FOXO3a regulates reactive oxygen metabolism by inhibiting mitochondrial gene expression

Ferber, Emma C.; Peck, Barrie; Delpuech, Oona; Bell, Graham P.; East, Philip; Schulze, Almut

doi:10.1038/cdd.2011.179

Cited by 240 publications

(210 citation statements)

References 41 publications

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“…In quiescent murine HSCs, Akt is not activated, and members of the FoxO family of transcription factors, which are important for suppressing ROS levels, 211 are localized to the nucleus. Upon cytokine stimulation of HSCs, Akt becomes activated, and FoxO proteins are exported from the nucleus to the cytoplasm.…”

Section: Quiescence In Fibroblastsmentioning

confidence: 99%

Staying alive

et al. 2012

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Ensuring the continuity of life requires that individual cells and entire organisms can survive not only in ideal environments, but also in conditions of scarcity. When conditions are unfavorable for proliferation, many cells have the capacity to enter a nondividing state, sometimes for years, while retaining their ability to reenter the proliferative cell cycle. 1,2 This state of reversible cell cycle arrest, known as quiescence, is common and can be seen in stem cells, eggs and spores. Some quiescent cells are surprisingly hardy: they can survive long periods of nutrient starvation, cold temperatures and even desiccation. Entry into quiescence is often associated with dramatic changes in metabolism, defined as the uptake of nutrients and the use of these nutrients for the synthesis of macromolecules and energy. Indeed, proliferating and quiescent fibroblasts are expected to have very different metabolic requirements. While proliferating cells must devote much of their metabolic capacity to biosynthesis in order to create the material necessary to form a new cell, quiescent cells are relieved of this steep metabolic requirement. Many but not all quiescent cells respond by downregulating the synthesis of proteins *Correspondence to: Hilary Coller; Email: hcoller@princeton.edu Submitted: 02/22/12; Accepted: 02/27/12 http://dx.doi.org/10. 4161/cc.19879 Quiescence is a state of reversible cell cycle arrest that can grant protection against many environmental insults. in some systems, cellular quiescence is associated with a low metabolic state characterized by a decrease in glucose uptake and glycolysis, reduced translation rates and activation of autophagy as a means to provide nutrients for survival. For cells in multiple different quiescence model systems, including Saccharomyces cerevisiae, mammalian lymphocytes and hematopoietic stem cells, the Pi3Kinase/TOr signaling pathway helps to integrate information about nutrient availability with cell growth rates. Quiescence signals often inactivate the TOr kinase, resulting in reduced cell growth and biosynthesis. However, quiescence is not always associated with reduced metabolism; it is also possible to achieve a state of cellular quiescence in which glucose uptake, glycolysis and flux through central carbon metabolism are not reduced. in this review, we compare and contrast the metabolic changes that occur with quiescence in different model systems. 2 The signals for quiescence vary for different types of cells. Bacteria and yeast can enter stationary phase, a condition in which they cease cell growth and proliferation, in response to depletion of the glucose in their culture medium or in response to deprivation for a specific nutrient. In mammals, the proliferative state of individual cells is regulated by a host of factors that include not only the presence or absence of nutrients, but also cues from proliferative signaling molecules such as mitogens and situational cues. Quiescent T lymphocytes respond to stimulation of their T-cell receptor with the approp...

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Section: Quiescence In Fibroblastsmentioning

confidence: 99%

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et al. 2012

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“…Induction of FOXO3a by hypoxia might help conserve ATP by restricting cell proliferation as well as by reprogramming cell metabolism. In this regard, FOXO3a was reported to regulate oxygen consumption and reactive oxygen species (ROS) production by inhibiting mitochondrial gene expression (Jensen et al 2011;Ferber et al 2012). FOXO3a activation by hypoxia could decrease mitochondrial gene expression and mitochondria DNA copy number, which could shift cellular metabolism from oxidative phosphorylation to glycolysis and reduce oxidative stress.…”

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confidence: 99%

Prolyl hydroxylation by EglN2 destabilizes FOXO3a by blocking its interaction with the USP9x deubiquitinase

et al. 2014

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The three EglN prolyl hydroxylases (EglN1, EglN2, and EglN3) regulate the stability of the HIF transcription factor. We recently showed that loss of EglN2, however, also leads to down-regulation of Cyclin D1 and decreased cell proliferation in a HIF-independent manner. Here we report that EglN2 can hydroxylate FOXO3a on two specific prolyl residues in vitro and in vivo. Hydroxylation of these sites prevents the binding of USP9x deubiquitinase, thereby promoting the proteasomal degradation of FOXO3a. FOXO transcription factors can repress Cyclin D1 transcription. Failure to hydroxylate FOXO3a promotes its accumulation in cells, which in turn suppresses Cyclin D1 expression. These findings provide new insights into post-transcriptional control of FOXO3a and provide a new avenue for pharmacologically altering Cyclin D1 activity.

