Targeted expression of baculovirus p35 caspase inhibitor in oligodendrocytes protects mice against autoimmune-mediated demyelination

Hisahara, Shin

doi:10.1093/emboj/19.3.341

Cited by 94 publications

(95 citation statements)

References 53 publications

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“…Indeed, P49 blocked virus-induced apoptosis in cultured cells from Drosophila (Figure 8). Apoptosis of DL-1 cells was also suppressed by P35, which has been shown to prevent programmed cell death in invertebrates and vertebrates (Hay et al, 1994;Sugimoto et al, 1994;Grether et al, 1995;Izquierdo et al, 1999;Hisahara et al, 2000;Viswanath et al, 2000). Since P49 and P35 were proteolytically cleaved in Drosophila cells (Figure 8), a substrate inhibitor mechanism for both apoptotic suppressors is likely.…”

Section: P49 Blocks Virus-induced Apoptosis In Drosophilamentioning

confidence: 93%

Baculovirus apoptotic suppressor P49 is a substrate inhibitor of initiator caspases resistant to P35 in vivo

Zoog¹

2002

The EMBO Journal

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Caspases play a critical role in the execution of metazoan apoptosis and are thus attractive therapeutic targets for apoptosis-associated diseases. Here we report that baculovirus P49, a homolog of pancaspase inhibitor P35, prevents apoptosis in invertebrates by inhibiting an initiator caspase that is P35 insensitive. Consequently P49 blocked proteolytic activation of effector caspases at a unique step upstream from that affected by P35 but downstream from inhibitor of apoptosis Op-IAP. Like P35, P49 was cleaved by and stably associated with its caspase target. Ectopically expressed P49 blocked apoptosis in cultured cells from a phylogenetically distinct organism, Drosophila melanogaster. Furthermore, P49 inhibited human caspase-9, demonstrating its capacity to affect a vertebrate initiator caspase. Thus, P49 is a substrate inhibitor with a novel in vivo speci®city for a P35-insensitive initiator caspase that functions at an evolutionarily conserved step in the caspase cascade. These data indicate that activated initiator caspases provide another effective target for apoptotic intervention by substrate inhibitors.

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Section: P49 Blocks Virus-induced Apoptosis In Drosophilamentioning

confidence: 93%

Baculovirus apoptotic suppressor P49 is a substrate inhibitor of initiator caspases resistant to P35 in vivo

Zoog¹

2002

The EMBO Journal

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“…The first IAP family member identified was p35, a baculoviral protein that suppresses apoptosis in a number of cell types (including cells of the CNS) and under a variety of conditions (Rabizadeh et al, 1993;Hisahara et al, 2000). Subsequent studies demonstrated that several IAPs exist and function by binding to the inactive pro-caspase and therefore, inhibiting its processing to the active form (Hay et al, 1994;Hay et al, 1995;Hay, 2000).…”

Section: The Caspase-3 Apoptotic Cascadementioning

confidence: 99%

“…A second potential step to target in the caspase-3 apoptotic cascade involves the events that are upstream of caspase-3, but downstream of the cytochrome c release, in particular the family of inhibitor of apoptosis proteins Duckett et al, 1998;Ekert et al, 1999;Ekert et al, 2001). The first identified IAP family member was p35, a baculoviral protein that suppresses apoptosis in a number of cell types (including cells of the CNS) and under a variety of conditions (Rabizadeh et al, 1993;Simons et al, 1999;Xu et al, 1999;Eberhardt et al, 2000;Hisahara et al, 2000;Kugler et al, 2000;Korhonen et al, 2001). Subsequent studies demonstrated that several IAPs exist and function by binding to the inactive pro-caspase, therefore, inhibiting its processing to the active form (Hay et al, 1994;Hay et al, 1995;Hay, 2000).…”

Section: Therapeutic Interventions: Delivery Of Anti-apoptotic Genes mentioning

confidence: 99%

Apoptotic Cell Death Following Traumatic Injury to the Central Nervous System

Springer¹

2002

BMB Reports

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Apoptotic cell death is a fundamental and highly regulated biological process in which a cell is instructed to actively participate in its own demise. This process of cellular suicide is activated by developmental and environmental cues and normally plays an essential role in eliminating superfluous, damaged, and senescent cells of many tissue types. In recent years, a number of experimental studies have provided evidence of widespread neuronal and glial apoptosis following injury to the central nervous system (CNS). These studies indicate that injury-induced apoptosis can be detected from hours to days following injury and may contribute to neurological dysfunction. Given these findings, understanding the biochemical signaling events controlling apoptosis is a first step towards developing therapeutic agents that target this cell death process. This review will focus on molecular cell death pathways that are responsible for generating the apoptotic phenotype. It will also summarize what is currently known about the apoptotic signals that are activated in the injured CNS, and what potential strategies might be pursued to reduce this cell death process as a means to promote functional recovery.

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“…29 The presence of the p35 transgene was also detected by PCR. The primers used in the Cell Death and Differentiation Conditional expression of p35 in cardiomyocytes T Araki et al PCR were as follows: forward: 5'-TGGATGGATTCCACGATAGC-3' (p35-3); reverse: 5'-TGCACACTCTCCACGTAAGC-3' (p35-4).…”

Section: Transgenic Micementioning

confidence: 99%

“…24 ± 28 We have generated mice carrying a p35 gene that can be expressed ubiquitously but that is not expressed under normal conditions because its open reading frame (ORF) has been disrupted by the insertion of a DNA segment flanked by loxP sites, the Cre recognition sites. 29 Expression of Cre, which mediates recombination of two loxP sites into a single site, with concomitant removal of the DNA segment they flank, restores the p35 ORF, thereby allowing production of p35 in the cell population of interest.…”

Section: Introductionmentioning

confidence: 99%

Conditional expression of anti-apoptotic protein p35 by Cre-mediated DNA recombination in cardiomyocytes from loxP-p35-transgenic mice

et al. 2000

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p35, a viral inhibitor of caspase, prevents cell death induced by various stimuli. We established an experimental system to study the involvement of caspases in cell death, using primary cultured cells from p35 transgenic mice in which the p35 open reading frame (ORF) had been disrupted by the insertion of a DNA segment flanked by loxP sites, the Cre recognition sites. In this system, p35 expression can be initiated by Cre recombinase. Cardiomyocytes, which are highly sensitive to hypoxic stress, were infected with an adenovirus carrying the cre gene (AxCANCre). Expression of p35 by infection with AxCANCre resulted in inhibition of caspase-3 activation and resistance to hypoxia-induced cell death. Hypoxia-induced cytochrome c release was also attenuated in p35-expressing cardiomyocytes. Our transgenic mice can be used as an experimental model for studying the involvement of caspases in various degenerative diseases as well as programmed cell death both in vitro and in vivo. Cell Death and Differentiation (2000) 7, 485 ± 492.

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Targeted expression of baculovirus p35 caspase inhibitor in oligodendrocytes protects mice against autoimmune-mediated demyelination

Cited by 94 publications

References 53 publications

Baculovirus apoptotic suppressor P49 is a substrate inhibitor of initiator caspases resistant to P35 in vivo

Baculovirus apoptotic suppressor P49 is a substrate inhibitor of initiator caspases resistant to P35 in vivo

Apoptotic Cell Death Following Traumatic Injury to the Central Nervous System

Conditional expression of anti-apoptotic protein p35 by Cre-mediated DNA recombination in cardiomyocytes from loxP-p35-transgenic mice

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