Stresses like low nutrients, systemic inflammation, cancer or infections provoke a catabolic state characterized by enhanced muscle proteolysis and amino acid release to sustain liver gluconeogenesis ...and tissue protein synthesis. These conditions activate the family of Forkhead Box (Fox) O transcription factors. Here we report that muscle-specific deletion of FoxO members protects from muscle loss as a result of the role of FoxOs in the induction of autophagy-lysosome and ubiquitin-proteasome systems. Notably, in the setting of low nutrient signalling, we demonstrate that FoxOs are required for Akt activity but not for mTOR signalling. FoxOs control several stress-response pathways such as the unfolded protein response, ROS detoxification, DNA repair and translation. Finally, we identify FoxO-dependent ubiquitin ligases including MUSA1 and a previously uncharacterised ligase termed SMART (Specific of Muscle Atrophy and Regulated by Transcription). Our findings underscore the central function of FoxOs in coordinating a variety of stress-response genes during catabolic conditions.
Forkhead Box O (FoxO) transcription factors act in adult stem cells to preserve their regenerative potential. Previously, we reported that FoxO maintains the long‐term proliferative capacity of ...neural stem/progenitor cells (NPCs), and that this occurs, in part, through the maintenance of redox homeostasis. Herein, we demonstrate that among the FoxO3‐regulated genes in NPCs are a host of enzymes in central carbon metabolism that act to combat reactive oxygen species (ROS) by directing the flow of glucose and glutamine carbon into defined metabolic pathways. Characterization of the metabolic circuit observed upon loss of FoxO3 revealed a drop in glutaminolysis and filling of the tricarboxylic acid (TCA) cycle. Additionally, we found that glucose uptake, glucose metabolism and oxidative pentose phosphate pathway activity were similarly repressed in the absence of FoxO3. Finally, we demonstrate that impaired glucose and glutamine metabolism compromises the proliferative potential of NPCs and that this is exacerbated following FoxO3 loss. Collectively, our findings show that a FoxO3‐dependent metabolic programme supports redox balance and the neurogenic potential of NPCs.
Detailed metabolic measurements in neural progenitor cells (NPCs) establish FoxO3 as a central regulator of cellular metabolism and redox homeostasis. These results may have a direct impact on the proliferative capacity of stem and progenitor populations in general.
Transcriptional regulatory mechanisms of cardiac oxidative stress resistance are not well defined. FoxO transcription factors are critical mediators of oxidative stress resistance in multiple cell ...types, but cardioprotective functions have not been reported previously. FoxO function in oxidative stress resistance was investigated in cultured cardiomyocytes and in mice with cardiomyocyte-specific combined deficiency of FoxO1 and FoxO3 subjected to myocardial infarction (MI) or acute ischemia/reperfusion (I/R) injury. Induction of oxidative stress in cardiomyocytes promotes FoxO1 and FoxO3 nuclear localization and target gene activation. Infection of cardiomyocytes with a dominant-negative FoxO1(Δ256) adenovirus results in a significant increase in reactive oxygen species and cell death, whereas increased FoxO1 or FoxO3 expression reduces reactive oxygen species and cell death. Mice generated with combined conditional deletion of FoxO1 and FoxO3 specifically in cardiomyocytes were subjected to I/R or MI. Loss of FoxO1 and FoxO3 in cardiomyocytes results in a significant increase in infarct area with decreased expression of the antiapoptotic molecules, PTEN-induced kinase1 (PINK1) and CBP/P300-interacting transactivator (CITED2). Expressions of the antioxidants catalase and manganese superoxide dismutase-2 (SOD2) and the autophagy-related proteins LC3II and Gabarapl1 also are decreased following I/R compared with controls. Mice with cardiomyocyte-specific FoxO deficiency subjected to MI have reduced cardiac function, increased scar formation, induction of stress-responsive signaling, and increased apoptotic cell death relative to controls. These data support a critical role for FoxOs in promoting cardiomyocyte survival during conditions of oxidative stress through induction of antioxidants and cell survival pathways.
