Dopaminergic (DA) neurons are involved in the integration of neuronal and hormonal signals to regulate food consumption and energy balance. Forkhead transcriptional factor O1 (FoxO1) in the hypothalamus plays a crucial role in mediation of leptin and insulin function. However, the homoeostatic role of FoxO1 in DA system has not been investigated.
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal parenchymal lung disease with limited therapeutic options, with fibroblast-to-myofibroblast transdifferentiation and hyperproliferation playing a major role. Investigating ex vivo-cultured (myo)fibroblasts from human IPF lungs as well as fibroblasts isolated from bleomycin-challenged mice, Forkhead box O3 (FoxO3) transcription factor was found to be less expressed, hyperphosphorylated, and nuclear-excluded relative to non-diseased controls.
More than half of human colorectal cancers (CRCs) carry either KRAS or BRAF mutations, and are often refractory to approved targeted therapies. We report that cultured CRC cells harboring KRAS or BRAF mutations are selectively killed when exposed to high levels of vitamin C.
Forkhead transcription factor family O (FoxO) maintains adult stem cell reserves by supporting their long-term proliferative potential. MicroRNAs (miRs) regulate neuronal stem/progenitor cell (NSPC) proliferation and differentiation during neural development by controlling the expression of a specific set of target genes. In the neurogenic subventricular zone, FoxO1 is specifically expressed in NSPCs and is no longer detected during the transition to neuroblast stage, forming an inverse correlation with miR-9 expression.
The differentiation of embryonic mesenchymal cells into chondrocytes and the subsequent formation of a cartilaginous scaffold that enables the formation of long bones are hallmarks of endochondral ossification. During this process, chondrocytes undergo a remarkable sequence of events involving proliferation, differentiation, hypertrophy and eventually apoptosis. Forkhead Box O (FoxO) transcription factors (TFs) are well-known regulators of such cellular processes. Although FoxO3a was previously shown to be regulated by 1,25-dihydroxyvitamin D3 in osteoblasts, a possible role for this family of TFs in chondrocytes during endochondral ossification remains largely unstudied.
REGULATION OF AUTOPHAGY AND THE UBIQUITIN-PROTEASOME SYSTEM BY THE FOXO TRANSCRIPTIONAL NETWORK DURING MUSCLE ATROPHY
Stresses like low nutrients, systemic inflammation, cancer or infections provoke a catabolic state characterized by enhanced muscle proteolysis and amino acid release to sustain liver gluconeogenesis and tissue protein synthesis. These conditions activate the family of Forkhead Box (Fox) O transcription factors. Here we report that muscle-specific deletion of FoxO members protects from muscle loss as a result of the role of FoxOs in the induction of autophagy-lysosome and ubiquitin-proteasome systems.
DEVELOPMENT OF RESISTANCE TO EGFR-TARGETED THERAPY IN MALIGNANT GLIOMA CAN OCCUR THROUGH EGFR-DEPENDENT AND -INDEPENDENT MECHANISMS
Epidermal growth factor receptor (EGFR) is highly amplified, mutated, and overexpressed in human malignant gliomas. Despite its prevalence and growth-promoting functions, therapeutic strategies to inhibit EGFR kinase activity have not been translated into profound beneficial effects in glioma clinical trials. To determine the roles of oncogenic EGFR signaling in gliomagenesis and tumor maintenance, we generated a novel glioma mouse model driven by inducible expression of a mutant EGFR (EGFR*).
METABOLIC CIRCUITS IN NEURAL STEM CELLS
Metabolic activity indicative of cellular demand is emerging as a key player in cell fate decision. Numerous studies have demonstrated that diverse metabolic pathways have a critical role in the control of the proliferation, differentiation and quiescence of stem cells.
PROLYL HYDROXYLATION BY EGLN2 DESTABILIZES FOXO3A BY BLOCKING ITS INTERACTION WITH THE USP9X DEUBIQUITINASE
The three EglN prolyl hydroxylases (EglN1, EglN2, and EglN3) regulate the stability of the HIF transcription factor. We recently showed that loss of EglN2, however, also leads to down-regulation of Cyclin D1 and decreased cell proliferation in a HIF-independent manner. Here we report that EglN2 can hydroxylate FOXO3a on two specific prolyl residues in vitro and in vivo.
