The FoxO code

Calnan, Daniel R.; Brunet, Anne-Christine

doi:10.1038/onc.2008.21

Cited by 1,047 publications

(1,049 citation statements)

References 114 publications

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“…The FoxO subgroup contains 4 members, including Foxo1, Foxo3a, Foxo4, and Foxo6 32. It has been demonstrated that FoxO3a is expressed in the heart and skeletal muscle 33, 34.…”

Section: Discussionmentioning

confidence: 99%

Resveratrol Ameliorates Cardiac Hypertrophy by Down‐regulation of miR‐155 Through Activation of Breast Cancer Type 1 Susceptibility Protein

Fan

Liu

Fang

et al. 2016

JAHA

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BackgroundThe polyphenol resveratrol (Rev) has been reported to exhibit cardioprotective effects, such as inhibition of TAC (transverse aortic constriction) or isoprenaline (ISO)‐induced hypertrophy. MicroRNA‐155 (miR‐155) was found to be decreased in hypertrophic myocardium, which could be further reduced by pretreatment of Rev. The study was designed to investigate the molecular effects of miR‐155 on cardiac hypertrophy, focusing on the role of breast cancer type 1 susceptibility protein (BRCA1).Methods and ResultsWe demonstrated that Rev alleviated severity of hypertrophic myocardium in a mice model of cardiac hypertrophy by TAC treatment. Down‐regulation of miR‐155 was observed in pressure overload– or ISO‐induced hypertrophic cardiomyoctyes. Interestingly, administration of Rev substantially attenuated miR‐155 level in cardiomyocytes. In agreement with its miR‐155 reducing effect, Rev relieved cardiac hypertrophy and restored cardiac function by activation of BRCA1 in cardiomyoctyes. Our results further revealed that forkhead box O3a (FoxO3a) was a miR‐155 target in the heart. And miR‐155 directly repressed FoxO3a, whose expression was mitigated in miR‐155 agomir and mimic treatment in vivo and in vitro.ConclusionsWe conclude that BRCA1 inactivation can increase expression of miR‐155, contributing to cardiac hypertrophy. And Rev produces their beneficial effects partially by down‐regulating miR‐155 expression, which might be a novel strategy for treatment of cardiac hypertrophy.

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“…The FoxO subgroup contains 4 members, including Foxo1, Foxo3a, Foxo4, and Foxo6 32. It has been demonstrated that FoxO3a is expressed in the heart and skeletal muscle 33, 34.…”

Section: Discussionmentioning

confidence: 99%

Resveratrol Ameliorates Cardiac Hypertrophy by Down‐regulation of miR‐155 Through Activation of Breast Cancer Type 1 Susceptibility Protein

Fan

Liu

Fang

et al. 2016

JAHA

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“…In spite of extensive information regarding the large array of FOXO3 PTMs, 7 there is relatively little known about how specific PTMs alter the FOXO3 transcriptional program. It has previously been shown that FOXO3 acetylation is related to its relative propensity to induce antioxidant versus apoptotic gene expression.…”

Section: Discussionmentioning

confidence: 99%

“…7 Its many transcriptional programs are frequently in opposition to each other as it induces apoptosis, yet it is also critical for cell survival and longevity. Although there is considerable information regarding the mechanisms that regulate the nuclear/cytosolic distribution and protein stability of FOXO3, the control mechanisms that regulate transcriptional specificity are poorly understood.…”

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confidence: 99%

Serine 574 phosphorylation alters transcriptional programming of FOXO3 by selectively enhancing apoptotic gene expression

