Role of Forkhead Box O (FOXO) transcription factor in aging and diseases

Tia, Neelam; Singh, Alok Kumar; Pandey, Poorti; Azad, Chandra Shekhar; Chaudhary, Pritee; Gambhir, Indrajeet Singh

doi:10.1016/j.gene.2018.01.051

Cited by 123 publications

(89 citation statements)

References 115 publications

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“…Because of this feature, these transcription factors are called Forkhead/ winged helix transcription factors. The Forkhead transcription factor family is currently divided into 17 subfamilies (named FoxA to FoxQ), the members of which have a wide range of biological functions [34,35]. Among these subfamilies, the Forkhead box O (FoxO) family is the most thoroughly studied.…”

Section: Akt Target Proteinsmentioning

confidence: 99%

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RETRACTED ARTICLE: Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumours

et al. 2020

Cell Biosci

469

263

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The PI3 K/AKT/mTOR signalling pathway plays an important role in the regulation of signal transduction and biological processes such as cell proliferation, apoptosis, metabolism and angiogenesis. Compared with those of other signalling pathways, the components of the PI3K/AKT/mTOR signalling pathway are complicated. The regulatory mechanisms and biological functions of the PI3K/AKT/mTOR signalling pathway are important in many human diseases, including ischaemic brain injury, neurodegenerative diseases, and tumours. PI3K/AKT/mTOR signalling pathway inhibitors include single-component and dual inhibitors. Numerous PI3K inhibitors have exhibited good results in preclinical studies, and some have been clinically tested in haematologic malignancies and solid tumours. In this review, we briefly summarize the results of research on the PI3K/AKT/mTOR pathway and discuss the structural composition, activation, communication processes, regulatory mechanisms and biological functions of the PI3K/AKT/mTOR signalling pathway in the pathogenesis of neurodegenerative diseases and tumours.

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Section: Akt Target Proteinsmentioning

confidence: 99%

“…Four distinct genes encode FoxO proteins in mammalian cells: FoxO1 (FKHR), FoxO3 (FKHRL1), FoxO4 (Afx) and FoxO6. The four homologous FoxO genes in humans are FoxO1, FoxO2, FoxO3a and FoxO4 [34]. FoxO functions in phosphorylation and acetylation posttranscriptional modifications at serine, threonine and lysine residues [35,36].…”

Section: Akt Target Proteinsmentioning

confidence: 99%

RETRACTED ARTICLE: Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumours

et al. 2020

Cell Biosci

469

263

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“…In line with this, antioxidants (including NAC that abrogates RIR), which have been proposed to protect against carcinogenesis, in fact foster lung carcinomas and metastasis (Breau et al, 2019;Le Gal et al, 2015;Wiel et al, 2019). More generally, defect in each of the players of the "Low-stress" response described here (NF-κB, PARP1, FOXO1, DUOX1 and DUOX2) share common phenotypes, such as defects in cell homeostasis and metabolism, ageing and cancer predisposition (Ewald, 2018;Tia et al, 2018;Tilstra et al, 2011;Vida et al, 2016;Little et al, 2017;Park & Hong, 2016;Pires et al, 2018). `…”

Section: Discussionmentioning

confidence: 61%

An adaptive pre-DNA-damage-response protects genome integrity

Ragu

Matos-Rodrigues

Droin

et al. 2020

Preprint

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The DNA damage response (DDR) interrupts cell cycle progression to restore genome integrity. However, unchallenged proliferating cells are continually exposed to endogenous stress, raising the question of a stress-threshold for DDR activation. Here, we identified a stress threshold below which primary human fibroblasts, activate a cellautonomous response that not activates full DDR and not arrests cell cycle progression,.We characterized this "pre-DDR" response showing that it triggers the production of reactive oxygen species (ROS) by the NADPH oxidases DUOX1 and DUOX2, under the control of NF-κB and PARP1. Then, replication stress-induced ROS (RIR) activates the FOXO1 detoxifying pathway, preventing the nuclear accumulation of the pre-mutagenic 8-oxoGuanine lesion, upon endogenous as well as exogenous pro-oxidant stress.Increasing the replication stress severity above the threshold triggers the canonical DDR, leading to cell cycle progression arrest, but also to RIR suppression. These data reveal that cells adapt their response to stress severity, unveiling a tightly regulated "pre-DDR" adaptive response that protects genome integrity without arresting cell cycle progression.

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“…As a member of the Bcl-2 family, Bim can be activated through various pro-apoptotic stimuli and facilitate cell death that is dependent on Bak and Bax (39). The FOXO (Forkhead box O) transcription factors participate in several biochemical processes, such as cell-cycle arrest, apoptosis, cell metabolism, and DNA damage repair (40). Several external stimuli, such as insulin, IGF-1, and a few other growth factors, can modulate FOXO transcription factors (41).…”

Section: Discussionmentioning

confidence: 99%

Alpelisib Inhibits PIK3CA-Mutant Breast Cancer Growth Through AKT-Dependent Bim Induction and Mcl-1 Degradation

Tan¹,

Zhang²,

Liu³

et al. 2020

Preprint

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Abstract Background: PIK3CA mutations are common genomic alterations in estrogen receptor (ER)-positive breast cancers, currently, the development of selective PI3Kα (phosphatidylinositol 3-kinase α) inhibitors is ongoing. The mechanisms contributing to the anticancer activity of alpelisib in PIK3CA-mutant breast cancer cells and the mechanism of acquired resistance to alpelisib remain elusive. Methods: Drug-sensitive cell lines were exposed to alpelisib to establish alpelisib-resistant cell lines. Western blotting was used to assess changes in protein expression. Apoptosis was evaluated by ﬂow cytometry. In vivo with mouse xenograft models and in vitro colony formation and MTS and assay were carried out to determine the growth inhibitory effects of the tested drugs. Protein half-lives were examined and proteasome inhibitors were used to estimate protein degradation. Gene knockdown was carried out using shRNA or siRNA. Results: In the present study, we report the potent induction of apoptosis by alpelisib in PIK3CA-mutant breast cancer cell lines. AKT phosphorylation suppression, AKT/Foxo3a-dependent Bim induction, and AKT/GSK-3β-dependent Mcl-1 degradation were observed. Apoptosis induced by alpelisib was attenuated by Mcl-1 (4A) overexpression or Bim suppression. Furthermore, alpelisib could not modulate Mcl-1 or Bim levels in cell lines that were resistant to alpelisib. AKT inhibitor and alpelisib combination restored the sensitivity of alpelisib-resistant cells to growth inhibition and apoptosis in vitro and in vivo. Conclusions: Therefore, modulation of Mcl-1 degradation and AKT-dependent Bim induction are crucial for mediating the resistance and sensitivity of PIK3CA-mutant breast tumor cells to alpelisib, thus making it a productive strategy for overcoming acquired resistance to alpelisib.

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Role of Forkhead Box O (FOXO) transcription factor in aging and diseases

Cited by 123 publications

References 115 publications

RETRACTED ARTICLE: Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumours

RETRACTED ARTICLE: Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumours

An adaptive pre-DNA-damage-response protects genome integrity

Alpelisib Inhibits PIK3CA-Mutant Breast Cancer Growth Through AKT-Dependent Bim Induction and Mcl-1 Degradation

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