Death by a thousand cuts: an ever increasing list of caspase substrates

Stroh, Christopher; Schulze‐Osthoff, Klaus

doi:10.1038/sj.cdd.4400451

Cited by 255 publications

(166 citation statements)

References 49 publications

Supporting

Mentioning

161

Contrasting

Unclassified

Order By: Relevance

“…Apoptosis entails proteolysis of several regulatory molecules and subsequent protein degradation as part of the process that lends to cessation of cellular functions and cell death (Stroh and Schulze-Osthoff, 1998). Splicing factors are particularly sensitive to proteolytic degradation (La Branche et al, 1991;Casciola-Rosen et al, 1994;Waterhouse et al, 1996;Shav-Tal et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Nuclear Relocalization of the Pre-mRNA Splicing Factor PSF during Apoptosis Involves Hyperphosphorylation, Masking of Antigenic Epitopes, and Changes in Protein Interactions

Shav‐Tal

Cohen

Lapter

et al. 2001

MBoC

View full text Add to dashboard Cite

The spatial nuclear organization of regulatory proteins often reflects their functional state. PSF, a factor essential for pre-mRNA splicing, is visualized by the B92 mAb as discrete nuclear foci, which disappeared during apoptosis. Because this mode of cell death entails protein degradation, it was considered that PSF, which like other splicing factors is sensitive to proteolysis, might be degraded. Nonetheless, during the apoptotic process, PSF remained intact and was N-terminally hyperphosphorylated on serine and threonine residues. Retarded gel migration profiles suggested differential phosphorylation of the molecule in mitosis vs. apoptosis and under-phosphorylation during blockage of cells at G1/S. Experiments with the use of recombinant GFP-tagged PSF provided evidence that in the course of apoptosis the antigenic epitopes of PSF are masked and that PSF reorganizes into globular nuclear structures. In apoptotic cells, PSF dissociated from PTB and bound new partners, including the U1-70K and SR proteins and therefore may acquire new functions. INTRODUCTIONSplicing factors are found within the nucleus both in a diffuse form and in distinct domains termed interchromatin granules (IG) or "speckles" (Spector, 1993). These functional compartments are spatially dynamic with regard to movement and composition (Eils et al., 2000). Splicing factors within IGs are highly mobile and are constantly associating and dissociating from their compartments (Phair and Misteli, 2000). The mAb, B92, which recognizes the polypyrimidine tract binding protein (PTB)-associated splicing factor (PSF), produces typical specked nuclear pattern in immunostaining. These PSF speckles disappear during granulocytic differentiation (Lee et al., 1996;Shav-Tal et al., 2000). We recently showed that this disappearance is associated with partial degradation (Shav-Tal et al., 2000) and by the formation of alternative nuclear structures (Shav-Tal et al., 2001). The present study indicates that PSF speckles disappear also through a different mechanism, involving conformational changes that cause breakdown of PSF speckles and relocalization of the molecule in the nucleus. The functional nature of speckles is a matter of some controversy (for review, see Park and De Boni, 1999). These structures have been suggested to play a role in storage and recycling of splicing factors (Jimenez-Garcia and Spector, 1993), whereas a portion may act as reservoirs for the recruitment to active sites of transcription (Huang and Spector, 1996;Zeng et al., 1997). This view does not predict a direct involvement of speckles in pre-mRNA splicing. On the other hand, it has been shown that nascent mRNA transcripts and transcription sites are closely associated with speckles, that transcription occurs at the surface of speckles (Clemson and Lawrence, 1996), and that microinjected pre-mRNAs have high affinity to speckles (Wang et al., 1991). It has thus been proposed that speckles can act coordinately in transcription and splicing and that pre-mRNA splicing can take place bo...

show abstract

Section: Discussionmentioning

confidence: 99%

Nuclear Relocalization of the Pre-mRNA Splicing Factor PSF during Apoptosis Involves Hyperphosphorylation, Masking of Antigenic Epitopes, and Changes in Protein Interactions