FOXO3 COORDINATES METABOLIC PATHWAYS TO MAINTAIN REDOX BALANCE IN NEURAL STEM CELLS
Forkhead Box O (FoxO) transcription factors act in adult stem cells to preserve their regenerative potential. Previously, we reported that FoxO maintains the long-term proliferative capacity of neural stem/progenitor cells (NPCs), and that this occurs, in part, through the maintenance of redox homeostasis. Herein, we demonstrate that among the FoxO3-regulated genes in NPCs are a host of enzymes in central carbon metabolism that act to combat reactive oxygen species (ROS) by directing the flow of glucose and glutamine carbon into defined metabolic pathways.
ZNF365 PROMOTES STALLED REPLICATION FORKS RECOVERY TO MAINTAIN GENOME STABILITY
The ZNF365 locus is associated with breast cancer risk in carriers of mutated BRCA1 and BRCA2, which are important molecules required for DNA damage response.
ZNF365 PROMOTES STABILITY OF FRAGILE SITES AND TELOMERES
Critically short telomeres activate cellular senescence or apoptosis, as mediated by the tumor suppressor p53, but in the absence of this checkpoint response, telomere dysfunction engenders chromosomal aberrations and cancer. Here, analysis of p53-regulated genes activated in the setting of telomere dysfunction identified Zfp365(ZNF365 in humans) as a direct p53 target that promotes genome stability.
FOXOS IN NEURAL STEM CELL FATE DECISION
Neural stem cells (NSCs) persist over the lifespan of mammals to give rise to committed progenitors and their differentiated cells in order to maintain the brain homeostasis. To this end, NSCs must be able to self-renew and otherwise maintain their quiescence. Suppression of aberrant proliferation or undesired differentiation is crucial to preclude either malignant growth or precocious depletion of NSCs. The PI3K-Akt-FoxO signaling pathway plays a central role in the regulation of multiple stem cells including one in the mammalian brain.
FOXO FAMILY MEMBERS IN CANCER
The PI3K-Akt-FoxO signaling pathway plays a central role in diverse physiological processes including cellular energy storage, growth, and survival, among others. As an important effector of this pathway, FoxO is involved in versatile activities that protect organisms from stress and aging. Recent studies on mammalian FoxO have established a direct role for this transcription factor family in cellular proliferation, oxidative stress response, and tumorigenesis. The review will focus on the recent developments pertaining to the function of FoxO as well as discuss the various contexts in which FoxO exerts distinct biological activity such as drug resistance and autophagy in cancer pathogenesis and therapy.
The transcription factor family FOXO and FOXO3a in particular is of central importance in the long-term maintenance of haematopoietic stem cell (HSC) quiescence, cell number, reactive oxygen species (ROS) scavenging and long-term repopulation potential. ROS scavengers such as n-acetyl-l-cysteine (NAC) are able to rescue FOXO deficient HSCs from some of these abnormalities.
Neurodegeneration resulting in cognitive and motor impairment is an inevitable consequence of aging. Little is known about the genetic regulation of this process despite its overriding importance in normal aging. Here, we identify the Forkhead Box O (FOXO) transcription factor 1, 3, and 4 isoforms as a guardian of neuronal integrity by inhibiting age-progressive axonal degeneration in mammals.
Nearly 3% of the human population carries bi-allelic loss-of-function variants in the gene encoding CLYBL. While largely healthy, these individuals exhibit reduced circulating vitamin B12 levels. In this issue of Cell, Shen and colleagues uncover the metabolic role of CLYBL, linking its function to B12 metabolism and the immunomodulatory metabolite, itaconate.
Loss of a cell’s ability to terminally differentiate because of mutations is a selected genetic event in tumorigenesis. Genomic analyses of low-grade glioma have reported recurrent mutations of far upstream element-binding protein 1 (FUBP1). Here we show that FUBP1 expression is dynamically regulated during neurogenesis and its downregulation in neural progenitors impairs terminal differentiation and promotes tumorigenesis collaboratively with expression of IDH1R132H.
THE PAIK LABORATORY- STEM CELL AGING AND CANCER
THE PAIK LABORATORY
STEM CELL AGING AND CANCER
The evolutionarily conserved FOXO family of transcription factors has emerged as a significant arbiter of neural cell fate and function in mammals. From the neural stem cell (NSC) state through mature neurons under both physiological and pathological conditions, they have been found to modulate neural cell survival, stress responses, lineage commitment, and neuronal signaling.