Increasing evidence suggests that exosomes are involved in retinal cell degeneration, including their insufficient release; hence, they have become important indicators of retinopathies. The exosomal ...microRNA (miRNA), in particular, play important roles in regulating ocular and retinal cell functions, including photoreceptor maturation, maintenance, and visual function. Here, we generated retinal organoids (ROs) from human induced pluripotent stem cells that differentiated in a conditioned medium for 60 days, after which exosomes were extracted from ROs (Exo-ROs). Subsequently, we intravitreally injected the Exo-RO solution into the eyes of the Royal College of Surgeons (RCS) rats. Intravitreal Exo-RO administration reduced photoreceptor apoptosis, prevented outer nuclear layer thinning, and preserved visual function in RCS rats. RNA sequencing and miRNA profiling showed that exosomal miRNAs are mainly involved in the mitogen-activated protein kinase (MAPK) signaling pathway. In addition, the expression of MAPK-related genes and proteins was significantly decreased in the Exo-RO-treated group. These results suggest that Exo-ROs may be a potentially novel strategy for delaying retinal degeneration by targeting the MAPK signaling pathway.
FoxO family members in cancer Zhang, Yuqing; Gan, Boyi; Liu, Debra ...
Cancer biology & therapy,
8/15/2011, 2011/08/15, 2011-Aug-15, 2011-08-15, 20110815, Letnik:
12, Številka:
4
Journal Article
Recenzirano
Odprti dostop
The PI3K-Akt-FoxO signaling pathway plays a central role in diverse physiological processes including cellular energy storage, growth, and survival, among others. As an important effector of this ...pathway, FoxO is involved in versatile activities that protect organisms from stress and aging. Recent studies on mammalian FoxO have established a direct role for this transcription factor family in cellular proliferation, oxidative stress response, and tumorigenesis. The review will focus on the recent developments pertaining to the function of FoxO as well as discuss the various contexts in which FoxO exerts distinct biological activity such as drug resistance and autophagy in cancer pathogenesis and therapy.
CD4(+) regulatory T cells (T(reg) cells) characterized by expression of the transcription factor Foxp3 have a pivotal role in maintaining immunological tolerance. Here we show that mice with T ...cell-specific deletion of both the Foxo1 and Foxo3 transcription factors (collectively called 'Foxo proteins' here) developed a fatal multifocal inflammatory disorder due in part to T(reg) cell defects. Foxo proteins functioned in a T(reg) cell-intrinsic manner to regulate thymic and transforming growth factor-beta (TGF-beta)-induced Foxp3 expression, in line with the ability of Foxo proteins to bind to Foxp3 locus and control Foxp3 promoter activity. Transcriptome analyses showed that Foxo proteins regulated the expression of additional T(reg) cell-associated genes and were essential for inhibiting the acquisition of effector T cell characteristics by T(reg) cells. Thus, Foxo proteins have crucial roles in specifying the T(reg) cell lineage.
Osteoporosis, a disease of low bone mass, is associated with decreased osteoblast numbers and increased levels of oxidative stress within osteoblasts. Since transcription factors of the FoxO family ...confer stress resistance, we investigated their potential impact on skeletal integrity. Here we employ cell-specific deletion and molecular analyses to show that, among the three FoxO proteins, only FoxO1 is required for proliferation and redox balance in osteoblasts and thereby controls bone formation. FoxO1 regulation of osteoblast proliferation occurs through its interaction with ATF4, a transcription factor regulating amino acid import, as well as through its regulation of a stress-dependent pathway influencing p53 signaling. Accordingly, decreasing oxidative stress levels or increasing protein intake normalizes bone formation and bone mass in mice lacking
FoxO1 specifically in osteoblasts. These results identify FoxO1 as a crucial regulator of osteoblast physiology and provide a direct mechanistic link between oxidative stress and the regulation of bone remodeling.