Zhao

Tikhanovich

et al. 2015

Cell Death Differ

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Forkhead box O3 (FOXO3) is a multispecific transcription factor that is responsible for multiple and conflicting transcriptional programs such as cell survival and apoptosis. The protein is heavily post-translationally modified and there is considerable evidence that post-transcriptional modifications (PTMs) regulate protein stability and nuclear-cytosolic translocation. Much less is known about how FOXO3 PTMs determine the specificity of its transcriptional program. In this study we demonstrate that exposure of hepatocytes to ethanol or exposure of macrophages to lipopolysaccharide (LPS) induces the c-Jun N-terminal kinase (JNK)-dependent phosphorylation of FOXO3 at serine-574. Chromatin immunoprecipitation (ChIP), mRNA and protein measurements demonstrate that p-574-FOXO3 selectively binds to promoters of pro-apoptotic genes but not to other well-described FOXO3 targets. Both unphosphorylated and p-574-FOXO3 bound to the B-cell lymphoma 2 (Bcl-2) promoter, but the unphosphorylated form was a transcriptional activator, whereas p-574-FOXO3 was a transcriptional repressor. The combination of increased TRAIL (TNF-related apoptosis-inducing ligand) and decreased Bcl-2 was both necessary and sufficient to induce apoptosis. LPS treatment of a human monocyte cell line (THP-1) induced FOXO3 S-574 phosphorylation and apoptosis. LPS-induced apoptosis was prevented by knockdown of FOXO3. It was restored by overexpressing wild-type FOXO3 but not by overexpressing a nonphosphorylatable S-574A FOXO3. Expression of an S-574D phosphomimetic form of FOXO3 induced apoptosis even in the absence of LPS. A similar result was obtained with mouse peritoneal macrophages where LPS treatment increased TRAIL, decreased Bcl-2 and induced apoptosis in wild-type but not FOXO3 −/− cells. This work thus demonstrates that S-574 phosphorylation generates a specifically apoptotic form of FOXO3 with decreased transcriptional activity for other well-described FOXO3 functions. Forkhead box O3 (FOXO3) is a multispecific transcription factor that serves as a longevity factor 1,2 and tumor suppressor and is critically involved in multiple seemingly independent biological process including cell-cycle arrest, 3 DNA repair, 4 antioxidant and stress responses, 5 apoptosis, 6 autophagy, glucose metabolism and aging. 7 Its many transcriptional programs are frequently in opposition to each other as it induces apoptosis, yet it is also critical for cell survival and longevity. Although there is considerable information regarding the mechanisms that regulate the nuclear/cytosolic distribution and protein stability of FOXO3, the control mechanisms that regulate transcriptional specificity are poorly understood.FOXO3 function is tightly regulated by multiple posttranslational modifications (PTMs) including phosphorylation, acetylation, ubiquitination and arginine and lysine methylation. Specific PTMs regulate the partitioning of FOXO3 between the cytosol and the nucleus 8-15 and its stability and degradation, 16 but the links between specific PTMs and FOXO3 tran...

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“…In mammals, this subfamily is involved in a wide range of crucial cellular processes regulating stress resistance, metabolism, cell cycle arrest, and apoptosis, but their role in longevity still remains to be elucidated. FOXO proteins function mainly as transcriptional activators by binding the consensus core recognition motif TTGTTTAC, and their activity is inhibited by the IIS pathway (Biggs et al ., 1999; Brunet et al ., 1999; Henderson & Johnson, 2001; Lin et al ., 2001; Calnan & Brunet, 2008; Zanella et al ., 2010; Webb & Brunet, 2014). Briefly, insulin or IGF‐1 triggers an intracellular pathway mediated by PI3K‐AKT, allowing phosphorylation of FOXO factors by the serine/threonine kinase AKT at three conserved residues within the FOXO proteins.…”

Section: Foxo Transcription Factorsmentioning

confidence: 99%

“…Conversely, in the absence of growth factor signaling or upon cellular stress, FOXOs translocate into the nucleus and activate FOXO‐dependent gene expression. A diverse set of posttranslational modifications in addition to phosphorylation, such as acetylation/deacetylation, methylation, or ubiquitination has been shown to promote changes of subcellular localization, protein levels, DNA binding, and transcriptional activity of FOXO factors (Calnan & Brunet, 2008; Webb & Brunet, 2014) The combinatorial result of FOXO posttranslational modifications has been proposed to lead to the recruitment of specific FOXO‐binding partners regulating different FOXO‐dependent gene expression programs (Greer et al ., 2007b; Calnan & Brunet, 2008; Hill et al ., 2014). Several mechanisms of how FOXO proteins promote longevity have been suggested.…”

Section: Foxo Transcription Factorsmentioning

confidence: 99%

Long live FOXO: unraveling the role of FOXO proteins in aging and longevity

2015

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SummaryAging constitutes the key risk factor for age‐related diseases such as cancer and cardiovascular and neurodegenerative disorders. Human longevity and healthy aging are complex phenotypes influenced by both environmental and genetic factors. The fact that genetic contribution to lifespan strongly increases with greater age provides basis for research on which “protective genes” are carried by long‐lived individuals. Studies have consistently revealed FOXO (Forkhead box O) transcription factors as important determinants in aging and longevity. FOXO proteins represent a subfamily of transcription factors conserved from Caenorhabditis elegans to mammals that act as key regulators of longevity downstream of insulin and insulin‐like growth factor signaling. Invertebrate genomes have one FOXO gene, while mammals have four FOXO genes: FOXO1, FOXO3, FOXO4, and FOXO6. In mammals, this subfamily is involved in a wide range of crucial cellular processes regulating stress resistance, metabolism, cell cycle arrest, and apoptosis. Their role in longevity determination is complex and remains to be fully elucidated. Throughout this review, the mechanisms by which FOXO factors contribute to longevity will be discussed in diverse animal models, from Hydra to mammals. Moreover, compelling evidence of FOXOs as contributors for extreme longevity and health span in humans will be addressed.

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The FoxO code

Cited by 1,047 publications

References 114 publications

Resveratrol Ameliorates Cardiac Hypertrophy by Down‐regulation of miR‐155 Through Activation of Breast Cancer Type 1 Susceptibility Protein

Resveratrol Ameliorates Cardiac Hypertrophy by Down‐regulation of miR‐155 Through Activation of Breast Cancer Type 1 Susceptibility Protein

Serine 574 phosphorylation alters transcriptional programming of FOXO3 by selectively enhancing apoptotic gene expression

Long live FOXO: unraveling the role of FOXO proteins in aging and longevity

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