Synaptic NMDAR activity suppresses FOXO1 expression via a cis-acting FOXO binding site: FOXO1 is a FOXO target gene

Al-Mubarak, Bashayer; Soriano, Francesc X.; Hardingham, Giles E.

doi:10.4161/chan.3.4.9381

Cited by 76 publications

(73 citation statements)

References 34 publications

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“…5C). Expression of the FOXO1 gene is itself transcriptionally regulated by FOXO3a (23,24), and FOXO1 expression was increased upon treatment with both compounds by gene expression microarray and confirmed at the protein level by Western blot analysis (Figs. 5C and 6B; Supplementary Table S5A and S5B).…”

Section: Gene Expression Microarray Analysismentioning

confidence: 84%

AT13148 Is a Novel, Oral Multi-AGC Kinase Inhibitor with Potent Pharmacodynamic and Antitumor Activity

Yap

Walton

Grimshaw

et al. 2012

Clinical Cancer Research

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Purpose: Deregulated phosphatidylinositol 3-kinase pathway signaling through AGC kinases including AKT, p70S6 kinase, PKA, SGK and Rho kinase is a key driver of multiple cancers. The simultaneous inhibition of multiple AGC kinases may increase antitumor activity and minimize clinical resistance compared with a single pathway component.Experimental Design: We investigated the detailed pharmacology and antitumor activity of the novel clinical drug candidate AT13148, an oral ATP-competitive multi-AGC kinase inhibitor. Gene expression microarray studies were undertaken to characterize the molecular mechanisms of action of AT13148.Results: AT13148 caused substantial blockade of AKT, p70S6K, PKA, ROCK, and SGK substrate phosphorylation and induced apoptosis in a concentration and time-dependent manner in cancer cells with clinically relevant genetic defects in vitro and in vivo. Antitumor efficacy in HER2-positive, PIK3CA-mutant BT474 breast, PTEN-deficient PC3 human prostate cancer, and PTEN-deficient MES-SA uterine tumor xenografts was shown. We show for the first time that induction of AKT phosphorylation at serine 473 by AT13148, as reported for other ATP-competitive inhibitors of AKT, is not a therapeutically relevant reactivation step. Gene expression studies showed that AT13148 has a predominant effect on apoptosis genes, whereas the selective AKT inhibitor CCT128930 modulates cell-cycle genes. Induction of upstream regulators including IRS2 and PIK3IP1 as a result of compensatory feedback loops was observed.Conclusions: The clinical candidate AT13148 is a novel oral multi-AGC kinase inhibitor with potent pharmacodynamic and antitumor activity, which shows a distinct mechanism of action from other AKT inhibitors. AT13148 will now be assessed in a first-in-human phase I trial.

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Section: Gene Expression Microarray Analysismentioning

confidence: 84%

AT13148 Is a Novel, Oral Multi-AGC Kinase Inhibitor with Potent Pharmacodynamic and Antitumor Activity

Yap

Walton

Grimshaw

et al. 2012

Clinical Cancer Research

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“…S-NMDAR activation also suppresses apoptotic signaling and increases antioxidant defenses. For example, activation of S-NMDARs suppresses forkhead box O (FOXO), a transcription factor involved in the regulation of oxidative stress and the modulation of genes involved in apoptosis [94].…”

Section: Synaptic Vs Extrasynaptic Nmdarsmentioning

confidence: 99%

The Role of the Tripartite Glutamatergic Synapse in the Pathophysiology of Alzheimer’s Disease

Rudy¹,

Hunsberger²,

Weitzner³

et al. 2015

Aging and disease

138

106

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Alzheimer's disease (AD) is the most common form of dementia in individuals over 65 years of age and is characterized by accumulation of beta-amyloid (Aβ) and tau. Both Aβ and tau alter synaptic plasticity, leading to synapse loss, neural network dysfunction, and eventually neuron loss. However, the exact mechanism by which these proteins cause neurodegeneration is still not clear. A growing body of evidence suggests perturbations in the glutamatergic tripartite synapse, comprised of a presynaptic terminal, a postsynaptic spine, and an astrocytic process, may underlie the pathogenic mechanisms of AD. Glutamate is the primary excitatory neurotransmitter in the brain and plays an important role in learning and memory, but alterations in glutamatergic signaling can lead to excitotoxicity. This review discusses the ways in which both beta-amyloid (Aβ) and tau act alone and in concert to perturb synaptic functioning of the tripartite synapse, including alterations in glutamate release, astrocytic uptake, and receptor signaling. Particular emphasis is given to the role of N-methyl-D-aspartate (NMDA) as a possible convergence point for Aβ and tau toxicity.

