ATF4 (activating transcription factor 4)
Activating transcription factor 4 (ATF-4 or ATF4); also known as GCN4, is a multifunctional transcription regulatory protein which, according to a number of studies, regulates longevity through cooperation with certain longevity factors to enhance the activity of multiple mechanisms that protect cellular functions, thereby driving lifespan extension.
ATF4- is expressed in most mammalian cell types, and it can participate in a variety of cellular responses to specific environmental stresses, intracellular derangements, and growth factors. The context-dependent role of this transcriptional master-regulator varies across a spectrum of growth and starvation programs. Regardless of context, ATF-4/Gcn4 is required for amino acid biosynthesis (particularly lysine and arginine biosynthesis), and for repression of ribosomal genes. Through ATF4 networks, cells can couple translation with metabolism, and manage resource allocations to sustain anabolism.
ATF-4 is hypothesized to mediate the lifespan extension effects of mTORC1 inhibition (target of rapamycin) and of translation inhibition. In fact, mTORC1 inhibition requires ATF-4 activation, which promotes hydrogen sulphide production and cooperates with lifespan regulators FOXO, Heat-Shock Factor 1 (HSF-1) and Nuclear Receptor Factor 1 (NRF-1). ATF-4 additionally regulates stress responses in mitochondria, up-regulating cytoprotective genes.
Identification of ATF4
ATF4 was originally identified as a widely expressed mammalian DNA binding protein that could bind a tax-responsive enhancer element in the LTR of HTLV-1. The encoded protein was isolated and characterized as the cAMP-response element binding protein 2 (CREB-2). It should be noted that ATF4 is not a functional transcription factor by itself, but one-half of many possible heterodimeric transcription factors. Because ATF4 can simultaneously participate in multiple distinct heterodimers, the overall set of genes that require ATF4 for maximal expression in a specific context (ATF4-dependent genes) can be a mixture of genes that are regulated by different ATF4 heterodimers, with some ATF4-dependent genes activated by one ATF4 heterodimer and other ATF4-dependent genes activated by other ATF4 heterodimers.
ATF4 as the effector of the ISR
ATF4 is a basic leucine zipper (bZIP) transcription factor that is selectively translated in response to specific forms of cellular stress to induce the expression of genes involved in program of adaptation to stress, known as the integrated stress response (ISR). In particular, treatment with ISRIB, an ISR inhibitor, reduced the induction of ATF4 and several of its target genes.
Prolonged or intense stimulation of the ISR can result in ATF4-driven expression of pro-apoptotic effectors to induce cell death.
Role of ATF4 in the response to hypoxic stress
Hypoxia is a stress condition in which oxygen levels are insufficient for typical cellular functions, such as protein translation and folding. It has been shown that at upon hypoxic exposure, ATF4 expression significantly increases. For example, in acute hypoxia, the cultured cells exhibited a 2.3-fold increase in ATF4 protein expression, while in chronic hypoxia, ATF4 levels increased by 5.7-fold compared with normoxia. 
Role of ATF4 in cancer cells
ATF4 is frequently upregulated in cancer cells. As the tumor increases in size, cells in the tumor core are challenged by limited levels of oxygen, glucose, and amino acids, each of which triggers metabolic changes that tune anabolic and catabolic pathways towards the accumulation of biomass. ATF4 regulates hypoxia inducible factor 1α in chronic hypoxia in pancreatic cancer cells. Additionally, inhibition of ATF4 expression reduces cell migration, invasion, and proliferation in breast cancer.
ATF4 target genes have been found to be critical for cell growth and cancer progression. Their activation depends on the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) at Ser51. The eIF2α-ATF4 axis plays a critical role in amino acid metabolic reprogramming of cancer cells, especially when cells are in a stressful nutrient-scarce microenvironment. eIF2α-ATF4 maintains intracellular amino acid levels via multiple mechanisms.
