The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Eric J. Nestler - One of the best experts on this subject based on the ideXlab platform.
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FOSB Induction in Nucleus Accumbens by Cocaine Is Regulated by E2F3a.
eNeuro, 2019Co-Authors: Hannah M. Cates, Rachael L Neve, Casey K. Lardner, Rosemary C. Bagot, Eric J. NestlerAbstract:The transcription factor ΔFOSB has been proposed as a molecular switch for the transition from casual, volitional drug use into a chronically addicted state, but the upstream regulatory mechanisms governing ΔFOSB expression are incompletely understood. In this study, we find a novel regulatory role for the transcription factor E2F3, recently implicated in transcriptional regulation by cocaine, in controlling ΔFOSB induction in the mouse nucleus accumbens (NAc) following cocaine administration. We find that an E2F consensus sequence 500 bp upstream of the FOSB transcription start site is enriched for E2F3 specifically over other E2F isoforms. We further conclude that ΔFOSB expression is regulated specifically by E2F3a, not E2F3b, that E2f3a expression is specific to D1 receptor-expressing medium spiny neurons, and that E2F3a overexpression in NAc recapitulates the induction of FOSB and ΔFOSB mRNA expression observed after chronic cocaine exposure. E2F3a knockdown in NAc does not abolish ΔFOSB induction by cocaine, a result consistent with previously published data showing that singular knockdown of upstream regulators of ΔFOSB is insufficient to block cocaine-induced expression. Finally, to elucidate potential combinatorial epigenetic mechanisms involved in E2F3a's regulation of FOSB, we explore H3K4me3 enrichment at the FOSB promoter and find that it is not enhanced by E2F3a overexpression, suggesting that it may instead be a pre-existing permissive mark allowing for E2F3a to interact with FOSB. Together, these findings support a role for E2F3a as a novel, upstream regulator of the addiction-mediating transcription factor ΔFOSB in NAc.
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cell type specific epigenetic editing at the FOSB gene controls susceptibility to social defeat stress
Neuropsychopharmacology, 2018Co-Authors: Peter J Hamilton, Alfred J. Robison, Eric J. Nestler, Dominika J Burek, Sonia I Lombroso, Rachael L Neve, Elizabeth A HellerAbstract:Chronic social defeat stress regulates the expression of FOSB in the nucleus accumbens (NAc) to promote the cell-type-specific accumulation of ΔFOSB in the two medium spiny neuron (MSN) subtypes in this region. ΔFOSB is selectively induced in D1-MSNs in the NAc of resilient mice, and in D2-MSNs of susceptible mice. However, little is known about the consequences of such selective induction, particularly in D2-MSNs. This study examined how cell-type-specific control of the endogenous FOSB gene in NAc regulates susceptibility to social defeat stress. Histone post-translational modifications (HPTMs) were targeted specifically to FOSB using engineered zinc-finger proteins (ZFPs). FOSB-ZFPs were fused to either the transcriptional repressor, G9a, which promotes histone methylation or the transcriptional activator, p65, which promotes histone acetylation. These ZFPs were expressed in D1- vs D2-MSNs using Cre-dependent viral expression in the NAc of mice transgenic for Cre recombinase in these MSN subtypes. We found that stress susceptibility is oppositely regulated by the specific cell type and HPTM targeted. We report that FOSB-targeted histone acetylation in D2-MSNs or histone methylation in D1-MSNs promotes a stress-susceptible, depressive-like phenotype, while histone methylation in D2-MSNs or histone acetylation in D1-MSNs increases resilience to social stress as quantified by social interaction behavior and sucrose preference. This work presents the first demonstration of cell- and gene-specific targeting of histone modifications, which model naturally occurring transcriptional phenomena that control social defeat stress behavior. This epigenetic-editing approach, which recapitulates physiological changes in gene expression, reveals clear differences in the social defeat phenotype induced by FOSB gene manipulation in MSN subtypes.