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“…Furthermore, Cyclophilin-D is found to interact with TFB2M for mitochondrial transcription 77 . TFB1M and TFB2M is found to be significantly reduced on FOXO3a activation 78 . While in colorectal cancer cases FOXO3a is found to be highly inhibited 79 & 80 .…”

Section: Dicationmentioning

confidence: 87%

Revealing ETC-1922159 Affected Unknown 3<em><sup>rd</sup></em> order WNT10B-X-X Combinations, in Silico

Sinha¹

2017

Preprint

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WNT10B belongs to the family of WNT proteins that are implicated in a range of phenomena that are affected by the Wnt signaling pathway. Recent studies have shown that WNT10B plays a role in colorectal cancer. WNTs have been found to directly affect the stemness of the tumor cells via regulation of ASCL2. Switching off the ASCL2 literally blocks the stemness process of the tumor cells and vice versa. Furthermore, recent findings suggest BVES to be highly suppressed in malignancies and in vitro deletions of BVES show higher Wnt signaling activity to induce stemness. WNT10B was found to be highly expressed in such cases. Often, in biology, we are faced with the problem of exploring relevant unknown biological hypotheses in the form of myriads of combination of factors that might be affecting the pathway under certain conditions. For example, WNT10B-ASCL2 is one such 2 nd order combination whose relation needs to be tested under the influence of recently developed porcupine-WNT inhibitor ETC-1922159. The inhibitor is known to suppress PORCN (porcupine) and thus inhibit a range of oncogenes known to be directly or indirectly affected by the Wnts. In a recent unpublished work in bioRxiv, Sinha 1 , we had the opportunity to rank these unknown biological hypotheses for down regulated genes at 2 nd order level after the drug was administered. The in silico observations showed that the combination of WNT10B-ASCL2 was assigned a relatively lower rank, thus validating the pipeline's efficacy with the confirmed wet lab experiment that indicate that both WNT10B and ASCL2 were down regulated after treatment in cancer cells. Here, we take one step further by in silico analysis of the 3 rd order combinations of WNT10B-X-X (X can be known or unknown factor), from a range of 100 randomly picked down regulated genes after ETC-1922159 treatment. The pipeline uses the density based HSIC (Hilbert Schmidt Information Criterion) sensitivity index with an rbf (radial basis function) kernel, which is known to be highly effective in sensitivity analysis. Various unknown/unexplored/untested 3 rd order biological hypotheses emerge some of which are confirmed in wet lab, while others need to be tested. The potential of such ranking is indispensable in the current era of search in a vast combinatorial forest. KEYWORDS -WNT pathway; porcupine inhibitor ETC-1922159; sensitivity analysis; colorectal cancer; unknown biological hypotheses; combinatorial search space; support vector ranking Conference, from 6-11 August 2017, held Significance WNT10B belongs to the family of WNT proteins that are implicated in a range of phenomena that are affected by the Wnt signaling pathway. Recent studies have shown that WNT10B plays a role in colorectal cancer. Often, we are faced with the problem of exploring relevant unknown biological hypotheses in the form of myriads of combination of factors that might be involved in the pathway. The current work reveals at in silico level, the 3rd order WNT10B associated combinations that might be affected by the admin...

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FOXO3a regulates reactive oxygen metabolism by inhibiting mitochondrial gene expression

Cited by 240 publications

References 41 publications

Staying alive

Staying alive

Prolyl hydroxylation by EglN2 destabilizes FOXO3a by blocking its interaction with the USP9x deubiquitinase

Revealing ETC-1922159 Affected Unknown 3<em><sup>rd</sup></em> order WNT10B-X-X Combinations, in Silico

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