The emerging role of FOXO transcription factors in pancreatic β cells

Abstract

FOXO transcription factors critically control fundamental cellular processes, including metabolism, cell differentiation, cell cycle arrest, DNA repair, and other reactions to cellular stress. FOXO factors sense the balance between stimuli promoting growth and differentiation versus stress stimuli signaling damage. Integrated through the FOXO system, these divergent stimuli decide on cell fate, a choice between proliferation, differentiation, or apoptosis. In pancreatic b cells, most recent evidence highlights complex FOXOdependent responses to glucose, insulin, or other growth factors, which include regulatory feedback. In the short term, FOXO-dependent mechanisms help b cells to accomplish their endocrine function, and may increase their resistance to oxidative stress due to transient hyperglycemia. In the long term, FOXO-dependent responses lead to the adaptation of b cell mass, conditioning the future ability of the organism to produce insulin and cope with changes in fuel abundance. FOXO emerges as a key factor for the maintenance of a functional endocrine pancreas and represents an interesting element in the development of therapeutic approaches to treat diabetes. This review on the role of FOXO transcription factors in pancreatic b cells has three parts. In Part I, FOXO transcription factors will be presented in general: structure, molecular mechanisms of regulation, cellular functions, and physiological roles. Part II will focus on specific data about FOXO factors in pancreatic b cells. Lastly in Part III, it will be attempted to combine general and b cell-specific knowledge with the aim to envisage globally the role of FOXO factors in b cell-linked physiology and disease. The DNA-binding domain (Forkhead box) is located in the N-terminal portion of these proteins, while the transactivation domain is located in the C-terminal portion. Furthermore, a 'nuclear export sequence' and a 'nuclear localization signal' have been delineated. These motifs allow FOXO factors to shuttle in and out of the nucleus (see below). FOXO proteins may be post-translationally modified by phosphorylation and/or acetylation at differentially conserved serine/threonine and lysine residues respectively. Structural features of FOXO proteins have been detailed in recent reviews (Barthel et al. 2005, Greer & Brunet 2005. Molecular regulation of FOXO transcription factorsAs illustrated in Fig. 1, multiple molecular mechanisms regulate FOXO transcription factor functions. Some control subcellular FOXO localization, while others modulate FOXO transactivation properties. Furthermore, FOXO factor abundance is regulated by site-specific protein cleavage or through the control of foxo gene expression.Subcellular localization FOXO factors shuttle between nucleus and cytoplasm. This represents a major event controlling FOXO activity that results from changes in FOXO phosphorylation. Two main classes of stimuli trigger FOXO phosphorylation with opposing effects on FOXO localization.

Forkhead box O1 mediates defects in palmitate-induced insulin granule exocytosis by downregulation of calcium/calmodulin-dependent serine protein kinase expression in INS-1 cells

“…Activation of FOXO1 is necessary for fatty-acid-induced apoptosis in pancreatic beta cells, while the inhibition of FOXO1 can effectively protect islet beta cells from the toxic effects of fatty acids [10,11]. Previously, we used palmitate-treated MIN6 cells as a model of apoptosis, and chromatin immunoprecipitation (ChIP) coupled to a DNA selection and ligation technology to identify 189 genes to which the FOXO1 protein bound [12].…”

The WNT signalling pathway and diabetes mellitus

“…It has been demonstrated that small interfering RNA (siRNA)-mediated knockdown of FOXO reverted the loss of β-cat binding to TCF after cellular oxidative stress [90]. The production and function of FOXO proteins in the pancreatic beta cells have been extensively investigated during the past few years [91]. It will be interesting to examine whether insulin and growth Fig.…”

“…Insulin/growth factors (GFs) help to restore the balance by two means. First, they stimulate the nuclear exclusion of FOXOs via phosphorylation mediated by PKB/serum-and glucocorticoid-inducible kinase (SGK) [81,82,91]. Second, they enhance the nuclear content of β-cat and the binding of β-cat/TCF to the WNT target gene promoters via a yet to be identified PKB-independent mechanism [13] factors control the balance between FOXO-mediated and WNT-mediated gene transcription (see below).…”

Un nouveau mode de régulation de FoxO1 par O-glycosylation

“…Il faut en outre rappeler que l'hyperglycémie chronique a également des effets délétères au niveau pancréatique, en diminuant la survie et en augmentant l'apoptose des cellules β du pancréas. Dans la mesure où FoxO1 joue un rôle central dans les mécanismes de mort cellulaire [7], en particulier dans la cellule β-pancréatique [8], une augmentation de son activité transcriptionnelle par O-glycosylation pourrait aussi expliquer certains effets toxiques du glucose sur la fonction pancréatique (Figure 2). …”