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generation and validation of a floxed FOSB mouse line
bioRxiv, 2017Co-Authors: Yoshinori N Ohnishi, Andrew L Eagle, Yoko H Ohnishi, Alexis J Wirtz, Michael E Cahill, Alfred J. Robison, Eric J. NestlerAbstract:Expression of the FOSB gene has been studied extensively in many fields using a variety of tools. However, previous techniques have had a variety of caveats, from potential off-target effects (e.g., overexpression of FOSB, ΔFOSB, or a dominant negative mutant of JunD, termed ΔJunD) or confounding developmental effects (e.g., the constitutive FOSB knockout mouse). Therefore, we sought to create a floxed FOSB mouse line that will allow true silencing of the FOSB gene with both spatial and temporal control. Here, we detail the cloning strategy, production, and validation of the floxed FOSB mouse. We demonstrate methodology for breeding and genotyping, and show that viral-mediated expression of Cre recombinase in a targeted, discrete brain region ablates expression of the FOSB gene in floxed but not wild type mice. Thus, the floxed FOSB mouse presented here represents an important new tool for the continued investigation of this critical gene.
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Differential induction of FOSB isoforms throughout the brain by fluoxetine and chronic stress.
Neuropharmacology, 2015Co-Authors: Vincent Vialou, Andrew L Eagle, Eric J. Nestler, Mackenzie Thibault, Sophia Kaska, Sarah Cooper, Paula A. Gajewski, Michelle S. Mazei-robison, Alfred J. RobisonAbstract:Major depressive disorder is thought to arise in part from dysfunction of the brain's "reward circuitry", consisting of the mesolimbic dopamine system and the glutamatergic and neuromodulatory inputs onto this system. Both chronic stress and antidepressant treatment regulate gene transcription in many of the brain regions that make up these circuits, but the exact nature of the transcription factors and target genes involved in these processes remain unclear. Here, we demonstrate induction of the FOSB family of transcription factors in ∼25 distinct regions of adult mouse brain, including many parts of the reward circuitry, by chronic exposure to the antidepressant fluoxetine. We further uncover specific patterns of FOSB gene product expression (i.e., differential expression of full-length FOSB, ΔFOSB, and Δ2ΔFOSB) in brain regions associated with depression--the nucleus accumbens (NAc), prefrontal cortex (PFC), and hippocampus--in response to chronic fluoxetine treatment, and contrast these patterns with differential induction of FOSB isoforms in the chronic social defeat stress model of depression with and without fluoxetine treatment. We find that chronic fluoxetine, in contrast to stress, causes induction of the unstable full-length FOSB isoform in the NAc, PFC, and hippocampus even 24 h following the final injection, indicating that these brain regions may undergo chronic activation when fluoxetine is on board, even in the absence of stress. We also find that only the stable ΔFOSB isoform correlates with behavioral responses to stress. These data suggest that NAc, PFC, and hippocampus may present useful targets for directed intervention in mood disorders (ie, brain stimulation or gene therapy), and that determining the gene targets of FOSB-mediated transcription in these brain regions in response to fluoxetine may yield novel inroads for pharmaceutical intervention in depressive disorders.
