A Novel Caspase-2 Complex Containing TRAF2 and RIP1

Lamkanfi, Mohamed; D'Hondt, Kathleen; Walle, Lieselotte Vande; Gurp, Maria van; Denecker, Geertrui; Demeulemeester, Jill; Kalai, Michaël; Declercq, Wim; Saelens, Xavier; Vandenabeele, Peter

doi:10.1074/jbc.m411180200

Cited by 66 publications

(68 citation statements)

References 77 publications

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“…Our findings that wild-type caspase-2 keeps NF-B activity in check and at a low level is in agreement with the above report. However, another report showed that caspase-2, in forming a complex with TRAF2 and RIP1, activates NF-B, which requires its caspase recruitment domain and is independent of its enzymatic activity and RIP1 cleavage (28). This discrepancy could be due to different experimental conditions and cell types.…”

Section: S139amentioning

confidence: 70%

Tumor-suppressing Function of Caspase-2 Requires Catalytic Site Cys-320 and Site Ser-139 in Mice

Ren

Porollo

et al. 2012

Journal of Biological Chemistry

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Background: Caspase-2 deficiency accelerates tumorigenesis in mice, but the underlying mechanisms remain unclear. Results: Caspase-2 catalytic site Cys-320 and Ser-139 residues sustain G 2 /M checkpoint and inhibit transformation and NF-B activation. Conclusion: Both residues are required for caspase-2 to suppress tumorigenesis in nude mice. Significance: These findings provide insight into tumor suppression at the cross-roads of apoptosis, cell cycle checkpoint, and NF-B pathways.

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Section: S139amentioning

confidence: 70%

Tumor-suppressing Function of Caspase-2 Requires Catalytic Site Cys-320 and Site Ser-139 in Mice

Ren

Porollo

et al. 2012

Journal of Biological Chemistry

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“…This isoform as a CARD protein could be involved in protein recruitment. 36 It will be interesting to test whether this variant is present in casp2À/À mice and might explain their phenotype. 37 The gene-targeting construct results in exon 8 deletion, and so the third minor form 2SL might still be expressed.…”

Section: Discussionmentioning

confidence: 99%

Caspase-independent death of meiotic and postmeiotic cells overexpressing p53: calpain involvement

et al. 2006

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In a model of male sterility (MTp53) owing to enforced p53 expression in spermatocytes II and spermatids of transgenic mice, we focused on the role of caspases. Most of them are expressed in all differentiation stages, but only the transcriptional levels of caspase-2 and caspase-3 are modified in MTp53 germ cells. In normal testis, cleaved caspase-3 and caspase-9 are detected during the elongation of spermatids. Despite this constitutive presence of caspases during terminal differentiation, calpains are the main effectors of germ cell loss in MTp53 testes: calpain 1 RNA levels are increased, caspase-3-like activity is markedly decreased while calpain activity is higher and the calpain inhibitor E64d ((2S, 3S)-trans-epoxysuccinyl-L-leucylamido-3-methylbutane ethyl ester) reduces TUNEL labeling in MTp53 testis, whereas pancaspase inhibitor zVADfmk (N-benzyloxycarbonyl-ValAla-Asp(OMe)-fluoromethylketone) has no effect. Our work suggests that despite the presence, and potent involvement, of caspases in male haploid cell maturation, calpains are the executioners of the death of terminally differentiating germ cells.

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“…This finding suggests that p38 acts upstream of caspase-2 and -3 in the pathway. Interestingly, a recent study demonstrated that caspase-2 activates p38 in a TRAF2-mediated manner (26). These studies indicate that the interplay between caspase-2 and p38 may be more complex, with interactions occurring in both directions.…”

Section: Discussionmentioning

confidence: 99%

Sphingosine-1-phosphate lyase potentiates apoptosis via p53- and p38-dependent pathways and is down-regulated in colon cancer

Oskouian

Sooriyakumaran

Borowsky

et al. 2006

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

201

198

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Sphingolipid metabolites such as sphingosine-1-phosphate (S1P) and ceramide modulate apoptosis during development and in response to stress. In general, ceramide promotes apoptosis, whereas S1P stimulates cell proliferation and protects against apoptosis. S1P is irreversibly degraded by the enzyme S1P lyase (SPL). In this study, we show a crucial role for SPL in mediating cellular responses to stress. SPL expression in HEK293 cells potentiated apoptosis in response to stressful stimuli including DNA damage. This effect seemed to be independent of ceramide generation but required SPL enzymatic activity and the actions of p38 MAP kinase, p53, p53-inducible death domain protein (PIDD), and caspase-2 as shown by molecular and chemical inhibition of each of these targets. Further, SPL expression led to constitutive activation of p38. Endogenous SPL expression was induced by DNA damage in WT cells, whereas SPL knockdown diminished apoptotic responses. Importantly, SPL expression was significantly downregulated in human colon cancer tissues in comparison with normal adjacent tissues, as determined by quantitative real-time PCR (Q-PCR) and immunohistochemical analysis. Down-regulation of S1P phosphatases was also observed, suggesting that colon cancer cells manifest a block in S1P catabolism. In addition, SPL expression and activity were down-regulated in adenomatous lesions of the Min mouse model of intestinal tumorigenesis. Taken together, these results indicate that endogenous SPL may play a physiological role in stress-induced apoptosis and provide an example of altered SPL expression in a human tumor. Our findings suggest that genetic or epigenetic changes affecting intestinal S1P metabolism may correlate with and potentially contribute to carcinogenesis.intestinal tumorigenesis ͉ Min mouse ͉ sphingolipid ͉ etoposide S phingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite and the final common product of complex sphingolipid metabolism. S1P acts through its cognate G proteincoupled receptors to inhibit apoptosis, regulate lymphocyte trafficking and to promote DNA synthesis, cell proliferation, cell migration, and angiogenesis (1, 2). The SPHK1 gene, which encodes the major sphingosine kinase responsible for S1P synthesis, can act as an oncogene in model systems (3). Further, parenteral administration of S1P-specific antibodies markedly slows human cancer xenograft progression and angiogenesis (4). S1P signaling has been implicated in the development of the drug resistant phenotype in cancer cells (5). Together, these findings strongly support a role for S1P signaling in promoting tumorigenesis and cancer progression. Despite these observations, evidence of genetic changes in human cancer tissues that would directly implicate S1P signaling in these processes is lacking. S1P is irreversibly degraded by the pyridoxal 5Ј-phosphatedependent enzyme, S1P lyase (SPL). SPL is highly conserved throughout evolution, is required for maintenance of physiological levels of S1P and other sphingolipid intermediates an...

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A Novel Caspase-2 Complex Containing TRAF2 and RIP1

Cited by 66 publications

References 77 publications

Tumor-suppressing Function of Caspase-2 Requires Catalytic Site Cys-320 and Site Ser-139 in Mice

Tumor-suppressing Function of Caspase-2 Requires Catalytic Site Cys-320 and Site Ser-139 in Mice

Caspase-independent death of meiotic and postmeiotic cells overexpressing p53: calpain involvement

Sphingosine-1-phosphate lyase potentiates apoptosis via p53- and p38-dependent pathways and is down-regulated in colon cancer

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