Caspase-2 at a glance

Fava, Luca; Bock, Florian; Geley, Stephan; Villunger, Andreas

doi:10.1242/jcs.115105

Cited by 85 publications

(79 citation statements)

References 70 publications

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“…3C). Together, these observations assign the PIDDosome and Caspase-2 an unanticipated prosurvival function upstream of p53 rather than the often postulated cell death function downstream from it Fava et al 2012).…”

Section: Discussionmentioning

confidence: 87%

“…However, PIDDosome loss-of-function analysis in mice failed to reveal any dysfunction in the DNA damage response (DDR), subsequent apoptosis, or tumor formation upon DNA damage (Manzl et al 2009(Manzl et al , 2013Fava et al 2012). As such, the specific cue activating the PIDDosome remained undefined and led to numerous hypotheses about its function Fava et al 2012).…”

mentioning

confidence: 99%

“…Notably, Caspase-2 has been repeatedly implicated in "mitotic catastrophe," yet its mode of activation and relevance therein remained disputed (Castedo et al 2004;Sidi et al 2008;Fava et al 2012;Manzl et al 2013). Our analyses demonstrate that Caspase-2 becomes selectively activated upon cytokinesis failure in a PIDDosome-dependent manner, resulting in MDM2 cleavage, p53 activation, and p21-dependent cell cycle arrest.…”

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confidence: 99%

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The PIDDosome activates p53 in response to supernumerary centrosomes

et al. 2017

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Centrosomes, the main microtubule-organizing centers in animal cells, are replicated exactly once during the cell division cycle to form the poles of the mitotic spindle. Supernumerary centrosomes can lead to aberrant cell division and have been causally linked to chromosomal instability and cancer. Here, we report that an increase in the number of mature centrosomes, generated by disrupting cytokinesis or forcing centrosome overduplication, triggers the activation of the PIDDosome multiprotein complex, leading to Caspase-2-mediated MDM2 cleavage, p53 stabilization, and p21-dependent cell cycle arrest. This pathway also restrains the extent of developmentally scheduled polyploidization by regulating p53 levels in hepatocytes during liver organogenesis. Taken together, the PIDDosome acts as a first barrier, engaging p53 to halt the proliferation of cells carrying more than one mature centrosome to maintain genome integrity.

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Section: Discussionmentioning

confidence: 87%

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confidence: 99%

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confidence: 99%

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The PIDDosome activates p53 in response to supernumerary centrosomes

et al. 2017

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“…In addition, the impact of LA on caspase-2 was studied, which exhibits unique features of both initiator and executioner caspases (Vakifahmetoglu-Norberg and Zhivotovsky 2010) and is involved in the regulation of cell death triggered by metabolic imbalance and endoplasmic reticulum stress (Fava et al 2012). Interestingly, we found an obvious LA-dependent degradation of full-length caspase-2, with the effect at higher LA doses comparable to that of the positive control STS (Fig.…”

Section: La Inhibits the Growth Of Colorectal Cancer Cells And Inducementioning

confidence: 99%

Lipoic acid induces p53-independent cell death in colorectal cancer cells and potentiates the cytotoxicity of 5-fluorouracil

et al. 2014

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Alpha-lipoic acid (LA), which plays a pivotal role in mitochondrial energy metabolism, is an endogenous dithiol compound with an array of antioxidative functions. It has been shown that LA triggers cell death in tumor cell lines, whereas non-transformed cells are hardly affected. In the present study, we analyzed the cytotoxicity of LA on colorectal cancer (CRC) cells differing in their p53 status and investigated a putative synergistic effect with the anticancer drug 5-fluorouracil (5-FU). We show that LA induces a dose-dependent decrease in cell viability, which was independent of the p53 status as attested in isogenic p53-proficient and p53-deficient cell lines. This effect was largely attributable to cell death induction as revealed by Annexin-V/PI staining. LA-treated HCT116 cells underwent caspase-dependent and caspase-independent cell death, which was blocked by the pan-caspase inhibitor zVAD and the RIP-kinase inhibitor Necrostatin-1, respectively. In CaCO-2 and HT29 cells, LA induced caspase-dependent cell demise via activation of caspase-9, caspase-3 and caspase-7 with subsequent PARP-1 cleavage as demonstrated by immunoblot analysis, activity assays and pan-caspase inhibition. Interestingly, LA treatment did neither activate p53 nor induced genotoxic effects as shown by lack of DNA strand breaks and phosphorylation of histone 2AX. Finally, we provide evidence that LA increases the cytotoxic effect induced by the anticancer drug 5-FU as revealed by significantly enhanced cell death rates in HCT116 and CaCO-2 cells. Collectively, these findings demonstrate that LA induces CRC cell death independent of their p53 status and potentiates the cytotoxicity of 5-FU without causing DNA damage on its own, which makes it a candidate for tumor therapy.

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“…However, only caspase-2 and caspase-8 have been experimentally demonstrated to have such a role. 15,25,26 As alluded to above and discussed in a number of recent reviews, 9,27 previous studies focusing on the role of caspase-2 in apoptosis have yielded somewhat contradictory findings, questioning the significance of caspase-2 in cell Caspase-2 is synthesized as a zymogen and is activated via a dimerization-dependent, autocatalytic cleavage mechanism. 45 Caspase-2 is made up of a C-terminal catalytic domain containing the active site (Cys320) and an amino terminal CARD, which mediates proteinprotein interactions and facilitates recruitment into activation platforms.…”

Section: Caspase-2 -The Anti-cancer Connectionmentioning

confidence: 99%

Caspase-2 as a tumour suppressor

2013

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Ever since its discovery 20 years ago, caspase-2 has been enigmatic and its function somewhat controversial. Although many in vitro studies suggested that caspase-2 was important for apoptosis, demonstrating an in vivo cell death role for this caspase has been more problematic, with caspase-2-deficient mice showing limited, tissue-specific cell death defects. Recent results from different laboratories suggest that at least one of its physiological roles in animals is to protect against cellular stress and transformation. As such, loss of caspase-2 augments tumorigenesis in some mouse models of cancer, assigning a tumour suppressor function to this enigmatic caspase. This review focuses on this seemingly non-apoptotic function of caspase-2 as a tumour suppressor and reconciles some of the recent findings in the field.

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Caspase-2 at a glance

Cited by 85 publications

References 70 publications

The PIDDosome activates p53 in response to supernumerary centrosomes

The PIDDosome activates p53 in response to supernumerary centrosomes

Lipoic acid induces p53-independent cell death in colorectal cancer cells and potentiates the cytotoxicity of 5-fluorouracil

Caspase-2 as a tumour suppressor

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