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A Role for Mitogen- and Stress-Activated Kinase 1 in L-DOPA-Induced Dyskinesia and ∆FOSB Expression
Biological psychiatry, 2014Co-Authors: Michael Feyder, Quincey Laplant, Vincent Vialou, Erik Södersten, Emanuela Santini, Emily L. Watts, Giada Spigolon, Klaus Hansen, Jocelyne Caboche, Eric J. NestlerAbstract:Abstract Background Abnormal regulation of extracellular signal-regulated kinases 1 and 2 has been implicated in 3,4-dihydroxy-l-phenylalanine (L-DOPA)-induced dyskinesia (LID), a motor complication affecting Parkinson's disease patients subjected to standard pharmacotherapy. We examined the involvement of mitogen- and stress-activated kinase 1 (MSK1), a downstream target of extracellular signal-regulated kinases 1 and 2, and an important regulator of transcription in LID. Methods 6-Hydroxydopamine was used to produce a model of Parkinson's disease in MSK1 knockout mice and in ∆FOSB- or ∆cJun-overexpressing transgenic mice, which were assessed for LID following long-term L-DOPA administration. Biochemical processes were evaluated by Western blotting or immunofluorescence. Histone H3 phosphorylation was analyzed by chromatin immunoprecipitation followed by promotor-specific quantitative polymerase chain reaction. Results Genetic inactivation of MSK1 attenuated LID and reduced the phosphorylation of histone H3 at Ser10 in the striatum. Chromatin immunoprecipitation analysis showed that this reduction occurred at the level of the FOSB gene promoter. In line with this observation, the accumulation of ∆FOSB produced by chronic L-DOPA was reduced in MSK1 knockout. Moreover, inducible overexpression of ∆FOSB in striatonigral medium spiny neurons exacerbated dyskinetic behavior, whereas overexpression of ∆cJun, which reduces ∆FOSB-dependent transcriptional activation, counteracted LID. Conclusions Results indicate that abnormal regulation of MSK1 contributes to the development of LID and to the concomitant increase in striatal ∆FOSB, which may occur via increased histone H3 phosphorylation at the FOSB promoter. Results also show that accumulation of ∆FOSB in striatonigral neurons is causally related to the development of dyskinesia.
Cristina Núñez - One of the best experts on this subject based on the ideXlab platform.
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Glucocorticoids Regulation of FOSB/ΔFOSB Expression Induced by Chronic Opiate Exposure in the Brain Stress System
PloS one, 2012Co-Authors: Daniel García-pérez, M. Luisa Laorden, M. Victoria Milanés, Cristina NúñezAbstract:Chronic use of drugs of abuse profoundly alters stress-responsive system. Repeated exposure to morphine leads to accumulation of the transcription factor ΔFOSB, particularly in brain areas associated with reward and stress. The persistent effects of ΔFOSB on target genes may play an important role in the plasticity induced by drugs of abuse. Recent evidence suggests that stress-related hormones (e.g., glucocorticoids, GC) may induce adaptations in the brain stress system that is likely to involve alteration in gene expression and transcription factors. This study examined the role of GC in regulation of FOSB/ΔFOSB in both hypothalamic and extrahypothalamic brain stress systems during morphine dependence. For that, expression of FOSB/ΔFOSB was measured in control (sham-operated) and adrenalectomized (ADX) rats that were made opiate dependent after ten days of morphine treatment. In sham-operated rats, FOSB/ΔFOSB was induced after chronic morphine administration in all the brain stress areas investigated: nucleus accumbens(shell) (NAc), bed nucleus of the stria terminalis (BNST), central amygdala (CeA), hypothalamic paraventricular nucleus (PVN) and nucleus of the solitary tract noradrenergic cell group (NTS-A2). Adrenalectomy attenuated the increased production of FOSB/ΔFOSB observed after chronic morphine exposure in NAc, CeA, and NTS. Furthermore, ADX decreased expression of FOSB/ΔFOSB within CRH-positive neurons of the BNST, PVN and CeA. Similar results were obtained in NTS-A2 TH-positive neurons and NAc pro-dynorphin-positive neurons. These data suggest that neuroadaptation (estimated as accumulation of FOSB/ΔFOSB) to opiates in brain areas associated with stress is modulated by GC, supporting the evidence of a link between brain stress hormones and addiction.
