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General Nutritional Considerations for Chronic Hyperglycemia—Type 2 Diabetes
Published in Robert Fried, Richard M. Carlton, Type 2 Diabetes, 2018
Robert Fried, Richard M. Carlton
Glucose production is activated by a transcriptional switch called CRTC2, which is normally outside the nucleus awaiting the signal to slip inside and perform its function. Once in the nucleus, CRTC2 links up with another protein, CREB, and together, they activate the genes necessary to increase glucose output.
Role of glucocorticoid negative feedback in the regulation of HPA axis pulsatility
Published in Stress, 2018
Julia K Gjerstad, Stafford L Lightman, Francesca Spiga
As we have previously discussed, the activity of pCREB at the CRH promoter depends on the binding to its co-regulators CRTC, in particular to CRTC2. Under un-stimulated conditions, phosphorylated CRTC2 is located in cytosol, but upon stimulation, CRTC2 dephosphorylates and translocates to the nucleus to enhance CREB transcriptional activity (Katoh et al., 2004; Screaton et al., 2004). In a recent study, Jeanneteau and colleagues suggest that phosphorylation and nuclear localization of hypothalamic CRTC2 can be modulated by GR signaling, via a calmodulin-mediated mechanism. Indeed, they have shown that both exposure to stress and administration of the synthetic glucocorticoid dexamethasone (DEX) enhance phosphorylation of CRTC2 in mice (Jeanneteau et al., 2012). In addition to its regulation of CRH transcription, there is evidence that CORT can regulate CRH translational activity and CRH mRNA stability (Ma et al., 2001).
Current and emerging gluconeogenesis inhibitors for the treatment of Type 2 diabetes
Published in Expert Opinion on Pharmacotherapy, 2021
Gluconeogenesis is triggered by PI3K with release of phosphatidylinositol-3,4,5-triphosphate (PIP3), which leads to activation of the three isoforms of AKT/PKB (Protein kinase B/PKB by PDK (phosphoinositide-dependent protein kinase) [45]. In addition to gene knockout, the use of gene knockdown with antisense RNA has contributed to detailed explanation of the roles of a host of transcription factors in the pathways of suppression and promotion of gluconeogenesis) [41]. There are four major targets of Protein kinase B: (a) forkhead box protein 01 (FOX01) (b), peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α) (c), glycogen synthase kinase 1β (GSK3β) and (d) salt-inducible kinase 2 (SIK2) [41]. FOXO1 and PGC1α are transcription activators of the key gluconeogenic hormones. GSK3β inactivates glycogen synthase. Active FOXO1 enters the nucleus and binds the transcriptional coactivator peroxisome proliferator activated receptor-γ coactivator 1-α (PGC1α) stimulating expression of glucose-6-phosphatase (G6pc) and phosphoenolpyruvate carboxykinase (PEPCK). In addition, FOXO1 binds the co-repressor SIN3A to decrease expression of glucokinase. These gluconeogenic effects are inhibited by protein kinase B phosphorylation of FOXO1 which prevents entry into the nucleus thus suppressing transcription of these enzymes. Similarly, protein kinase B phosphorylation of SIK2 inhibits the cAMP responsive element (CRE)-binding protein (CREB)/cAMP-regulated transcriptional co-activator 2 (CRTC2) pathway. The enzymes affected by insulin, the metabolic hormones, and the genomic activators and suppressors are potential targets for pharmacotherapy.
14-3-3 proteins at the crossroads of neurodevelopment and schizophrenia
Published in The World Journal of Biological Psychiatry, 2022
André S. L. M. Antunes, Verônica M. Saia-Cereda, Fernanda Crunfli, Daniel Martins-de-Souza
The plethora of processes regulated by these well-known 14-3-3 interaction partners highlight the pivotal role of this protein family in health and disease states. Notable interaction partners are AKT, LRRK2 and YAP1, described in gene ontology (GO) terms as involved in neurogenesis, a process directly linked to schizophrenia-like endophenotypes and 14-3-3 abnormal expression (Toyo-Oka et al. 2014). Furthermore, AKT, LRRK2 and TP3 light up for the GO terms ‘autophagy’ and ‘regulation of macroautophagy’, processes well-known to be involved in the pathology of schizophrenia (Merenlender-Wagner et al. 2015). Autophagy is the catabolic pathway that controls recycling of cellular components and is crucial for homeostasis maintenance. This process is also essential for oligodendrocyte development and myelination (Bankston et al. 2019) and both the autophagy pathway as well as oligodendrocytes have gained increased attention as potential therapeutic targets for several diseases, including schizophrenia (Ktistakis and Tooze 2016; Gouvêa-Junqueira et al. 2020). 14-3-3 proteins have been previously described as regulators of autophagy via Raptor and ULK1 binding (Gwinn et al. 2008; Lee et al. 2010) in the PI3K/AKT/mTOR pathway (reviewed in Pozuelo-Rubio 2012). Furthermore, the transcriptional co-activator CRTC2, which is involved in hepatic lipid metabolism and appears connected to AKT, has been previously reported as a transcriptional regulator of autophagy (Seok et al. 2014). One notable protein is ABL1, a secondary node linked to 14-3-3 proteins via TP53, CDKN1B and YAP1 and lights up in String for the GO terms ‘neurogenesis’, ‘autophagy’ and ‘regulation of cytoskeleton organization’.