number of mod(mdg4) cDNA clones (8)(9)(10)(11)(12) and the available genomic sequence of the mod-(mdg4) locus (13) indicated that usage of both DNA strands as coding strands is a general property of the mod(mdg4) locus. The common exons 1-4, which are found in all identified transcripts, are located at the 5Ј end of the locus whereas the alternatively spliced 3Ј-specific exons are organized in five groups on both DNA strands.…”

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confidence: 99%

Transgene analysis proves mRNA trans-splicing at the complex mod(mdg4) locus in Drosophila

Dorn

Reuter

Loewendorf

2001

Proc. Natl. Acad. Sci. U.S.A.

122

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The Drosophila BTB domain containing gene mod(mdg4) produces a large number of protein isoforms combining a common Nterminal region of 402 aa with different C termini. We have deduced the genomic structure of this complex locus and found that at least seven of the mod(mdg4) isoforms are encoded on both of its antiparallel DNA strands, suggesting the generation of mature mRNAs by trans-splicing. In transgenic assays, we demonstrate the ability of Drosophila to produce mod(mdg4) mRNAs by trans-splicing of pre-mRNAs generated from transgenes inserted at distant chromosomal positions. Furthermore, evidence is presented for occurring of trans-splicing of mod(mdg4)-specific exons encoded by the parallel DNA strand. The mod(mdg4) locus represents a new type of comlpex gene structure in which genetic complexity is resolved by extensive trans-splicing, giving important implications for genome sequencing projects. Demonstration of naturally occurring trans-splicing in the model organism Drosophila opens new experimental approaches toward an analysis of the underlying mechanisms.T rans-splicing is a process that produces mature transcripts by combining exons of independent pre-mRNA molecules and was first reported in trypanosomes (1-3). The capability of mammalian cells for mRNA trans-splicing was first shown by Eul et al. (4). Recently, additional reports demonstrated transsplicing in higher eukaryotes. Li et al. (5) identified a splice variant of the human acyltransferase ACAT-1 that contains a 5Ј-untranslated exon encoded from chromosome 7 connected with exons 1-16 encoded from chromosome 1. In rat liver cells, carnitine octanoyltransferase mRNA variants with duplications of coding exons 2 and 3 not present in the genomic complement have been identified (6). In this case, different proteins are encoded by the splice variants. However, the physiological significance of these trans-splicing events remains largely unknown.So far no experimental proof for naturally occurring transsplicing in insects has been documented. Recently, Labrador et al. (7) have shown that the mod(mdg4)-67.2 isoform in Drosophila is encoded on both DNA strands and suggested formation of the mature mRNA by trans-splicing of two independent transcripts.Sequence analysis of a large number of mod(mdg4) cDNA clones (8-12) and the available genomic sequence of the mod-(mdg4) locus (13) indicated that usage of both DNA strands as coding strands is a general property of the mod(mdg4) locus. The common exons 1-4, which are found in all identified transcripts, are located at the 5Ј end of the locus whereas the alternatively spliced 3Ј-specific exons are organized in five groups on both DNA strands. In transgenic assays, we provide evidence that trans-splicing is the basic mechanism responsible for production of multiple mod(mdg4) isoforms. (14) in both orientations. The construct was partially sequenced and used for germline mediated transformation. However, by sequencing the transgene specific reverse transcription (RT)-PCR product, we found a frame shift...

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Doom, a Product of the Drosophila mod(mdg4) Gene, Induces Apoptosis and Binds to Baculovirus Inhibitor-of-Apoptosis Proteins

Cited by 88 publications

References 46 publications

The APC Tumor Suppressor Promotes Transcription-Independent Apoptosis In vitro

The APC Tumor Suppressor Promotes Transcription-Independent Apoptosis In vitro

The inhibitors of apoptosis (IAPs) and their emerging role in cancer

Transgene analysis proves mRNA trans-splicing at the complex mod(mdg4) locus in Drosophila

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