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glucocorticoids regulation of FOSB δFOSB expression induced by chronic opiate exposure in the brain stress system
PLOS ONE, 2012Co-Authors: Daniel Garciaperez, Victoria M Milanes, Luisa M Laorden, Cristina NúñezAbstract:Chronic use of drugs of abuse profoundly alters stress-responsive system. Repeated exposure to morphine leads to accumulation of the transcription factor ΔFOSB, particularly in brain areas associated with reward and stress. The persistent effects of ΔFOSB on target genes may play an important role in the plasticity induced by drugs of abuse. Recent evidence suggests that stress-related hormones (e.g., glucocorticoids, GC) may induce adaptations in the brain stress system that is likely to involve alteration in gene expression and transcription factors. This study examined the role of GC in regulation of FOSB/ΔFOSB in both hypothalamic and extrahypothalamic brain stress systems during morphine dependence. For that, expression of FOSB/ΔFOSB was measured in control (sham-operated) and adrenalectomized (ADX) rats that were made opiate dependent after ten days of morphine treatment. In sham-operated rats, FOSB/ΔFOSB was induced after chronic morphine administration in all the brain stress areas investigated: nucleus accumbens(shell) (NAc), bed nucleus of the stria terminalis (BNST), central amygdala (CeA), hypothalamic paraventricular nucleus (PVN) and nucleus of the solitary tract noradrenergic cell group (NTS-A2). Adrenalectomy attenuated the increased production of FOSB/ΔFOSB observed after chronic morphine exposure in NAc, CeA, and NTS. Furthermore, ADX decreased expression of FOSB/ΔFOSB within CRH-positive neurons of the BNST, PVN and CeA. Similar results were obtained in NTS-A2 TH-positive neurons and NAc pro-dynorphin-positive neurons. These data suggest that neuroadaptation (estimated as accumulation of FOSB/ΔFOSB) to opiates in brain areas associated with stress is modulated by GC, supporting the evidence of a link between brain stress hormones and addiction.
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induction of FOSB δFOSB in the brain stress system related structures during morphine dependence and withdrawal
Journal of Neurochemistry, 2010Co-Authors: Cristina Núñez, Fátima Martín, Anna Földes, Krisztina Kovács, Luisa M Laorden, Victoria M MilanesAbstract:J. Neurochem. (2010) 114, 475–487. Abstract The transcription factor ΔFOSB is induced in the nucleus accumbens (NAc) by drugs of abuse. This study was designed to evaluate the possible modifications in FOSB/ΔFOSB expression in both hypothalamic and extrahypothalamic brain stress system during morphine dependence and withdrawal. Rats were made dependent on morphine and, on day 8, were injected with saline or naloxone. Using immunohistochemistry and western blot, the expression of FOSB/ΔFOSB, tyrosine hydroxylase (TH), corticotropin-releasing factor (CRF) and pro-dynorphin (DYN) was measured in different nuclei from the brain stress system in morphine-dependent rats and after morphine withdrawal. Additionally, we studied the expression of FOSB/ΔFOSB in CRF-, TH- and DYN-positive neurons. FOSB/ΔFOSB was induced after chronic morphine administration in the parvocellular part of the hypothalamic paraventricular nucleus (PVN), NAc-shell, bed nucleus of the stria terminalis, central amygdala and A2 noradrenergic part of the nucleus tractus solitarius (NTS-A2). Morphine dependence and withdrawal evoked an increase in FOSB/ΔFOSB-TH and FOSB/ΔFOSB-CRF double labelling in NTS-A2 and PVN, respectively, besides an increase in TH levels in NTS-A2 and CRF expression in PVN. These data indicate that neuroadaptation to addictive substances, observed as accumulation of FOSB/ΔFOSB, is not limited to the reward circuits but may also manifest in other brain regions, such as the brain stress system, which have been proposed to be directly related to addiction.
