BBA - Molecular Cell Research (v.1813, #11)

PI3K-AKT-FoxO axis in cancer and aging by Guri Tzivion; Nissim Hay (1925).

The PKB/FOXO switch in aging and cancer by David E.A. Kloet; Boudewijn M.T. Burgering (1926-1937).
Aging is characterized by the general decline in tissue and body function and the increased susceptibility to age-related pathologies, such as cancer. To maintain optimal tissue and body function, organisms have developed complex mechanisms for tissue homeostasis. Importantly, it is becoming apparent that these same mechanisms when deregulated also result in the development of age-related disease. The build in failsafe mechanisms of homeostasis, which prevent skewing toward disease, themselves contribute to aspects of aging. Thus, longevity is limited by an intrinsic trade-off between optimal tissue function and disease. Consequently, aging and age-related diseases, such as cancer and diabetes are driven by the same genetic determinants. Illustrative in this respect is the insulin/IGF-1 signaling pathway acting through PI3K/PKB and FOXO. Loss of PKB signaling contributes to diabetes, whereas gain of function of PKB drives cancer. Enhanced FOXO activity, at least in model organism contributes to extended lifespan and acts as a tumor suppressive mechanism. Here, we focus on the linkage between PKB and FOXO as a central switch in contributing to tissue homeostasis and age-related diseases in particular cancer. This article is part of a Special Issue entitled: P13K-AKT-FoxO axis in cancer and aging.►PKB and FOXO regulate cell turnover and cell renewal in an antagonistic manner. ►PKB controls FOXO, but during stress FOXO controls PKB. ►c-MYC and FOXO regulate tumorigenesis in an antagonistic manner.
Keywords: PKB; FOXO; Aging; Cancer; Cell and tissue homeostasis;

FoxO transcription factors; Regulation by AKT and 14-3-3 proteins by Guri Tzivion; Melissa Dobson; Gopalakrishnan Ramakrishnan (1938-1945).
The forkhead box O (FoxO) transcription factor family is a key player in an evolutionary conserved pathway downstream of insulin and insulin-like growth factor receptors. The mammalian FoxO family consists of FoxO1, 3, 4 and 6, which share high similarity in their structure, function and regulation. FoxO proteins are involved in diverse cellular and physiological processes including cell proliferation, apoptosis, reactive oxygen species (ROS) response, longevity, cancer and regulation of cell cycle and metabolism. The regulation of FoxO protein function involves an intricate network of posttranslational modifications and protein–protein interactions that provide integrated cellular response to changing physiological conditions and cues. AKT was identified in early genetic and biochemical studies as a main regulator of FoxO function in diverse organisms. Though other FoxO regulatory pathways and mechanisms have been delineated since, AKT remains a key regulator of the pathway. The present review summarizes the current knowledge of FoxO regulation by AKT and 14-3-3 proteins, focusing on its mechanistic and structural aspects and discusses its crosstalk with the other FoxO regulatory mechanisms. This article is part of a Special Issue entitled: PI3K–AKT–FoxO axis in cancer and aging.► FoxO regulation by AKT and 14-3-3. ► Cross Talk relationships in FoxO regulation. ► Acetylation, ubiquitination and phosphorylation in FoxO regulation.
Keywords: AKT; 14-3-3; FoxO; FKHR; FKHRL1; Forkhead transcription factors;

Structural basis for DNA recognition by FOXO proteins by Tomas Obsil; Veronika Obsilova (1946-1953).
The FOXO forkhead transcription factors are involved in metabolism control, cell survival, cellular proliferation, DNA damage repair response, and stress resistance. Their transcriptional activity is regulated through a number of posttranslational modifications, including phosphorylation, acetylation and ubiquitination. The recently determined three-dimensional structures of FOXO forkhead domains bound to DNA enable to explain the structural basis for DNA recognition by FOXO proteins and its regulation. The aim of this review is to summarize the recent structural characterization of FOXO proteins, the mechanisms of DNA recognition and the role of posttranslational modifications in the regulation of FOXO DNA-binding properties. This article is part of a Special Issue entitled: PI3K-AKT-FOXO axis in cancer and aging.Display Omitted►Summary of the recent structural characterization of FOXO proteins. ►The mechanisms of DNA recognition by FOXO proteins. ►The regulation of FOXO DNA-binding properties.
Keywords: Forkhead; FOXO; DNA; Structure; DNA recognition;

Regulation of FoxO transcription factors by acetylation and protein–protein interactions by Hiroaki Daitoku; Jun-ichi Sakamaki; Akiyoshi Fukamizu (1954-1960).
The forkhead box O transcription factors convert a variety of external stimuli, including growth factors, nutrients, and oxidative stress, into diverse biological responses through modulation of specific gene expression. Forkhead box O regulation is principally achieved by two distinct mechanisms: post-translational modifications and protein–protein interactions. Among several modifications of forkhead box O factors, we focus on reversible acetylation, describing past research and current advances. In the latter part of this review, we also provide an overview of forkhead box O-binding partners that control the transcriptional activity of forkhead box O factors. These two layers of regulation mostly overlap and thereby enable a more precise fine-tuning of forkhead box O functions involved in metabolism, longevity, and tumor suppression. This article is part of a Special Issue entitled: PI3K–AKT–FoxO axis in cancer and aging.► FoxO transcription factors convert environmental changes into biological responses. ► They are regulated by post-translational modifications and protein–protein interactions. ► Here we focus on reversible acetylation, describing past research and current advances. ► We also overview FoxO-binding partners that control the activity of FoxO factors.
Keywords: FoxO; Acetylation; Protein–protein interactions;

