ATF4 (activating transcription factor 4)

From Longevity Wiki

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.[1][2][3][4][5][6]

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.[7] 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.[8]

ATF-4 is hypothesized to mediate the lifespan extension effects of mTORC1 inhibition (target of rapamycin) and of translation inhibition.[9] 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).[10] ATF-4 additionally regulates stress responses in mitochondria, up-regulating cytoprotective genes.[11]

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.[12][13] The encoded protein was isolated and characterized as the cAMP-response element binding protein 2 (CREB-2).[14] 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.[15]

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).[16][17][18] In particular, treatment with ISRIB, an ISR inhibitor, reduced the induction of ATF4 and several of its target genes.[19][20]

Prolonged or intense stimulation of the ISR can result in ATF4-driven expression of pro-apoptotic effectors to induce cell death.[21]

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. [22]

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.[22] ATF4 regulates hypoxia inducible factor 1α in chronic hypoxia in pancreatic cancer cells.[23] Additionally, inhibition of ATF4 expression reduces cell migration, invasion, and proliferation in breast cancer.[24]

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.[25] 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.[26][27][28]

ATF4 also plays a critical role in the maintenance of survival and anti-tumor activities of CD8+ T cells,[29] and is required for the IFN-γ production by Th1 cells, particularly when T cells are in the higher oxidizing environment.[30] 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.[31]

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.[32] ATF4 is involved in vascular injury through the activation of a signaling pathway involving PERK, eIF2α and CHOP, key molecules in endoplasmic reticulum stress.[33][34]

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.[35][33] ISRIB treatment could ameliorate VC pathogenesis via blocking the elevation of ATF4 phosphorylation in the calcified aorta.[36]

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.[37][38]

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.[15] 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.[39] 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).[40][41] 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.[42][43][15]

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.[44]

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.[45] 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.[44]

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,[46] DNA repair,[47] and cell survival.[48] 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.[47] It has been proposed that GADD45A mediates passive DNA demethylation via interaction with the catalytic domain of DNA (cytosine-5)-methyltransferase 1 (DNMT1).[49]

Gadd45a might promote epigenetic gene activation by repair-mediated DNA demethylation.[50] 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−/−).[51] 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.[52] 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.[53]

Gadd45a can interact with key cell regulators such as p21,[54] 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.[55][56]

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.[57][58] 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.[46][59] FOXO proteins (such as FOXO1), enhance the promoter activity of target genes in cooperation with C/EBPδ and ATF4,[60] and regulate longevity regulation pathways via promoting the expression of Gadd45a, Sod2, and Cat.[61]

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.[62]

Medications that could be used to preserve muscle mass during catabolic situations

Tomatidine

Tomatidine has been identified as a natural compound that inhibits skeletal muscle atrophy in mice via a system-based discovery strategy.[63] It has been found that by inhibiting ATF4 tomatidine can reduce age-related skeletal muscle weakness and atrophy.[43] 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.[64] 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.[64]

Ursolic acid

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.[65][43]

