Toward the understanding of autophagy regulation and its interplay with cell death pathways

Fimia, Gian María; Piacentini, Mauro

doi:10.1038/cdd.2009.47

Cited by 17 publications

(16 citation statements)

References 19 publications

(31 reference statements)

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“…In parallel, we are contemplating the inclusion of other modalities of cell death such as autophagy [65], which inhibits apoptosis through BCL2 and is itself inhibited by apoptosis through Beclin1. The functioning of the intrinsic apoptotic pathway and the internal cellular mechanisms capable of triggering it could be investigated in more details, taking advantage of recent molecular analyses [66],[67].…”

Section: Discussionmentioning

confidence: 99%

Mathematical Modelling of Cell-Fate Decision in Response to Death Receptor Engagement

et al. 2010

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Cytokines such as TNF and FASL can trigger death or survival depending on cell lines and cellular conditions. The mechanistic details of how a cell chooses among these cell fates are still unclear. The understanding of these processes is important since they are altered in many diseases, including cancer and AIDS. Using a discrete modelling formalism, we present a mathematical model of cell fate decision recapitulating and integrating the most consistent facts extracted from the literature. This model provides a generic high-level view of the interplays between NFκB pro-survival pathway, RIP1-dependent necrosis, and the apoptosis pathway in response to death receptor-mediated signals. Wild type simulations demonstrate robust segregation of cellular responses to receptor engagement. Model simulations recapitulate documented phenotypes of protein knockdowns and enable the prediction of the effects of novel knockdowns. In silico experiments simulate the outcomes following ligand removal at different stages, and suggest experimental approaches to further validate and specialise the model for particular cell types. We also propose a reduced conceptual model implementing the logic of the decision process. This analysis gives specific predictions regarding cross-talks between the three pathways, as well as the transient role of RIP1 protein in necrosis, and confirms the phenotypes of novel perturbations. Our wild type and mutant simulations provide novel insights to restore apoptosis in defective cells. The model analysis expands our understanding of how cell fate decision is made. Moreover, our current model can be used to assess contradictory or controversial data from the literature. Ultimately, it constitutes a valuable reasoning tool to delineate novel experiments.

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Section: Discussionmentioning

confidence: 99%

Mathematical Modelling of Cell-Fate Decision in Response to Death Receptor Engagement

et al. 2010

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“…This argument is based on the fact that many studies that claim autophagic cell death prove that autophagy occurs, and that death ensues, but do not rigorously show that one causes the other (8)(9)(10). In other words, enhanced autophagy seems to constitute a failed attempt to adapt to stress and to survive, rather than a lethal catabolic process (14)(15)(16)(17). These scenarios are again reminiscent of the potential prosurvival function of autophagy in MM (11) and raise the possibility that manipulating autophagy might modulate susceptibility of MM cells to apoptotic stimuli.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, genetic knockdown of phylogenetically conserved autophagy-related (Atg) genes, such as Beclin 1 and Atg5, usually accelerates, rather than prevents, cell death in these settings (8). Thus, it seems plausible that autophagy induction seen in response to antineoplastic therapies mostly represents a prosurvival mechanism activated to counteract the deleterious effects of endogenous metabolic stress and possibly also treatment on tumor cells (11)(12)(13)(14)(15)(16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

Targeting Autophagy Augments In Vitro and In Vivo Antimyeloma Activity of DNA-Damaging Chemotherapy