Role of ATF4 in anoikis resistance
Anoikis is a specialized form of cell death (apoptosis) caused by loss of contact with the extracellular matrix (ECM) or inappropriate cell adhesion. Metastatic cancer cells have been shown to develop resistance to anoikis by activating several signaling pathways that impinge on extrinsic and mitochondria-mediated apoptosis. ATF4 plays a central role in mediating an antioxidant and proautophagic ISR that enables cancer cells to survive and migrate to secondary sites during tumor metastasis.
ATF4 also plays a critical role in the maintenance of survival and anti-tumor activities of CD8+ T cells, and is required for the IFN-γ production by Th1 cells, particularly when T cells are in the higher oxidizing environment. Therefore, care must be taken when using agents that can undermine these ATF4 functions for anticancer therapy.
The most widely expressed type of a cell-surface chondroitin sulfate/heparan sulfate proteoglycan is the Transforming Growth Factor Beta Receptor III (TGFBR3) which acts as an anoikis mediator through the inhibition of ATF4. Inhibition of TGFBR3 impairs epithelial anoikis by activating ATF4 signaling.
ATF4 in vascular injury
It has been shown that ATF4 up-regulation can induce vascular smooth muscle cells (VSMCs) to proliferate and ATF4 knockdown blocks injury-inducible intimal proliferation. ATF4 is involved in vascular injury through the activation of a signaling pathway involving PERK, eIF2α and CHOP, key molecules in endoplasmic reticulum stress.
Vascular calcification is essential risk factor for cardiovascular events. ATF4 was involved at least in part in the process of endoplasmic reticulum stress (ERS)-mediated apoptosis contributing to vascular calcification (VC) and ATF4 knockdown attenuated ERS-induced apoptosis in calcified vascular smooth muscle cells (VSMC)s. ISRIB treatment could ameliorate VC pathogenesis via blocking the elevation of ATF4 phosphorylation in the calcified aorta.
Treatment with epigallocatechin-3-gallate (EGCG), the most bioactive and abundant polyphenolic compound in green tea, can initiate proapoptotic signaling pathways via targeting endoplasmic reticulum (ER) stress, but later, due to subsequent ATF4 activation, it helps the remaining cells to survive.
Role of ATF4 in skeletal muscle weakness and atrophy
ATF4 induction by skeletal muscle stresses such as fasting, muscle immobilization, and muscle denervation, results in muscle wasting. ATF4 is an essential mediator of skeletal muscle aging. During skeletal muscle aging, ATF4 promotes induction of transcripts involved in inflammation, cellular senescence, and Rho GTPase signaling. During skeletal muscle aging, ATF4 promotes repression of transcripts involved in mitochondrial function, protein synthesis, and metabolism of amino acids, polyamines, glutathione, and nicotinamide. ATF4 promotes muscle atrophy by increasing the levels of specific mRNAs in skeletal muscle fibers, most notably Gadd45a (growth arrest and DNA damage-inducible 45 α). The Gadd45 gene encodes a ubiquitously expressed evolutionary conserved small, highly acidic proteins which do not have any known enzymatic activity, but nevertheless fulfill a plethora of different functions in the cell, mostly mediated via protein-protein interactions.
The induction of the ATF4 pathway can be dissociated from muscle atrophy. For example, hibernating bears (Ursidae family) are naturally resistant to muscle atrophy when facing two major atrophic inducers: prolonged fasting and physical inactivity. Fasting and physical inactivity in hibernating bears can last up to 5–7 months, however during this time Atf4 and ATF4-regulated Gadd45a are upregulated in skeletal muscle, compared to non-hibernating bears.
Halofuginone improves muscle functions during physical inactivity
Halofuginone, a racemic halogenated derivative of plant alkaloid febrifugine, is capable of reducing fibrosis and inflammation and improve muscle functions in muscular dystrophies. Halofuginone treatment has been shown to reproduced the muscle features of hibernating bears in gastrocnemius mice muscles with (I) the activation of ATF4-regulated atrogenes and (II) the concurrent inhibition of TGF-β signalling and promotion of BMP signalling, without resulting in muscle atrophy. These characteristics were associated with mitigated muscle atrophy during physical inactivity.
