Insulin Inhibition of Transcription Stimulated by the Forkhead Protein Foxo1 Is Not Solely due to Nuclear Exclusion

Tsai, Wen-Chi; Bhattacharyya, Nisan; Han, Liying; Hanover, John A.; Rechler, Matthew M.

doi:10.1210/en.2003-0481

Cited by 59 publications

(48 citation statements)

References 77 publications

(80 reference statements)

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“…In mammals, p38 MAPK physically interacts with the C terminus of OGT-1 and is known to activate O-GlcNAcylation of some substrates during starvation (60). Our data are also consistent with results from mammalian cells demonstrating that nuclear localization of the DAF-16 homolog FOXO1 is not sufficient to stimulate transcription in the presence of insulin signaling (61). Mutants in smk-1 (a presumptive phosphatase) affect stress, longevity, and innate immunity downstream of DAF-16 nuclear localization (62).…”

Section: Disruption Of O-glcnac Cycling Affects the Aging Pathway Andsupporting

confidence: 90%

Dynamic O-GlcNAc cycling at promoters of Caenorhabditis elegans genes regulating longevity, stress, and immunity

Love

Ghosh

Mondoux

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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133

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Nutrient-driven O-GlcNAcylation of key components of the transcription machinery may epigenetically modulate gene expression in metazoans. The global effects of GlcNAcylation on transcription can be addressed directly in C. elegans because knockouts of the O-GlcNAc cycling enzymes are viable and fertile. Using anti-O-GlcNAc ChIP-on-chip whole-genome tiling arrays on wild-type and mutant strains, we detected over 800 promoters where O-GlcNAc cycling occurs, including microRNA loci and multigene operons. Intriguingly, O-GlcNAc-marked promoters are biased toward genes associated with PIP3 signaling, hexosamine biosynthesis, and lipid/carbohydrate metabolism. These marked genes are linked to insulin-like signaling, metabolism, aging, stress, and pathogen-response pathways in C. elegans . Whole-genome transcriptional profiling of the O-GlcNAc cycling mutants confirmed dramatic deregulation of genes in these key pathways. As predicted, the O-GlcNAc cycling mutants show altered lifespan and UV stress susceptibility phenotypes. We propose that O-GlcNAc cycling at promoters participates in a molecular program impacting nutrient-responsive pathways in C. elegans , including stress, pathogen response, and adult lifespan. The observed impact of O-GlcNAc cycling on both signaling and transcription in C. elegans has important implications for human diseases of aging, including diabetes and neurodegeneration.

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Section: Disruption Of O-glcnac Cycling Affects the Aging Pathway Andsupporting

confidence: 90%

Dynamic O-GlcNAc cycling at promoters of Caenorhabditis elegans genes regulating longevity, stress, and immunity

Love

Ghosh

Mondoux

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

133

164

View full text Add to dashboard Cite

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“…14-3-3 contributes to FoxO release from DNA by modifying the characteristics of FoxO DNA-binding domain (Boura et al, 2007) (Figure 3). These findings are consistent with the observation that a mutant of FoxO1 in which the nuclear export sequence is disrupted-and is therefore sequestered in the nucleus-is still inhibited by the PI3K-AKT/SGK pathway, presumably because it is released from DNA (Tsai et al, 2003). It will be important to examine whether the phosphorylation of S256 also affects the binding of FoxO1 in the context of chromatin in vivo.…”

Section: Foxo Phosphorylation By Aktsupporting

confidence: 79%

The FoxO code

2008

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“…In addition to governing nuclear/cytoplasm shuttling, phosphorylation of FOXO can decrease its inherent transactivation potential notably by disrupting the interactions with co-activators (Perrot & Rechler 2003, Puigserver et al 2003, Tsai et al 2003.…”

Section: Modulation Of Foxo Transcriptional Propertiesmentioning

confidence: 99%

The emerging role of FOXO transcription factors in pancreatic β cells

Glauser

Schlegel

2007

Journal of Endocrinology

132

105

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FOXO transcription factors critically control fundamental cellular processes, including metabolism, cell differentiation, cell cycle arrest, DNA repair, and other reactions to cellular stress. FOXO factors sense the balance between stimuli promoting growth and differentiation versus stress stimuli signaling damage. Integrated through the FOXO system, these divergent stimuli decide on cell fate, a choice between proliferation, differentiation, or apoptosis. In pancreatic b cells, most recent evidence highlights complex FOXOdependent responses to glucose, insulin, or other growth factors, which include regulatory feedback. In the short term, FOXO-dependent mechanisms help b cells to accomplish their endocrine function, and may increase their resistance to oxidative stress due to transient hyperglycemia. In the long term, FOXO-dependent responses lead to the adaptation of b cell mass, conditioning the future ability of the organism to produce insulin and cope with changes in fuel abundance. FOXO emerges as a key factor for the maintenance of a functional endocrine pancreas and represents an interesting element in the development of therapeutic approaches to treat diabetes. This review on the role of FOXO transcription factors in pancreatic b cells has three parts. In Part I, FOXO transcription factors will be presented in general: structure, molecular mechanisms of regulation, cellular functions, and physiological roles. Part II will focus on specific data about FOXO factors in pancreatic b cells. Lastly in Part III, it will be attempted to combine general and b cell-specific knowledge with the aim to envisage globally the role of FOXO factors in b cell-linked physiology and disease. The DNA-binding domain (Forkhead box) is located in the N-terminal portion of these proteins, while the transactivation domain is located in the C-terminal portion. Furthermore, a 'nuclear export sequence' and a 'nuclear localization signal' have been delineated. These motifs allow FOXO factors to shuttle in and out of the nucleus (see below). FOXO proteins may be post-translationally modified by phosphorylation and/or acetylation at differentially conserved serine/threonine and lysine residues respectively. Structural features of FOXO proteins have been detailed in recent reviews (Barthel et al. 2005, Greer & Brunet 2005. Molecular regulation of FOXO transcription factorsAs illustrated in Fig. 1, multiple molecular mechanisms regulate FOXO transcription factor functions. Some control subcellular FOXO localization, while others modulate FOXO transactivation properties. Furthermore, FOXO factor abundance is regulated by site-specific protein cleavage or through the control of foxo gene expression.Subcellular localization FOXO factors shuttle between nucleus and cytoplasm. This represents a major event controlling FOXO activity that results from changes in FOXO phosphorylation. Two main classes of stimuli trigger FOXO phosphorylation with opposing effects on FOXO localization.

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Insulin Inhibition of Transcription Stimulated by the Forkhead Protein Foxo1 Is Not Solely due to Nuclear Exclusion

Cited by 59 publications

References 77 publications

Dynamic O-GlcNAc cycling at promoters of Caenorhabditis elegans genes regulating longevity, stress, and immunity

Dynamic O-GlcNAc cycling at promoters of Caenorhabditis elegans genes regulating longevity, stress, and immunity

The FoxO code

The emerging role of FOXO transcription factors in pancreatic β cells

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