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      Forkhead Box Protein O1: Functional Diversity and Post-Translational Modification, a New Therapeutic Target?


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          Forkhead box protein O1 (FoXO1) is a transcription factor involved in the regulation of a wide variety of physiological process including glucose metabolism, lipogenesis, bone mass, apoptosis, and autophagy. FoXO1 dysfunction is involved in the pathophysiology of various diseases including metabolic diseases, atherosclerosis, and tumors. FoXO1 activity is regulated in response to different physiological or pathogenic conditions by changes in protein expression and post-translational modifications. Various modifications cooperate to regulate FoXO1 activity and FoXO1 target gene transcription. In this review, we summarize how different post-translational modifications regulate FoXO1 physiological function, which may provide new insights for drug design and development.

          Most cited references119

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          Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor.

          Survival factors can suppress apoptosis in a transcription-independent manner by activating the serine/ threonine kinase Akt, which then phosphorylates and inactivates components of the apoptotic machinery, including BAD and Caspase 9. In this study, we demonstrate that Akt also regulates the activity of FKHRL1, a member of the Forkhead family of transcription factors. In the presence of survival factors, Akt phosphorylates FKHRL1, leading to FKHRL1's association with 14-3-3 proteins and FKHRL1's retention in the cytoplasm. Survival factor withdrawal leads to FKHRL1 dephosphorylation, nuclear translocation, and target gene activation. Within the nucleus, FKHRL1 triggers apoptosis most likely by inducing the expression of genes that are critical for cell death, such as the Fas ligand gene.
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            Mammalian SIRT1 represses forkhead transcription factors.

            The NAD-dependent deacetylase SIR2 and the forkhead transcription factor DAF-16 regulate lifespan in model organisms, such as yeast and C. elegans. Here we show that the mammalian SIR2 ortholog SIRT1 deacetylates and represses the activity of the forkhead transcription factor Foxo3a and other mammalian forkhead factors. This regulation appears to be in the opposite direction from the genetic interaction of SIR2 with forkhead in C. elegans. By restraining mammalian forkhead proteins, SIRT1 also reduces forkhead-dependent apoptosis. The inhibition of forkhead activity by SIRT1 parallels the effect of this deacetylase on the tumor suppressor p53. We speculate how down-regulating these two classes of damage-responsive mammalian factors may favor long lifespan under certain environmental conditions, such as calorie restriction.
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              Protein O-GlcNAcylation: emerging mechanisms and functions

              Many cellular proteins are reversibly modified by O-linked N-acetylglucosamine (O-GlcNAc) moieties on Ser and Thr residues. Studies on the mechanisms and functions of O-GlcNAcylation and its links to metabolism reveal the importance of this modification in the maintenance of cellular and organismal homeostasis.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                03 May 2021
                : 15
                : 1851-1860
                [1 ]Department of Cardiology, Shandong Rongjun General Hospital , Jinan, 250013, People’s Republic of China
                [2 ]Department of Emergency, Shandong Rongjun General Hospital , Jinan, 250013, People’s Republic of China
                [3 ]Blood Purification Center, Affiliated Hospital of Shandong University of Traditional Chinese Medicine , Jinan, 250011, People’s Republic of China
                Author notes
                Correspondence: Huimin Liu Blood Purification Center, Affiliated Hospital of Shandong University of Traditional Chinese Medicine , No. 42, Wenhua West Road, Lixia District, Jinan, 250011, Shandong Province, People’s Republic of ChinaTel +86 531 6861 7808 Email hans4@126.com
                © 2021 Zhang et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                : 02 February 2021
                : 19 April 2021
                Page count
                Figures: 2, Tables: 2, References: 119, Pages: 10

                Pharmacology & Pharmaceutical medicine
                forkhead box protein o1,post-translational modification,transcription


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