Pan

Gao

Chen

et al. 2011

Clinical Cancer Research

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Purpose: Although autophagy occurs in most tumor cells following DNA damage, it is still a mystery how this DNA-damaging event turns on the autophagy machinery in multiple myeloma (MM) and how the functional status of autophagy impacts on its susceptibility to death in response to DNA-damaging chemotherapy.Experimental Design: We investigate the effects of DNA damage on autophagy in MM cells and elucidate its underlying molecular mechanism. Then, we examined the impacts of pharmacologic or genetic inhibition of autophagy on DNA damage-induced apoptosis. Furthermore, the antimyeloma activity of autophagy inhibitor in combination with DNA-damaging agents was evaluated in MM xenograft models.Results: We showed that DNA-damaging drugs, doxorubicin and melphalan, induce caspase-dependent apoptosis and concurrently trigger Beclin 1-regulated autophagy in human MM cell lines H929 and RPMI 8226. Mechanistically, association of autophagy execution proteins Beclin 1 with class III phosphoinositide 3-kinase, which is inhibited by Bcl-2 recruitment, contributes directly to the autophagic process. Importantly, targeting suppression of autophagy by minimally toxic concentrations of pharmacologic inhibitors (hydroxychloroquine and 3-methyladenine) or short hairpin RNAs against autophagy genes, Beclin 1 and Atg5, dramatically augments proapoptotic activity of DNA-damaging chemotherapy both in vitro using MM cell lines or purified patient MM cells and in vivo in a human plasmacytoma xenograft mouse model.Conclusion: These data can help unravel the underlying molecular mechanism of autophagy in DNAdamaged MM cells and also provide a rationale for clinical evaluation of autophagy inhibitors in combination with DNA-damaging chemotherapy in MM. Clin Cancer Res; 17(10); 3248-58. Ó2011 AACR.

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“…Formation of autophagosomes requires a molecular complex that recruits the Class III phosphatidylinositol 3-kinase (PI3K)-vacuolar protein sorting 34 (Vps34) to produce phosphatidylinositol-3-phosphate (PI3). PI3K activity is regulated by an interaction between myosin-like bcl2-interacting protein (Becn1) and several other proteins, including activating molecule in becn-1-regulated autophagy (Ambra1) and ultraviolet irradiation resistance associated gene (Uvrag; Fimia and Piacentini 2009). In addition, there is a correlation between cellular levels of microtubule-associated protein 1 light chain 3 isoform II (LC3-II) and the number of autophagosomes, with the conversion of LC3-I to LC3-II a reliable assay of autophagosome formation (Klionsky 2007).…”

Section: Introductionmentioning

confidence: 99%

Interplay between autophagy and apoptosis in the development of Danio rerio follicles and the effects of a probiotic

Gioacchini

Valle

Benato

et al. 2013

Reprod. Fertil. Dev.

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The present study investigated autophagic processes in Danio rerio preovulatory follicles (Stage III and IV). There were more autophagosomes, as revealed by electron microscopy, in follicles from females fed the probiotic Lactobacillus rhamnosus IMC 501. This was confirmed by increased expression of genes involved in the autophagic process, namely ambra1, becn1, lc3 and uvrag. In addition, preovulatory follicles from females fed the probiotic contained more microtubule-associated protein 1 light chain 3 isoform II (LC3-II) and less p62 protein. The increased autophagy in preovulatory follicles from females fed the probiotic was concomitant with a decrease in the apoptotic process in the ovary, as evidenced by terminal deoxyribonucleotidyl transferase-mediated dUTP–digoxigenin nick end-labelling analysis and confirmed by lower expression of genes involved in apoptosis (i.e. p53, bax, apaf and cas3) and higher expression as igfII and igf1r. The results of the present study provide preliminary evidence of the involvement of autophagy during follicle development in the zebrafish ovary. In addition, we have demonstrated for the first time that a functional food, such as L. rhamnosus IMC 501, can modulate the balance between apoptosis and autophagy that regulates ovary physiology in zebrafish by inhibiting follicular apoptosis and improving follicular survival

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Toward the understanding of autophagy regulation and its interplay with cell death pathways

Cited by 17 publications

References 19 publications

Mathematical Modelling of Cell-Fate Decision in Response to Death Receptor Engagement

Mathematical Modelling of Cell-Fate Decision in Response to Death Receptor Engagement

Targeting Autophagy Augments In Vitro and In Vivo Antimyeloma Activity of DNA-Damaging Chemotherapy

Interplay between autophagy and apoptosis in the development of Danio rerio follicles and the effects of a probiotic

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