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“…Akt, when activated, phosphorylates two categories of downstream enzymes: the proapoptotic substrates, which are deactivated by phosphorylation, and the antiapoptotic substrates, which are activated by phosphorylation (14,32). Among its many actions, Akt activation leads to increased forkhead box O (FOXO) phosphorylation and promotes FOXO nuclear export, thereby inhibiting the capacity of FOXOs to upregulate proapoptotic genes (1). Stress signaling p38 has been implicated in apoptosis and inflammation (40) and has been shown to be involved in multiple models of cardioprotection against ischemia-reperfusion injury (2).…”

mentioning

confidence: 99%

Regulation of phosphatase and tensin homolog on chromosome 10 in response to hypoxia

Qian

Ling

Castillo

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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Phosphatase and tensin homolog on chromosome 10 (PTEN) is downregulated during hypertrophic and cancerous cell growth, leading to activation of the prosurvival Akt pathway. However, PTEN regulation in cardiac myocytes upon exposure to hypoxia remains unclear. We explored the role of PTEN in response to hypoxia/ischemia in the myocardium. We validated that PTEN is a transcriptional target of activating transcription factor 2 (ATF-2) and is positively regulated via a p38/ATF-2 signaling pathway. Accordingly, hypoxia-induced upregulation of phosphorylation of ATF-2 and PTEN were reversed by a dominant negative mutant p38. Inhibition of PTEN in cardiomyocytes attenuated hypoxiainduced cell death and apoptosis. Cardiac-specific knockout of PTEN resulted in increased phosphorylation of Akt and forkhead box O 1 (forkhead transcription factors), limited infarct size in animals exposed to ischemia-reperfusion injury, and ameliorated deterioration of left ventricular function and remodeling following permanent coronary artery occlusion. In addition, the activation of Bim, FASL, and caspase was coupled with PTEN activation, all of which were attenuated by PTEN inhibition. In conclusion, cardiomyocyte-specific conditional PTEN deletion limited myocardial infarct size in an in vivo model of ischemia-reperfusion injury and attenuated adverse remodeling in a model of chronic permanent coronary artery ligation. p38; activating transcription factor 2; Akt; forkhead box O 1; FAS ligand; ischemia; infarct size; reperfusion PHOSPHOINOSITIDE 3-KINASE (PI3K) phosphorylates phosphatidylinositol, producing phosphatidylinositol (3,4,5)-triphosphate (PIP3), which recruits and facilitates activation of Akt (14, 32). Phosphatase and tensin homolog on chromosome 10 (PTEN) is a dual protein-lipid phosphatase that degrades PIP3 to inactive phosphatidylinositol (4,5)-diphosphate (PIP2; Refs. 22,26,38,47) and so negatively regulates the PI3K/Akt prosurvival signaling pathway. Loss or mutation of PTEN, with subsequent uncontrolled activation of the prosurvival pathways, is common in many tumors, including endometrial carcinoma, melanoma, renal, breast, prostate, and lung cancer (6, 9, 23). Dysregulation of PTEN has also been reported in heart diseases such as cardiac hypotrophy, heart failure, and ischemic heart disease (37,46,55,58). We (18) have shown that pharmacological inhibition of PTEN protects the heart against ischemiareperfusion injury through upregulation of the PI3K/Akt/endothelial nitric oxide synthase/ERK prosurvival pathway. Overexpression of PTEN increases apoptosis in neonatal cardiomyocytes, whereas expression of inactive mutant PTEN leads to Akt activation and reduces apoptosis (42). Moreover, myocardial levels of PTEN are increased in diabetic rats compared with nondiabetic rats, leading to reduced ability to phosphorylate Akt and, hence, blunting the protective effects of ischemic preconditioning (31, 52). Only two studies (41, 46) have assessed the effect of genetic deletion of PTEN on myocardial infarct size, both in an is...

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Synaptic NMDAR activity suppresses FOXO1 expression via a cis-acting FOXO binding site: FOXO1 is a FOXO target gene

Cited by 76 publications

References 34 publications

AT13148 Is a Novel, Oral Multi-AGC Kinase Inhibitor with Potent Pharmacodynamic and Antitumor Activity

AT13148 Is a Novel, Oral Multi-AGC Kinase Inhibitor with Potent Pharmacodynamic and Antitumor Activity

The Role of the Tripartite Glutamatergic Synapse in the Pathophysiology of Alzheimer’s Disease

Regulation of phosphatase and tensin homolog on chromosome 10 in response to hypoxia

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