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induction of FOSB δFOSB in the brain stress system related structures during morphine dependence and withdrawal
Journal of Neurochemistry, 2010Co-Authors: Cristina Núñez, Fátima Martín, Anna Földes, Luisa M Laorden, Krisztina J Kovacs, Victoria M MilanesAbstract:The transcription factor DeltaFOSB is induced in the nucleus accumbens (NAc) by drugs of abuse. This study was designed to evaluate the possible modifications in FOSB/DeltaFOSB expression in both hypothalamic and extrahypothalamic brain stress system during morphine dependence and withdrawal. Rats were made dependent on morphine and, on day 8, were injected with saline or naloxone. Using immunohistochemistry and western blot, the expression of FOSB/DeltaFOSB, tyrosine hydroxylase (TH), corticotropin-releasing factor (CRF) and pro-dynorphin (DYN) was measured in different nuclei from the brain stress system in morphine-dependent rats and after morphine withdrawal. Additionally, we studied the expression of FOSB/DeltaFOSB in CRF-, TH- and DYN-positive neurons. FOSB/DeltaFOSB was induced after chronic morphine administration in the parvocellular part of the hypothalamic paraventricular nucleus (PVN), NAc-shell, bed nucleus of the stria terminalis, central amygdala and A(2) noradrenergic part of the nucleus tractus solitarius (NTS-A(2)). Morphine dependence and withdrawal evoked an increase in FOSB/DeltaFOSB-TH and FOSB/DeltaFOSB-CRF double labelling in NTS-A(2) and PVN, respectively, besides an increase in TH levels in NTS-A(2) and CRF expression in PVN. These data indicate that neuroadaptation to addictive substances, observed as accumulation of FOSB/DeltaFOSB, is not limited to the reward circuits but may also manifest in other brain regions, such as the brain stress system, which have been proposed to be directly related to addiction.
Noboru Hiroi - One of the best experts on this subject based on the ideXlab platform.
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Pleiotropic impact of constitutive FOSB inactivation on nicotine-induced behavioral alterations and stress-related traits in mice
Human molecular genetics, 2007Co-Authors: Hongwen Zhu, Moon Sook Lee, Soh Agatsuma, Noboru HiroiAbstract:Multiple genes are thought to influence both susceptibility to nicotine dependence and its comorbid behavioral traits in humans. However, which specific genes contribute to this pleiotropic effect is poorly understood. Previous rodent studies have shown that many addictive substances and stressful stimuli increase the expression of the transcription factor FOSB in limbic and associated regions and that the protein products of FOSB contribute to certain behavioral effects of cocaine and morphine. However, the role of this gene in nicotine-regulated behaviors and dependence-related behavioral traits is unknown. We tested the hypothesis that a constitutive level of FOSB affects nicotine-regulated behaviors and comorbid behavioral traits using constitutive FOSB knockout (KO) mice. Following repeated or prolonged nicotine administration, but not a single acute administration, KO mice were impaired in conditioned place preference, oral nicotine intake and motor suppression. In wild-type mice, repeated nicotine injections, but not a single acute injection, increased the expression of FOSB and its truncated variant DFOSB in the targets but not at the origins of the mesolimbic and nigrostriatal dopamine pathways; no detectable level of FOSB/DFOSB was found in KO mice. In tasks designed to assess behavioral traits, KO mice exhibited more pronounced behavioral abnormalities when stress levels were high than when they were minimized. Our results suggest that the constitutive absence of FOSB has a pleiotropic influence on the behavioral effects of repeated or prolonged nicotine administration and on stress-related behavioral traits in mice.
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chronic treatment with atypical neuroleptics induces striosomal FOSB δFOSB expression in rats
Biological Psychiatry, 2003Co-Authors: Cristina Grande, Hongwen Zhu, Moon Sook Lee, Noboru Hiroi, Ana B. Martín, Oscar Ortiz, Rosario MoratallaAbstract:Abstract Background Studies have shown that neuroleptics regulate expression of the transcription factor FOSB/ΔFOSB in the striatum, including the accumbens and caudate-putamen; however, the striatum is also divided into another structural dimension, the striosome and matrix compartments. The precise distribution of FOSB/ΔFOSB induced by chronic neuroleptics in these striatal compartments is poorly understood. Methods Rats received either single acute injections or chronic injections of clozapine (0 or 20 mg/kg, intraperitoneally [IP]), olanzapine (0 or 5 mg/kg, IP), or haloperidol (0 or 1.5 mg/kg, IP) for 25 days. The levels and compartmental distribution of FOSB/ΔFOSB were examined. Results Chronic clozapine induced clustered FOSB/ΔFOSB expression within striosomes of the caudate-putamen. This pattern was due to increased levels of FOSB/ΔFOSB in striosomes within the ventrolateral caudate-putamen and reduced levels of basal FOSB/ΔFOSB in the matrix in the entire caudate-putamen. In contrast, chronic haloperidol increased FOSB/ΔFOSB equally within the matrix and striosomes throughout the entire caudate-putamen. Chronic olanzapine induced an intermediate pattern. Conclusions The relative absence of FOSB/ΔFOSB expression in the matrix correlates with the lack of parkinsonism of atypical neuroleptics. Expression of FOSB/ΔFOSB in the matrix may contribute to parkinsonism of typical neuroleptics.