Shav‐Tal

Cohen

Lapter

et al. 2001

MBoC

View full text Add to dashboard Cite

show abstract

“…In principle, caspase-mediated cleavage should result in different effects, such as (1) a halt of cell cycle progression, (2) disabling of repair mechanisms, (3) disassembly of molecular structures, (4) cell detachment, and (5) tagging of the apoptotic cell for engulfment by phagocytes. 78 Experimental data showed that not all roads to cell death depend on the activation of caspases. Caspase-independent cell death includes necrosis but also some forms related to apoptosis.…”

Section: Initiator and Effector Caspases And Their Targetsmentioning

confidence: 99%

The kiss of death: promises and failures of death receptors and ligands in cancer therapy

et al. 2001

View full text Add to dashboard Cite

“…Active caspase-8 in turn triggers the proteolytic activation of downstream caspases including caspase-3. Downstream caspases ultimately degrade a broad range of cellular proteins, and apoptosis is finalized (for review see Stroh and Schulze-Osthoff, 1998;Fischer et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Combined treatment of colorectal tumours with agonistic TRAIL receptor antibodies HGS-ETR1 and HGS-ETR2 and radiotherapy: enhanced effects in vitro and dose-dependent growth delay in vivo

et al. 2006

View full text Add to dashboard Cite

We and others have demonstrated already that TRAIL (TNF-related apoptosis-inducing ligand) is a very promising candidate for molecular targeted anticancer therapy, especially when combined with ionizing radiation or other DNA-damaging agents. Agonist monoclonal antibodies that activate and are specific for the death signaling TRAIL receptors are an alternative method to stimulate the programmed cell death pathway. Phase 1 clinical trials have subsequently been conducted and shown a very good tolerability of these antibodies. In order to assess the efficacy of TRAIL receptor stimulation to induce cell death by this alternate method, we studied the combination of the agonistic-TRAIL receptor antibodies HGS-ETR1 and HGS-ETR2 with radiation in vitro and in vivo. Induction of apoptosis after combined treatment with TRAIL receptor antibodies HGS-ETR1 and/or HGS-ETR2 (0.01, 0.1, 1.0 mg/ml) and irradiation with 2, 5 or 10 Gy was determined by fluorescence microscopy and Western blot analysis of caspase-8 and PARP. The colorectal tumour cell lines Colo 205, HCT 116 and HCT-15 were used for in vitro experiments. Growth delay experiments were performed with combined treatment with fractionated irradiation (days 1-5 and 3 Gy single dose/day) and the receptor antibodies (intraperitonially, three different concentrations, application on days 1, 4 and 8) on Colo 205 xenograft-bearing NMRI (nu/nu) nude mice. HGS-ETR1 and HGS-ETR2 induced apoptotic cell death in a dose-dependent fashion and significantly increased cell death in combination with irradiation in vitro when compared to either irradiation or antibody treatment alone. The efficacy of the combined treatment seems to be at least partially Bax-dependent. Similar to the results from cell culture experiments, in vivo experiments demonstrated a dose-dependent delay in tumour growth after combined treatment. In vivo, in the Colo205 xenograft model, HGS-ETR2 revealed a higher activity than HGS-ETR1. This is the first study to demonstrate significant efficacy of combined treatment with the monoclonal agonistic TRAIL receptor antibodies HGS-ETR1 and HGS-ETR2 and ionising radiation in in vitro and in vivo models. We postulate that HGS-ETR1 and HGS-ETR2 will be very promising new agents in the field of molecular targeted multi-modality anticancer therapy.

show abstract

Death by a thousand cuts: an ever increasing list of caspase substrates

Cited by 255 publications

References 49 publications

Nuclear Relocalization of the Pre-mRNA Splicing Factor PSF during Apoptosis Involves Hyperphosphorylation, Masking of Antigenic Epitopes, and Changes in Protein Interactions

Nuclear Relocalization of the Pre-mRNA Splicing Factor PSF during Apoptosis Involves Hyperphosphorylation, Masking of Antigenic Epitopes, and Changes in Protein Interactions

The kiss of death: promises and failures of death receptors and ligands in cancer therapy

Combined treatment of colorectal tumours with agonistic TRAIL receptor antibodies HGS-ETR1 and HGS-ETR2 and radiotherapy: enhanced effects in vitro and dose-dependent growth delay in vivo

Contact Info

Product

Resources

About