Forkhead box O-class (FOXO) proteins are evolutionally conserved transcription factors. They belong to a family of proteins consisting of FOXO1, FOXO3a, FOXO4 and FOXO6 in humans. Increasing evidence suggests that FOXO proteins function as tumor suppressors by transcriptionally regulating expression of genes involved in cell cycle arrest, apoptosis, DNA repair and oxidative stress resistance. Activation of various protein kinases, including Akt, IκB kinase (IKK) and ERK, leads to phosphorylation of FOXO proteins and their ubiquitination mediated by E3 ligases such as SKP2 and MDM2 in human primary tumors and cancer cell lines. As a result, the tumor suppressor functions of FOXO proteins are either diminished or abrogated due to their ubiquitination–proteasome degradation, thereby favoring cell transformation, proliferation and survival. Thus, ubiquitination and proteasome degradation of FOXO proteins play an important role in tumorigenesis and represent a viable target for cancer treatment. This article is part of a Special Issue entitled: PI3K–AKT–FoxO axis in cancer and aging.► Akt activation promotes FOXO protein degradation. ► SKP2 works in concert with Akt to induce FOXO1 ubiquitination and proteasome degradation. ► Regulation of SKP2-mediated ubiquitination and proteasome degradation of FOXO1 by other pathways. ► FOXO proteins undergo monoubiquitination and deubiquitination. ► Proteasome degradation of FOXO proteins plays a role in cell transformation and tumorigenesis
Keywords: FOXO; Forkhead; Ubiquitination; Proteasome; Tumor suppressor; Tumorigenesis;

Interplay between FOXO, TOR, and Akt by Nissim Hay (1965-1970).
FOXO transcription factors have emerged as rheostats that coordinate the activities of Akt and targets of rapamycin complexes (TORCs). This review summarizes the regulatory circuits mediated by the activation of FOXO, which in turn modulate Akt and TORCs activities. The biological significance of these regulatory circuits is discussed in this article. This article is part of a Special Issue entitled: P13K-AKT-FoxO axis in cancer and aging.► The interactions between FOXO, Akt, and TOR in mammals, fly, and worms. ► FOXO maintains cellular energy homeostasis by coordinating Akt and mTORC1 activities. ► Implications of the FOXO, Akt, and mTORC1 interactions for aging and cancer.
Keywords: FOXO; AKT; TOR; Sestrin; AMPK; Aging; Cancer;

CNK1 and other scaffolds for Akt/FoxO signaling by Rafael D. Fritz; Gerald Radziwill (1971-1977).
FoxO transcription factors mediate anti-proliferative and pro-apoptotic signals and act as tumor suppressors in cancer. Posttranslational modifications including phosphorylation and acetylation regulate FoxO activity by a cytoplasmic–nuclear shuttle mechanism. Scaffold proteins coordinating signaling pathways in time and space play a critical role in this process. CNK1 acts as a scaffold protein in several signaling pathways controlling the function of FoxO proteins. An understanding of CNK1 and other scaffolds in the FoxO signaling network will provide insights how to release the tumor suppressor function of FoxO as a possibility to block oncogenic pathways. This article is part of a Special Issue entitled: P13K-AKT-FoxO axis in cancer and aging.► Scaffold proteins regulate the function of FoxO. ► The scaffold CNK1 controls cytoplasmic sequestration of FoxO. ► Overexpressed FoxO counteracts oncogenic function of CNK1.
Keywords: Posttranslational modification; Proliferation; Scaffold; Signaling; Tumorigenesis;

Akt, FoxO and regulation of apoptosis by Xinbo Zhang; Naimei Tang; Timothy J. Hadden; Arun K. Rishi (1978-1986).
Forkhead box O (FoxO) transcription factors are downstream targets of the serine/threonine protein kinase B (PKB)/Akt. The Akt kinase regulates processes of cellular proliferation and survival. Phosphorylation of FoxOs by Akt inhibits transcriptional functions of FoxOs and contributes to cell survival, growth and proliferation. Emerging evidence suggests involvement of FoxOs in diverse intracellular signaling pathways with critical roles in a number of physiological as well as pathological conditions including cancer. The FoxO signaling is regulated by their interactions with other intracellular proteins as well as their post-translational modifications such as phosphorylation. FoxOs promote cell growth inhibitory and/or apoptosis signaling by either inducing expression of multiple pro-apoptotic members of the Bcl2-family of mitochondria-targeting proteins, stimulating expression of death receptor ligands such as Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), or enhancing levels of various cyclin-dependent kinase inhibitors (CDKIs). Coupled with their ability to cross-talk with p53, FoxOs represent an important class of tumor suppressors in a variety of cancers. This review summarizes our current understanding of mechanisms by which Akt and FoxOs regulate cell growth and survival that in turn offers opportunities for development of novel strategies to combat cancer. This article is part of a Special Issue entitled: P13K-AKT-FOxO axis in cancer and aging.► Akt and FoxOs regulate cell growth and survival. ► FoxOs are involved in regulating nutrient metabolism by insulin-Akt axis. ► FoxOs regulate cell cycle and apoptosis signaling. ► FoxO-Akt axis is a target for tumor suppression.
Keywords: PKB/Akt; FoxO; Tumor suppression;