Forkhead Box O1 (FOXO1) Protein, but Not p53, Contributes to Robust Induction of p21 Expression in Fasted Mice

Tinkum, Kelsey L.; White, Lynn S.; Marpegan, Luciano; Herzog, Erik D.; Piwnica‐Worms, David; Piwnica‐Worms, Helen

doi:10.1074/jbc.m113.494328

Cited by 30 publications

(34 citation statements)

References 25 publications

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“…Loss of SATB1 in DA neurons caused a ~300% elevation in CDKN1A transcription, but did not significantly alter levels in CTX neurons. It is tempting to speculate that the CDKN1A locus is under a constant transcriptional activation pressure in DA neurons compared to CTX neurons, which is reflected by significantly higher expression of CDKN1A-promoting factors ( Figure S5 D,E; Tinkum et al, 2013). These findings suggest that the intrinsic properties of DA neurons, be they structural (size, branching), energetic demand, or high stress level (Pacelli et al, 2015) may render these cells vulnerable to cellular senescence.…”

Section: Discussionmentioning

confidence: 99%

Loss of SATB1 Induces a p21 Dependent Cellular Senescence Phenotype in Dopaminergic Neurons

Rießland

Kolisnyk

et al. 2018

Preprint

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Cellular senescence is a mechanism used by mitotic cells to prevent uncontrolled cell division. As senescent cells persist in tissues, they cause local inflammation and are harmful to surrounding cells, contributing to aging. Generally, neurodegenerative diseases, such as Parkinson's, are disorders of aging. The contribution of cellular senescence to neurodegeneration is still unclear. SATB1 is a DNA binding protein associated with Parkinson's disease. We report that SATB1 prevents cellular senescence in post-mitotic dopaminergic neurons. Loss of SATB1 causes activation of a cellular senescence transcriptional program in dopamine neurons, both in human stem cell-derived dopaminergic neurons and in mice. We observed phenotypes which are central to cellular senescence in SATB1 knockout dopamine neurons in vitro and in vivo. Moreover, we found that SATB1 directly represses expression of the pro-senescence factor, p21, in dopaminergic neurons. Our data implicate senescence of dopamine neurons as a contributing factor to the pathology of Parkinson's disease. hESC shows normal appearance. Scale bar: 200 µm. (D) Immunolabeling of DA precursor markers in WT and SATB1 KO hESC derived DA neurons after 16 days of differentiation reveals no difference in marker expression. (E) Depiction of spontaneous action potentials of WT and SATB1 KO DA neurons at different time points show that both genotypes differentiate into mature DA neurons between day 35 and 40. Scale bar: 20 mV, 2 s. (F) DA neurons at day 40 show significant differences in maintenance of response to positive current injections. Scale bar: 20 mV, 200 ms. (G) Longitudinal comparison of cell survival of WT vs. SATB1 KO DA neurons revealed a significant reduction in SATB1 KO survival between day 30 and 40, reaching a plateau at ~50%. Data are represented as mean ± SEM. (H) Quantification of neurite morphology and complexity in WT and SATB1 KO DA neurons. Data are represented as mean ± SEM. (I) Triple immunolabeling of cortical shows that both WT as well as SATB1 KO neurons express the essential markers for cortical neurons. Scale bar: 50 µm. (J) SATB1 KO cortical neurons show no significant change in survival during differentiation. Data are represented as mean ± SEM. (K) Quantification of neurite morphology and complexity in WT and SATB1 KO CTX neurons. (L)Representative western blot and quantification depicts that WT DA neurons express significantly higher levels of SATB1 than WT cortical neurons, suggesting a higher demand in DA neurons. Data are represented as mean ± SEM. See also Figure S1.

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Section: Discussionmentioning

confidence: 99%

Loss of SATB1 Induces a p21 Dependent Cellular Senescence Phenotype in Dopaminergic Neurons

Rießland

Kolisnyk

et al. 2018

Preprint

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“…This research was originally published in ref. 61. Copyright (2013) the American Society for Biochemistry and Molecular Biology.…”

Section: Figmentioning

confidence: 99%

“…[138,148] Osmotic pumps and alternative delivery mechanisms will also be useful in this regard. [61,147]…”

Section: Introductionmentioning

confidence: 99%

Bioluminescence: a versatile technique for imaging cellular and molecular features

2014

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Bioluminescence is a ubiquitous imaging modality for visualizing biological processes in vivo. This technique employs visible light and interfaces readily with most cell and tissue types, making it a versatile technology for preclinical studies. Here we review basic bioluminescence imaging principles, along with applications of the technology that are relevant to the medicinal chemistry community. These include noninvasive cell tracking experiments, analyses of protein function, and methods to visualize small molecule metabolites. In each section, we also discuss how bioluminescent tools have revealed insights into experimental therapies and aided drug discovery. Last, we highlight the development of new bioluminescent tools that will enable more sensitive and multi-component imaging experiments and, thus, expand our broader understanding of living systems.

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“…In a 2010 study of C57Bl/6 mice undergoing a 48-h food deprivation, p21/Cdkn1a expression was significantly up-regulated (Poplawski et al 2010). More recently, in a 2013 paper, liver and hypothalamus of mice fasted 24 and 48 h showed significant induction of a p21/Cdkn1a promoter construct (Tinkum et al 2013). Further examination of our dataset revealed that there were many genes with GO categories related to cell cycle processes.…”

Section: Discussionmentioning

confidence: 69%

Characterization of the hypothalamic transcriptome in response to food deprivation reveals global changes in long noncoding RNA, and cell cycle response genes

et al. 2015

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The hypothalamus integrates energy balance information from the periphery using different neuronal subtypes within each of the hypothalamic areas. However, the effects of prandial state on global mRNA, microRNA and long noncoding (lnc) RNA expression within the whole hypothalamus are largely unknown. In this study, mice were given either a 24-h fast, or ad libitum access to food. RNA samples were analyzed by microarray, and then a subset was confirmed using quantitative real-time PCR (QPCR). A total of 540 mRNAs were either up-or downregulated with food deprivation. Since gene ontology enrichment analyses identified several categories of mRNAs related to cell cycle processes, ten cell-cycle-related genes were further analyzed using QPCR with six confirmed to be significantly up-regulated and one downregulated in response to 24-h fasting. While 22 independent microRNAs were differentially expressed by microarray, secondary analysis by QPCR failed to confirm significant changes with fasting. There were 622 lncRNAs identified as differentially expressed, and of three tested by QPCR, two were confirmed. Overall, this is the first time that expression of hypothalamic lncRNAs has been shown to be responsive to food deprivation. In addition, this study is the first to identify a list of lncRNAs with high expression in RNA extracted from hypothalamus. Individual contributions from specific miRNA, lncRNA and mRNAs to the food deprivation response can now be further studied at the physiological and biochemical levels.

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Forkhead Box O1 (FOXO1) Protein, but Not p53, Contributes to Robust Induction of p21 Expression in Fasted Mice

Cited by 30 publications

References 25 publications

Loss of SATB1 Induces a p21 Dependent Cellular Senescence Phenotype in Dopaminergic Neurons

Loss of SATB1 Induces a p21 Dependent Cellular Senescence Phenotype in Dopaminergic Neurons

Bioluminescence: a versatile technique for imaging cellular and molecular features

Characterization of the hypothalamic transcriptome in response to food deprivation reveals global changes in long noncoding RNA, and cell cycle response genes

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