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FOSB mutant mice loss of chronic cocaine induction of fos related proteins and heightened sensitivity to cocaine s psychomotor and rewarding effects
Proceedings of the National Academy of Sciences of the United States of America, 1997Co-Authors: Noboru Hiroi, Jennifer R Brown, Colin N Haile, Michael E Greenberg, Eric J. NestlerAbstract:Chronic exposure to cocaine leads to prominent, long-lasting changes in behavior that characterize a state of addiction. The striatum, including the nucleus accumbens and caudoputamen, is an important substrate for these actions. We previously have shown that long-lasting Fos-related proteins of 35–37 kDa are induced in the striatum by chronic cocaine administration. In the present study, the identity and functional role of these Fos-related proteins were examined using FOSB mutant mice. The striatum of these mice completely lacked basal levels of the 35- to 37-kDa Fos-related proteins as well as their induction by chronic cocaine administration. This deficiency was associated with enhanced behavioral responses to cocaine: FOSB mutant mice showed exaggerated locomotor activation in response to initial cocaine exposures as well as robust conditioned place preference to a lower dose of cocaine, compared with wild-type littermates. These results establish the long-lasting Fos-related proteins as products of the FOSB gene (specifically ΔFOSB isoforms) and suggest that transcriptional regulation by FOSB gene products plays a critical role in cocaine-induced behavioral responses. This finding demonstrates that a Fos family member protein plays a functional role in behavioral responses to drugs of abuse and implicates FOSB gene products as important determinants of cocaine abuse.
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Regulation of delta FOSB and FOSB-like proteins by electroconvulsive seizure and cocaine treatments.
Molecular pharmacology, 1995Co-Authors: Jingshan Chen, Noboru Hiroi, Yusaku Nakabeppu, Heather E. Nye, Max B. Kelz, Bruce T. Hope, Eric J. NestlerAbstract:Previous work has shown that c-Fos and several Fos-like proteins or Fras (Fos-related antigens) are induced acutely in brain in response to a wide variety of stimuli. In contrast, several stimuli induce apparently distinct Fos-like proteins, termed chronic Fras, after chronic administration. We show that delta FOSB, a truncated splice variant of FOSB, responds like the other acute Fras: it is induced rapidly and transiently in cerebral cortex after acute electroconvulsive seizure (ECS) and in striatum after acute cocaine but does not accumulate after chronic ECS or cocaine treatment. Although the chronic Fras are immunochemically related to delta FOSB, they can be distinguished from delta FOSB based on their temporal properties in that they are induced after chronic ECS and cocaine treatments only. Moreover, the chronic Fras and delta FOSB can be distinguished by their migration patterns on one- and two-dimensional gel electrophoresis. The chronic Fras, therefore, appear to be novel FOSB-related proteins. We also provide evidence that the chronic Fras heterodimerize primarily with Jun-D and Jun-B, as opposed to c-Jun. The possibility that AP-1 complexes containing the chronic Fras function as negative regulators of AP-1 mediated transcription is discussed.
Jyh-yih Chen - One of the best experts on this subject based on the ideXlab platform.