References

  1. ↑ Li, W., & Miller, R. A. (2015). Elevated ATF4 function in fibroblasts and liver of slow-aging mutant mice. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences, 70(3), 263-272. PMID: 24691093 PMC4351389 DOI: 10.1093/gerona/glu040
  2. ↑ Li, W., Li, X., & Miller, R. A. (2014). ATF 4 activity: a common feature shared by many kinds of slow‐aging mice. Aging cell, 13(6), 1012-1018. PMID: 25156122 PMC4326926 DOI: 10.1111/acel.12264
  3. ↑ Statzer, C., Meng, J., Venz, R., Bland, M., Robida-Stubbs, S., Patel, K., ... & Ewald, C. Y. (2022). ATF-4 and hydrogen sulfide signalling mediate longevity in response to inhibition of translation or mTORC1. Nature communications, 13(1), 1-15. PMID: 35181679 PMC8857226 DOI: 10.1038/s41467-022-28599-9
  4. ↑ McIntyre, R. L., Molenaars, M., Schomakers, B. V., Gao, A. W., Kamble, R., Jongejan, A., ... & Janssens, G. E. (2023). Anti-retroviral treatment with zidovudine alters pyrimidine metabolism, reduces translation, and extends healthy longevity via ATF-4. Cell Reports, 42(1), 111928. PMID: 36640360 DOI: 10.1016/j.celrep.2022.111928
  5. ↑ Robbins, C. E., Patel, B., Sawyer, D. L., Wilkinson, B., Kennedy, B. K., & McCormick, M. A. (2022). Cytosolic and mitochondrial tRNA synthetase inhibitors increase lifespan in a GCN4/atf-4-dependent manner. Iscience, 25(11), 105410. PMID: 36388960 PMC9647507 DOI: 10.1016/j.isci.2022.105410
  6. ↑ Mittal, N., Guimaraes, J. C., Gross, T., Schmidt, A., Vina-Vilaseca, A., Nedialkova, D. D., ... & Zavolan, M. (2017). The Gcn4 transcription factor reduces protein synthesis capacity and extends yeast lifespan. Nature communications, 8(1), 1-12. PMID: 28878244 PMC5587724 DOI: 10.1038/s41467-017-00539-y
  7. ↑ Srinivasan, R., Walvekar, A. S., Rashida, Z., Seshasayee, A., & Laxman, S. (2020). Genome-scale reconstruction of Gcn4/ATF4 networks driving a growth program. PLoS Genetics, 16(12), e1009252. PMID: 33378328 PMC7773203 DOI: 10.1371/journal.pgen.1009252
  8. ↑ Wortel, I. M., van der Meer, L. T., Kilberg, M. S., & van Leeuwen, F. N. (2017). Surviving stress: modulation of ATF4-mediated stress responses in normal and malignant cells. Trends in Endocrinology & Metabolism, 28(11), 794-806.PMID: 28797581 PMC5951684 DOI: 10.1016/j.tem.2017.07.003
  9. ↑ Statzer, C., Meng, J., Venz, R. et al. ATF-4 and hydrogen sulfide signalling mediate longevity in response to inhibition of translation or mTORC1. Nat Commun 13, 967 (2022). https://doi.org/10.1038/s41467-022-28599-9
  10. ↑ Statzer, C., Meng, J., Venz, R. et al. ATF-4 and hydrogen sulfide signalling mediate longevity in response to inhibition of translation or mTORC1. Nat Commun 13, 967 (2022). https://doi.org/10.1038/s41467-022-28599-9
  11. ↑ Quirós, P. M., Prado, M. A., Zamboni, N., D’Amico, D., Williams, R. W., Finley, D., ... & Auwerx, J. (2017). Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals. Journal of Cell Biology, 216(7), 2027-2045.
  12. ↑ Ameri, K., & Harris, A. L. (2008). Activating transcription factor 4. The international journal of biochemistry & cell biology, 40(1), 14-21. PMID: 17466566 DOI: 10.1016/j.biocel.2007.01.020
  13. ↑ Hai, T., & Curran, T. (1991). Cross-family dimerization of transcription factors Fos/Jun and ATF/CREB alters DNA binding specificity. Proceedings of the national academy of sciences, 88(9), 3720-3724. PMID: 1827203 PMC51524 DOI: 10.1073/pnas.88.9.3720
  14. ↑ Karpinski, B. A., Morle, G. D., Huggenvik, J., Uhler, M. D., & Leiden, J. M. (1992). Molecular cloning of human CREB-2: an ATF/CREB transcription factor that can negatively regulate transcription from the cAMP response element. Proceedings of the National Academy of Sciences, 89(11), 4820-4824. PMID: 1534408 PMC49179 DOI: 10.1073/pnas.89.11.4820
  15. ↑ 15.0 15.1 15.2 Ebert, S. M., Rasmussen, B. B., Judge, A. R., Judge, S. M., Larsson, L., Wek, R. C., ... & Adams, C. M. (2022). Biology of activating transcription factor 4 (ATF4) and its role in skeletal muscle atrophy. The Journal of Nutrition, 152(4), 926-938. PMID:34958390 PMC8970988 DOI:10.1093/jn/nxab440
  16. ↑ Costa-Mattioli, M., & Walter, P. (2020). The integrated stress response: From mechanism to disease. Science, 368(6489), eaat5314. PMID: 32327570 PMC8997189 DOI: 10.1126/science.aat5314
  17. ↑ Harding, H. P., Novoa, I., Zhang, Y., Zeng, H., Wek, R., Schapira, M., & Ron, D. (2000). Regulated translation initiation controls stress-induced gene expression in mammalian cells. Molecular cell, 6(5), 1099-1108. PMID: 11106749 DOI: 10.1016/s1097-2765(00)00108-8