► FoxO1 is required for normal osteoblast proliferation and bone formation ► FoxO1 interacts with ATF4 to promote amino acid import in osteoblasts ► Normal protein synthesis allows FoxO1 to maintain redox balance in osteoblasts ► These events downregulate p19/p16/p53 signaling and promote osteoblast proliferation
Differential WNT and Notch signaling regulates differentiation of Lgr5+ crypt-based columnar cells (CBCs) into intestinal cell lineages. Recently we showed that mitochondrial activity supports CBCs, ...while adjacent Paneth cells (PCs) show reduced mitochondrial activity. This implies that CBC differentiation into PCs involves a metabolic transition toward downregulation of mitochondrial dependency. Here we show that Forkhead box O (FoxO) transcription factors and Notch signaling interact in determining CBC fate. In agreement with the organoid data, Foxo1/3/4 deletion in mouse intestine induces secretory cell differentiation. Importantly, we show that FOXO and Notch signaling converge on regulation of mitochondrial fission, which in turn provokes stem cell differentiation into goblet cells and PCs. Finally, scRNA-seq-based reconstruction of CBC differentiation trajectories supports the role of FOXO, Notch, and mitochondria in secretory differentiation. Together, this points at a new signaling-metabolic axis in CBC differentiation and highlights the importance of mitochondria in determining stem cell fate.
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•FOXO1/3 knockdown leads to stem cell differentiation into secretory cells•High and low abundance of mitochondria define stem cells and Paneth cells, respectively•FOXO and NOTCH functionally interact and their inhibition induces mitochondrial fission•Mitochondrial fission is a requisite for differentiation into Paneth and goblet cells
Changes in cellular metabolism regulate the stem cell state and differentiation. In particular, intestinal stem cells are enriched in mitochondria when compared to secretory linages. Here, Ludikhuize et al. show that downregulation of FOXO1/3 and Notch1 signaling induces mitochondrial fission, which is a requisite for the differentiation of stem cells into goblet and Paneth cells.
The PI3K-AKT-FoxO pathway is integral to lifespan regulation in lower organisms and essential for the stability of long-lived cells in mammals. Here, we report the impact of combined FoxO1, 3, and 4 ...deficiencies on mammalian brain physiology with a particular emphasis on the study of the neural stem/progenitor cell (NSC) pool. We show that the FoxO family plays a prominent role in NSC proliferation and renewal. FoxO-deficient mice show initial increased brain size and proliferation of neural progenitor cells during early postnatal life, followed by precocious significant decline in the NSC pool and accompanying neurogenesis in adult brains. Mechanistically, integrated transcriptomic, promoter, and functional analyses of FoxO-deficient NSC cultures identified direct gene targets with known links to the regulation of human brain size and the control of cellular proliferation, differentiation, and oxidative defense. Thus, the FoxO family coordinately regulates diverse genes and pathways to govern key aspects of NSC homeostasis in the mammalian brain.
The transcription factor Foxp3 is essential for optimal regulatory T (T reg) cell development and function. Here, we show that CD4(+) T cells from Cbl-b RING finger mutant knockin or Cbl-b-deficient ...mice show impaired TGF-beta-induced Foxp3 expression. These T cells display augmented Foxo3a phosphorylation, but normal TGF-beta signaling. Expression of Foxo3a rescues Foxp3 expression in Cbl-b-deficient T cells, and Foxo3a deficiency results in defective TGF-beta-driven Foxp3 induction. A Foxo3a-binding motif is present in a proximal region of the Foxp3 promoter, and is required for Foxo3a association. Foxo1 exerts similar effects as Foxo3a on Foxp3 expression. This study reveals that Foxo factors promote transcription of the Foxp3 gene in induced T reg cells, and thus provides new mechanistic insight into Foxo-mediated T cell regulation.
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