A Systems Biology Analysis of Apoptosome Formation and Apoptosis Execution Supports Allosteric Procaspase-9 Activation

Würstle, Maximilian L.; Rehm, Markus

doi:10.1074/jbc.m114.590034

Cited by 27 publications

(17 citation statements)

References 69 publications

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“…6c). To this end, several studies have shown that activation of Caspase-8 as well as that of Caspase-9 and Apaf-1 (via formation of the apoptosome) can lead to the activation of Caspase-3 which is an established mechanism for the execution of apoptosis [50][51][52][53][54][55][56][57][58][59].…”

Section: Resultsmentioning

confidence: 99%

Anticancer activity of a novel methylated analogue of L-mimosine against an in vitro model of human malignant melanoma

et al. 2019

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The anticancer activity of a series of novel synthesized, hydroxypyridone-based metal chelators (analogues of L-mimosine) was evaluated in an in vitro model of melanoma consisting of malignant melanoma (A375), non-melanoma epidermoid carcinoma (A431) and immortalized non-malignant keratinocyte (HaCaT) cells. More specifically, we have demonstrated that the L-enantiomer of a methylated analogue of L-mimosine (compound 22) can exert a potent anticancer effect in A375 cells when compared to either A431 or HaCaT cells. Moreover, we have demonstrated that this analogue has the ability to i) promote increased generation of reactive oxygen species (ROS), ii) activate both intrinsic and extrinsic apoptosis and iii) induce perturbations in cell cycle growth arrest. Our data highlights the potential of compound 22 to act as a promising therapeutic agent against an in vitro model of human malignant melanoma.

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Section: Resultsmentioning

confidence: 99%

Anticancer activity of a novel methylated analogue of L-mimosine against an in vitro model of human malignant melanoma

et al. 2019

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“…In general, death-inducing signaling complexes have been identified as activators of caspase-8 [33, 34], while apoptosomes provide the activation platform for initiation of caspase-9 [29, 35]. A recent study [36] revealed that caspase-9 was activated allosterically by binding to apoptosomes, in which a platform was assembled in response to mitochondria-dependent apoptosis under the influence of XIAP. In the inflammatory response, spinal cord injury activates inflammasomes containing ASC and leads to the cleavage of XIAP [37].…”

Section: Discussionmentioning

confidence: 99%

ASC Induces Apoptosis via Activation of Caspase-9 by Enhancing Gap Junction-Mediated Intercellular Communication

Kitazawa¹,

Hida²,

Fujii³

et al. 2017

PLoS ONE

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ASC (apoptosis-associated speck-like protein containing a CARD) is a key adaptor molecule of inflammasomes that mediates inflammatory and apoptotic signals. Aberrant methylation-induced silencing of ASC has been observed in a variety of cancer cells, thus implicating ASC in tumor suppression, although this role remains incompletely defined especially in the context of closely neighboring cell proliferation. As ASC has been confirmed to be silenced by abnormal methylation in HT1080 fibrosarcoma cells as well, this cell line was investigated to characterize the precise role and mechanism of ASC in tumor progression. The effects of ASC were examined using in vitro cell cultures based on comparisons between low and high cell density conditions as well as in a xenograft murine model. ASC overexpression was established by insertion of the ASC gene into pcDNA3 and pMX-IRES-GFP vectors, the latter being packed into a retrovirus and subjected to reproducible competitive assays using parental cells as an internal control, for evaluation of cell viability. p21 and p53 were silenced using shRNA. Cell viability was suppressed in ASC-expressing transfectants as compared with control cells at high cell density conditions in in vitro culture and colony formation assays and in in vivo ectopic tumor formation trials. This suppression was not detected in low cell density conditions. Furthermore, remarkable progression of apoptosis was observed in ASC-introduced cells at a high cell density, but not at a low one. ASC-dependent apoptosis was mediated not by p21, p53, or caspase-1, but rather by cleavage of caspase-9 as well as by suppression of the NF-κB-related X-linked inhibitor-of-apoptosis protein. Caspase-9 cleavage was observed to be dependent on gap junction formation. The remarkable effect of ASC on the induction of apoptosis through caspase-9 and gap junctions revealed in this study may lead to promising new approaches in anticancer therapy.

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“…After a death‐inducing signaling, caspases are activated by proteolytic cleavage in a coordinated manner that involves a cascade of cellular elements (McIlwain et al, ; Man and Kanneganti, ). Furthermore, apoptotic signaling pathways are able to modulate the mitochondrial membrane permeability, resulting in a non‐selective opening of the inner membrane pores, loss of mitochondrial transmembrane potential (Δψ), and release of cytochrome c into the cytosol (Ooi and Ma, ) in a multiprotein complex named apoptosome (Würstle and Rehm, ), which is able to induce apoptosis (Guicciardi et al, ). In addition, multiple elements contribute to the processes of apoptosis such as the Bcl‐2 family of proteins, divided into anti‐apoptotic proteins (Bcl‐2, Bcl‐xL, Bcl‐x, Bcl‐XL, Bcl‐XS, Bcl‐w, and BAG) and pro‐apoptotic proteins (Bax, Bak, BH3, Bid, Bad, Bim, Bik, and Blk) (Letai et al, ).…”

Section: Cellular Apoptosis and Its Correlation With Hepatic Fibrosismentioning

confidence: 99%

Molecular interplays in hepatic stellate cells: apoptosis, senescence, and phenotype reversion as cellular connections that modulate liver fibrosis

Silva

Ramos

Moraes

2017

Cell Biology International

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Liver fibrosis is a pathophysiological process correlated with intense repair and cicatrization mechanisms in injured liver, and over the past few years, the characterization of the fine-tuning of molecular interconnections that support the development of liver fibrosis has been investigated. In this cellular process, the hepatic stellate cells (HSCs) support the organ fibrogenesis. The HSCs are found in two distinct morpho-physiological states: quiescent and activated. In normal liver, most HSCs are found in quiescent state, presenting a considerable amount of lipid droplets in the cytoplasm, while in injured liver, the activated phenotype of HSCs is a myofibroblast, that secrete extracellular matrix elements and contribute to the establishment of the fibrotic process. Studies on the molecular mechanisms by which HSCs try to restore their quiescent state have been performed; however, no effective treatment to reverse fibrosis has been so far prescribed. Therefore, the elucidation of the cellular and molecular mechanisms of apoptosis, senescence, and the cell reversion phenotype process from activate to quiescent state will certainly contribute to the development of effective therapies to treat hepatic fibrosis. In this context, this review aimed to address central elements of apoptosis, senescence, and reversal of HSC phenotype in the control of hepatic fibrogenesis, as a guide to future development of therapeutic strategies.

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A Systems Biology Analysis of Apoptosome Formation and Apoptosis Execution Supports Allosteric Procaspase-9 Activation

Cited by 27 publications

References 69 publications

Anticancer activity of a novel methylated analogue of L-mimosine against an in vitro model of human malignant melanoma

Anticancer activity of a novel methylated analogue of L-mimosine against an in vitro model of human malignant melanoma

ASC Induces Apoptosis via Activation of Caspase-9 by Enhancing Gap Junction-Mediated Intercellular Communication

Molecular interplays in hepatic stellate cells: apoptosis, senescence, and phenotype reversion as cellular connections that modulate liver fibrosis

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