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FOSB pcdhb13 axis disrupts the microtubule network in non small cell lung cancer
Cancers, 2019Co-Authors: Chen-hung Ting, Yi-chun Chen, Jyh-yih Chen, Kang Yun Lee, Po Hao Feng, Yao Fei ChanAbstract:Non-small cell lung cancer (NSCLC) is among the leading causes of human mortality. One reason for high rates of NSCLC mortality is that drug resistance is a major problem for both conventional chemotherapies and less-toxic targeted therapies. Thus, novel mechanistic insights into disease pathogenesis may benefit the development of urgently needed therapies. Here we show that FBJ murine osteosarcoma viral oncogene homolog B (FOSB) was induced by an antimicrobial peptide, tilapia piscidin-4 (TP4), through the dysregulation of mitochondrial Ca2+ homeostasis in NSCLC cells. Transcriptomic, chromatin immunoprecipitation quantitative PCR, and immunocytochemical studies reveal that protocadherin-β13 (PCDHB13) as a target of FOSB that was functionally associated with microtubule. Overexpression of either PCDHB13 or FOSB attenuated NSCLC growth and survival in vitro and in vivo. Importantly, downregulation of both FOSB and PCDHB13 was observed in NSCLC patients and was negatively correlated with pathological grade. These findings introduce the FOSB–PCDHB13 axis as a novel tumor suppressive pathway in NSCLC.
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FOSB–PCDHB13 Axis Disrupts the Microtubule Network in Non-Small Cell Lung Cancer
MDPI AG, 2019Co-Authors: Chen-hung Ting, Yi-chun Chen, Kang Yun Lee, Po Hao Feng, Yao Fei Chan, Jyh-yih ChenAbstract:Non-small cell lung cancer (NSCLC) is among the leading causes of human mortality. One reason for high rates of NSCLC mortality is that drug resistance is a major problem for both conventional chemotherapies and less-toxic targeted therapies. Thus, novel mechanistic insights into disease pathogenesis may benefit the development of urgently needed therapies. Here we show that FBJ murine osteosarcoma viral oncogene homolog B (FOSB) was induced by an antimicrobial peptide, tilapia piscidin-4 (TP4), through the dysregulation of mitochondrial Ca2+ homeostasis in NSCLC cells. Transcriptomic, chromatin immunoprecipitation quantitative PCR, and immunocytochemical studies reveal that protocadherin-β13 (PCDHB13) as a target of FOSB that was functionally associated with microtubule. Overexpression of either PCDHB13 or FOSB attenuated NSCLC growth and survival in vitro and in vivo. Importantly, downregulation of both FOSB and PCDHB13 was observed in NSCLC patients and was negatively correlated with pathological grade. These findings introduce the FOSB–PCDHB13 axis as a novel tumor suppressive pathway in NSCLC
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Targeting FOSB with a cationic antimicrobial peptide, TP4, for treatment of triple-negative breast cancer.
Oncotarget, 2016Co-Authors: Chen-hung Ting, Yi-chun Chen, Jyh-yih ChenAbstract:// Chen-Hung Ting 1 , Yi-Chun Chen 1 , Chang-Jer Wu 2 , Jyh-Yih Chen 1 1 Marine Research Station, Institute of Cellular and Organismic Biology, Academia Sinica, Jiaushi, Ilan 262, Taiwan 2 Department of Food Science, National Taiwan Ocean University, Keelung 202, Taiwan Correspondence to: Jyh-Yih Chen, email: zoocjy@gate.sinica.edu.tw Keywords: TP4, cationic antimicrobial peptide, triple-negative breast cancer, calcium, FOSB Received: February 12, 2016 Accepted: May 02, 2016 Published: May 26, 2016 ABSTRACT Triple-negative breast cancer (TNBC) currently lacks a suitable therapeutic candidate and is thus difficult to treat. Here, we report that a cationic antimicrobial peptide (CAP), tilapia piscidin 4 (TP4), which was derived from Nile tilapia ( Oreochromis niloticus ), is selectively toxic to TNBC. TP4 acts by inducing an AP-1 protein called FOSB, the expression of which is negatively associated with the pathological grade of TNBC. We show that TP4 is bound to the mitochondria where it disrupts calcium homeostasis and activates FOSB. FOSB overexpression results in TNBC cell death, whereas inhibition of calcium signaling eliminates FOSB induction and blocks TP4-induced TNBC cell death. Both TP4 and anthracyclines strongly induced FOSB, particularly in TNBC, indicating that FOSB may be suitable as a biomarker of drug responses. This study thus provides a novel therapeutic approach toward TNBC through FOSB induction.
