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      Role of Forkhead Transcription Factors in Diabetes-Induced Oxidative Stress

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      Experimental Diabetes Research
      Hindawi Publishing Corporation

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          Abstract

          Diabetes is a chronic metabolic disorder, characterized by hyperglycemia resulting from insulin deficiency and/or insulin resistance. Recent evidence suggests that high levels of reactive oxygen species (ROS) and subsequent oxidative stress are key contributors in the development of diabetic complications. The FOXO family of forkhead transcription factors including FOXO1, FOXO3, FOXO4, and FOXO6 play important roles in the regulation of many cellular and biological processes and are critical regulators of cellular oxidative stress response pathways. FOXO1 transcription factors can affect a number of different tissues including liver, retina, bone, and cell types ranging from hepatocytes to microvascular endothelial cells and pericytes to osteoblasts. They are induced by oxidative stress and contribute to ROS-induced cell damage and apoptosis. In this paper, we discuss the role of FOXO transcription factors in mediating oxidative stress-induced cellular response.

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          Most cited references45

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          The emerging roles of forkhead box (Fox) proteins in cancer.

          Forkhead box (Fox) proteins are a superfamily of evolutionarily conserved transcriptional regulators, which control a wide spectrum of biological processes. As a consequence, a loss or gain of Fox function can alter cell fate and promote tumorigenesis as well as cancer progression. Here we discuss the evidence that the deregulation of Fox family transcription factors has a crucial role in the development and progression of cancer, and evaluate the emerging role of Fox proteins as direct and indirect targets for therapeutic intervention, as well as biomarkers for predicting and monitoring treatment responses.
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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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              AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1.

              The Forkhead transcription factors AFX, FKHR and FKHR-L1 are orthologues of DAF-16, a Forkhead factor that regulates longevity in Caenorhabditis elegans. Here we show that overexpression of these Forkhead transcription factors causes growth suppression in a variety of cell lines, including a Ras-transformed cell line and a cell line lacking the tumour suppressor PTEN. Expression of AFX blocks cell-cycle progression at phase G1, independent of functional retinoblastoma protein (pRb) but dependent on the cell-cycle inhibitor p27kip1. Indeed, AFX transcriptionally activates p27kip1, resulting in increased protein levels. We conclude that AFX-like proteins are involved in cell-cycle regulation and that inactivation of these proteins is an important step in oncogenic transformation.
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                Author and article information

                Journal
                Exp Diabetes Res
                EDR
                Experimental Diabetes Research
                Hindawi Publishing Corporation
                1687-5214
                1687-5303
                2012
                31 January 2012
                : 2012
                : 939751
                Affiliations
                School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104-6030, USA
                Author notes

                Academic Editor: Robert A. Harris

                Article
                10.1155/2012/939751
                3290826
                22454632
                da646394-3485-45f0-aa3a-91d0981a8538
                Copyright © 2012 Bhaskar Ponugoti et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 6 September 2011
                : 11 October 2011
                : 26 October 2011
                Categories
                Review Article

                Endocrinology & Diabetes
                Endocrinology & Diabetes

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