Gadd45a role in longevity
Gadd45a plays a pivotal role as a cellular stress sensor, by interacting with and modulating the function of proteins regulating cell cycle control, DNA repair, and cell survival. In particular, in the absence of Gadd45α, the amount of DNA breaks accumulates due to the reduced efficiency of repair, while Histone Deacetylase Inhibitors (HDIs) dependent induction of Gadd45α promotes DNA repair. It has been proposed that GADD45A mediates passive DNA demethylation via interaction with the catalytic domain of DNA (cytosine-5)-methyltransferase 1 (DNMT1).
Gadd45a might promote epigenetic gene activation by repair-mediated DNA demethylation. There is also evidence that GADD45a induces the demethylation of CpG islands that are dependent on base excision repair to produce a permissible chromatin state for DNA damage response (DDR), especially in the short telomere/subtelomere regions. Depletion of GADD45a promotes chromatin condensation in the subtelomere regions.
GADD45a knockout can improve the function of intestinal stem cells and extend the lifespan of telomerase-deficient mice (G3Terc−/−). Additionally, Gadd45a has been identified to be a RNA binding protein that can be recruited by an R-loop (RNA-DNA hybrid) formed on a CG-rich promoter region, which then guides the Tet enzyme for local DNA demethylation. Normally, CpG-rich regions have a relatively lower methylation rate, which correlates with gene activation, while gene-specific methylation on CpG normally induces gene silencing. This makes it possible to estimate age and the presence of age-related diseases, using a statistical method called the epigenetic clock, which is based on the strongly correlated with age specific set of methylated loci.
Gadd45a can interact with key cell regulators such as p21, cdc2/cyclinB1, proliferating cell nuclear antigen, p38, and MAP kinase kinase kinase (MEKK4). Primary mouse embryo fibroblasts (MEFs) are cells with limited lifespan, which undergo senescence in vitro due to stress and hyperoxic conditions which result in accumulation of DNA damage. However, loss of Gadd45a in MEFs results in escape from senescence in vitro in response to Ras-driven tumorigenesis.
Disruption of Gadd45a (Growth arrest and DNA-damage-inducible protein 45 alpha), a p53- and BRCA1-regulated stress-inducible gene, in mice results in genomic instability and increased carcinogenesis. Therefore, Gadd45a appears to be an important component in the cellular defense network that is required for maintenance of genomic stability. The Gadd45a gene also plays important roles in the control of cell cycle checkpoints, DNA repair and apoptosis. FOXO proteins (such as FOXO1), enhance the promoter activity of target genes in cooperation with C/EBPδ and ATF4, and regulate longevity regulation pathways via promoting the expression of Gadd45a, Sod2, and Cat.
Additionally, Gadd45a regulates beta-catenin distribution and maintains cell-cell adhesion/contact. Gadd45a is involved in the control of cell contact inhibition and cell-cell adhesion. Gadd45a can serve as an adapter to enhance the interaction between beta-catenin and Caveolin-1, and in turn induces beta-catenin translocation to cell membrane for maintaining cell-cell adhesion/contact inhibition.
Medications that could be used to preserve muscle mass during catabolic situations
Tomatidine has been identified as a natural compound that inhibits skeletal muscle atrophy in mice via a system-based discovery strategy. It has been found that by inhibiting ATF4 tomatidine can reduce age-related skeletal muscle weakness and atrophy. In C. elegans, tomatidine protects muscle function from age-related deterioration by activating the Nrf2/SKN-1-DCT-1 pathway and by up-regulating mitophagy and antioxidant cellular defences. The beneficial effects of tomatidine in counteracting age-related deterioration of muscle function in C. elegans are not the result of effects on muscle stem cells or immune cells, but instead, via the influence of either the muscle cells themselves, or the nervous system associated with muscle function, and therefore may be particularly relevant to processes occurring within skeletal muscle fibre cells in sarcopenia.
Ursolic acid is a natural pentacyclic triterpenoid carboxylic acid found in apples (a major compound of apple wax) and other fruits; it is known to improve skeletal muscle function and reduce the aging related muscular atrophy pathways possibly by the suppression of p53/ATF4/p21 signaling.
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