Jennifer R Brown - One of the best experts on this subject based on the ideXlab platform.
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fos family members induce cell cycle entry by activating cyclin d1
Molecular and Cellular Biology, 1998Co-Authors: Jennifer R Brown, Elizabeth A Nigh, Richard J Lee, Margaret A Thompson, Frederic Saudou, Richard G PestellAbstract:Expression of the fos family of transcription factors is stimulated by growth factors that induce quiescent cells to reenter the cell cycle, but the cellular targets of the Fos family that regulate cell cycle reentry have not been identified. To address this issue, mice that lack two members of the fos family, c-fos and FOSB, were derived. The FOSB 2/2 c-fos 2/2 mice are similar in phenotype to c-fos 2/2 mice but are 30% smaller. This decrease in size is consistent with an abnormality in cell proliferation. Fibroblasts derived from FOSB 2/2 c-fos 2/2 mice were found to have a defect in proliferation that results at least in part from a failure to induce cyclin D1 following serum-stimulated cell cycle reentry. Although definitive evidence that c-Fos and FOSB directly induce cyclin D1 transcription will require further analysis, these findings raise the possibility that c-Fos and FOSB are either direct or indirect transcriptional regulators of the cyclin D1 gene and may function as a critical link between serum stimulation and cell cycle progression.
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FOSB mutant mice loss of chronic cocaine induction of fos related proteins and heightened sensitivity to cocaine s psychomotor and rewarding effects
Proceedings of the National Academy of Sciences of the United States of America, 1997Co-Authors: Noboru Hiroi, Jennifer R Brown, Colin N Haile, Michael E Greenberg, Eric J. NestlerAbstract:Chronic exposure to cocaine leads to prominent, long-lasting changes in behavior that characterize a state of addiction. The striatum, including the nucleus accumbens and caudoputamen, is an important substrate for these actions. We previously have shown that long-lasting Fos-related proteins of 35–37 kDa are induced in the striatum by chronic cocaine administration. In the present study, the identity and functional role of these Fos-related proteins were examined using FOSB mutant mice. The striatum of these mice completely lacked basal levels of the 35- to 37-kDa Fos-related proteins as well as their induction by chronic cocaine administration. This deficiency was associated with enhanced behavioral responses to cocaine: FOSB mutant mice showed exaggerated locomotor activation in response to initial cocaine exposures as well as robust conditioned place preference to a lower dose of cocaine, compared with wild-type littermates. These results establish the long-lasting Fos-related proteins as products of the FOSB gene (specifically ΔFOSB isoforms) and suggest that transcriptional regulation by FOSB gene products plays a critical role in cocaine-induced behavioral responses. This finding demonstrates that a Fos family member protein plays a functional role in behavioral responses to drugs of abuse and implicates FOSB gene products as important determinants of cocaine abuse.
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a defect in nurturing in mice lacking the immediate early gene FOSB
Cell, 1996Co-Authors: Jennifer R Brown, Michael E Greenberg, Roderick T Bronson, Pieter DikkesAbstract:Abstract Although expression of the Fos family of transcription factors is induced by environmental stimuli that trigger adaptive neuronal responses, eidence that Fos family members mediate these responses is lacking. To address this issue, mice were generated with an inactivating mutation in the FOSB gene. FOSB mutant mice are profoundly deficient in their ability to nurture young animals but are normal with respect to other cognitive and sensory functions. The nurturing defect is likely due to the absence of FOSB in the preoptic area, a region of the hypothalamus that is critical for nurturing. These observations suggest that a transcription factor controls a complex behavior by regulating a specific neuronal circuit and indicate that nurturing in mammals has a genetic component.