A Complex between Atg7 and Caspase-9

Han, Jie; Hou, Wen Chi; Goldstein, Leslie A.; Stolz, Donna B.; Watkins, Simon C.; Rabinowich, Hannah

doi:10.1074/jbc.m113.536854

Cited by 88 publications

(50 citation statements)

References 60 publications

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“…As ganetespib reduces the expression level of ATG7, we investigated its impact on the interaction between ATG7 and CASP9 that we previously identified as a pro-autophagy and anti-apoptosis complex. 21 In accordance with its ability to downregulate ATG7 expression, ganetespib was also confirmed to inhibit ATG7-CASP9 complex formation: in the presence of ganetespib, immunoprecipitated CASP9 failed to co-precipitate ATG7 in A549 cells (Fig. 5A), and in multiple other tumor cell lines (data not shown).…”

Section: Association Between Stabilization Of Casp9 Prodomain and Ressupporting

confidence: 54%

“…17,18 The current study was designed to investigate the molecular effects of HSP90 inhibition, particularly by ganetespib, on the autophagic capability of KRAS-mutant NSCLC cells. We report that in contrast to multiple antitumor drugs that induce autophagy, 19,20 ganetespib reduces tumor cell autophagic capability via ATG7 diminution, the consequent elimination of the pro-autophagy complex between ATG7 and CASP9 21 and repression of late events in the autophagic cascade, culminating in inhibition of ATG7-dependent, bafilomycin A 1 (BafA1)-sensitive long-lived protein degradation. Thus, unlike other anticancer drugs that induce autophagy as a resistance mechanism, ganetespib does not induce such a protective response (in either wild-type [WT] or mutant KRAS NSCLC cells) and therefore would not require its combination with an autophagy inhibitor for therapeutic purposes.…”

Section: Introductionmentioning

confidence: 99%

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HSP90 inhibition targets autophagy and induces a CASP9-dependent resistance mechanism in NSCLC

et al. 2018

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Macroautophagy/autophagy has emerged as a resistance mechanism to anticancer drug treatments that induce metabolic stress. Certain tumors, including a subset of KRAS-mutant NSCLCs have been shown to be addicted to autophagy, and potentially vulnerable to autophagy inhibition. Currently, autophagy inhibition is being tested in the clinic as a therapeutic component for tumors that utilize this degradation process as a drug resistance mechanism. The current study provides evidence that HSP90 (heat shock protein 90) inhibition diminishes the expression of ATG7, thereby impeding the cellular capability of mounting an effective autophagic response in NSCLC cells. Additionally, an elevation in the expression level of CASP9 (caspase 9) prodomain in KRAS-mutant NSCLC cells surviving HSP90 inhibition appears to serve as a cell survival mechanism. Initial characterization of this survival mechanism suggests that the altered expression of CASP9 is mainly ATG7 independent; it does not involve the apoptotic activity of CASP9; and it localizes to a late endosomal and pre-lysosomal phase of the degradation cascade. HSP90 inhibitors are identified here as a pharmacological approach for targeting autophagy via destabilization of ATG7, while an induced expression of CASP9, but not its apoptotic activity, is identified as a resistance mechanism to the cellular stress brought about by HSP90 inhibition.

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Section: Association Between Stabilization Of Casp9 Prodomain and Ressupporting

confidence: 54%

Section: Introductionmentioning

confidence: 99%

HSP90 inhibition targets autophagy and induces a CASP9-dependent resistance mechanism in NSCLC

et al. 2018

Self Cite

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“…ATG7 deficiency suppresses apoptosis and cell death induced by lysosomal photodamage (Kessel, Price, & Reiners, 2012). ATG7 directly interacts with caspase-9 and represses its apoptotic activity, which is not related to its autophagic function (Han et al, 2014). ATG7 is involved in a process designated LC3-associated phagocytosis, which is independent of autophagic process (Sanjuan et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Functional variants of the ATG7 gene promoter in acute myocardial infarction

Zhang

et al. 2018

Molec Gen & Gen Med

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BackgroundCoronary artery disease including acute myocardial infarction (AMI) is mainly caused by atherosclerosis, an inflammatory and metabolic disease. Autophagy has been demonstrated to play critical roles in lipid metabolism and inflammation. Altered autophagic activity has been reported in AMI patients. However, molecular basis for dysfunctional autophagy in AMI remains unexplained.MethodsIn this study, the promoter of the ATG7 gene, encoding a core protein for autophagy, was genetically and functionally analyzed in large cohorts of AMI patients (n = 355) and ethnic‐matched healthy controls (n = 363). Related molecular mechanisms were also explored.ResultsA total of 19 DNA sequence variants (DSVs) including single‐nucleotide polymorphisms (SNPs) were found in the ATG7 gene promoter. Two novel DSVs and five SNPs were only identified in AMI patients group. These DSVs and SNPs, except one SNP, significantly altered the transcriptional activity of the ATG7 gene promoter in both HEK‐293 and H9c2 cells (p < 0.05). Further electrophoretic mobility shift assay revealed that the DSVs and SNPs evidently affected the binding of transcription factors.Conclusions ATG7 gene DSVs and SNPs identified in AMI patients may alter the transcriptional activity of the ATG7 gene promoter and change ATG7 level, contributing to the AMI development as a rare risk factor.

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“…There have been lots of studies showing the complex relationship between autophagy and apoptosis [21–26]. Generally, autophagy could rescue cells from death when they are under stress such as DNA damage [27], mitochondrial dysfunction [28], or starvation [29].…”

Section: Discussionmentioning

confidence: 99%

Umbilical Cord‐Derived Mesenchymal Stem Cells Suppress Autophagy of T Cells in Patients with Systemic Lupus Erythematosus via Transfer of Mitochondria

Chen

Wang

Feng

et al. 2016

Stem Cells International

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Aberrant autophagy played an important role in the pathogenesis of autoimmune diseases, especially in systemic lupus erythematosus (SLE). In this study, we showed that T cells from SLE patients had higher autophagic activity than that from healthy controls. A correlation between autophagic activity and apoptotic rate was observed in activated T cells. Moreover, activation of autophagy with rapamycin increased T cell apoptosis, whereas inhibition of autophagy with 3-MA decreased T cell apoptosis. Umbilical cord-derived mesenchymal stem cells (UC-MSCs) could inhibit respiratory mitochondrial biogenesis in activated T cells to downregulate autophagy and consequently decrease T cell apoptosis through mitochondrial transfer and thus may play an important role in SLE treatment.

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A Complex between Atg7 and Caspase-9

Cited by 88 publications

References 60 publications

HSP90 inhibition targets autophagy and induces a CASP9-dependent resistance mechanism in NSCLC

HSP90 inhibition targets autophagy and induces a CASP9-dependent resistance mechanism in NSCLC

Functional variants of the ATG7 gene promoter in acute myocardial infarction

Umbilical Cord‐Derived Mesenchymal Stem Cells Suppress Autophagy of T Cells in Patients with Systemic Lupus Erythematosus via Transfer of Mitochondria

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