  18. ↑ Kalinin, A., Zubkova, E., & Menshikov, M. (2023). Integrated Stress Response (ISR) Pathway: Unraveling Its Role in Cellular Senescence. International Journal of Molecular Sciences, 24(24), 17423. PMID: 38139251 PMC10743681 DOI: 10.3390/ijms242417423
  19. ↑ Quirós, P. M., Prado, M. A., Zamboni, N., D’Amico, D., Williams, R. W., Finley, D., ... & Auwerx, J. (2017). Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals. Journal of Cell Biology, 216(7), 2027-2045. PMID: 28566324 PMC5496626 DOI: 10.1083/jcb.201702058
  20. ↑ Sasaki, K., Uchiumi, T., Toshima, T., Yagi, M., Do, Y., Hirai, H., ... & Kang, D. (2020). Mitochondrial translation inhibition triggers ATF4 activation, leading to integrated stress response but not to mitochondrial unfolded protein response. Bioscience reports, 40(11). PMID: 33165592 PMC7685009 DOI: 10.1042/BSR20201289
  21. ↑ Nwosu, G. O., Powell, J. A., & Pitson, S. M. (2022). Targeting the integrated stress response in hematologic malignancies. Experimental Hematology & Oncology, 11(1), 1-15. PMID: 36348393 PMC9644628 DOI: 10.1186/s40164-022-00348-0
  22. ↑ 22.0 22.1 Chee, N. T., Carriere, C. H., Miller, Z., Welford, S., & Brothers, S. P. (2023). Activating transcription factor 4 regulates hypoxia inducible factor 1α in chronic hypoxia in pancreatic cancer cells. Oncology Reports, 49(1), 1-14. PMID: 36416348 PMC9713860 DOI: 10.3892/or.2022.8451
  23. ↑ Chee, N. T., Carriere, C. H., Miller, Z., Welford, S., & Brothers, S. P. (2023). Activating transcription factor 4 regulates hypoxia inducible factor 1α in chronic hypoxia in pancreatic cancer cells. Oncology Reports, 49(1), 1-14.
  24. ↑ González-González, A., Muñoz-Muela, E., Marchal, J. A., Cara, F. E., Molina, M. P., Cruz-Lozano, M., ... & Granados-Principal, S. (2018). Activating Transcription Factor 4 Modulates TGFβ-Induced Aggressiveness in Triple-Negative Breast Cancer via SMAD2/3/4 and mTORC2 SignalingATF4, Biomarker, and Target in Triple-Negative Breast Cancer. Clinical Cancer Research, 24(22), 5697-5709. PMID: 30012564 DOI: 10.1158/1078-0432.CCR-17-3125
  25. ↑ Simpson, C. D., Anyiwe, K., & Schimmer, A. D. (2008). Anoikis resistance and tumor metastasis. Cancer letters, 272(2), 177-185.
  26. ↑ Mo, H., Guan, J., Mo, L., He, J., Wu, Z., Lin, X., ... & Yuan, Z. (2018). ATF4 regulated by MYC has an important function in anoikis resistance in human osteosarcoma cells. Molecular Medicine Reports, 17(3), 3658-3666. PMID: 29257326 PMC5802171 DOI: 10.3892/mmr.2017.8296
  27. ↑ Dey, S., Sayers, C. M., Verginadis, I. I., Lehman, S. L., Cheng, Y., Cerniglia, G. J., ... & Koumenis, C. (2015). ATF4-dependent induction of heme oxygenase 1 prevents anoikis and promotes metastasis. The Journal of clinical investigation, 125(7), 2592-2608. PMID: 26011642 PMC4563676 DOI: 10.1172/JCI78031
  28. ↑ Yu, Y., Liu, B., Li, X., Lu, D., Yang, L., Chen, L., ... & Xing, Y. (2022). ATF4/CEMIP/PKCα promotes anoikis resistance by enhancing protective autophagy in prostate cancer cells. Cell death & disease, 13(1), 1-13. PMID: 35013120 PMC8748688 DOI: 10.1038/s41419-021-04494-x
  29. ↑ Lu, Z., Bae, E. A., Verginadis, I. I., Zhang, H., Cho, C., McBrearty, N., ... & Fuchs, S. Y. (2022). Induction of the activating transcription factor-4 in the intratumoral CD8+ T cells sustains their viability and anti-tumor activities. Cancer Immunology, Immunotherapy, 1-12. PMID: 36063172 DOI: 10.1007/s00262-022-03286-2
  30. ↑ Yang, X., Xia, R., Yue, C., Zhai, W., Du, W., Yang, Q., ... & Lu, B. (2018). ATF4 regulates CD4+ T cell immune responses through metabolic reprogramming. Cell reports, 23(6), 1754-1766. PMID: 29742431 PMC6051420 DOI: 10.1016/j.celrep.2018.04.032
  31. ↑ Hsu, Y. J., Yin, Y. J., Tsai, K. F., Jian, C. C., Liang, Z. W., Hsu, C. Y., & Wang, C. C. (2022). TGFBR3 supports anoikis through suppressing ATF4 signaling. Journal of Cell Science, 135(17), jcs258396. PMID: 35912788 DOI: 10.1242/jcs.258396
  32. ↑ Malabanan, K. P., & Khachigian, L. M. (2010). Activation transcription factor-4 and the acute vascular response to injury. Journal of molecular medicine, 88(6), 545-552. PMID: 20306012 DOI: 10.1007/s00109-010-0615-4
  33. ↑ 33.0 33.1 Masuda, M., Miyazaki‐Anzai, S., Levi, M., Ting, T. C., & Miyazaki, M. (2013). PERK‐eIF2α‐ATF4‐CHOP signaling Contributes to TNF α‐Induced vascular Calcification. Journal of the American Heart Association, 2(5), e000238. PMID: 24008080 PMC3835225 DOI: 10.1161/JAHA.113.000238
  34. ↑ Chin, M. T. (2008). ATF-4 and vascular injury: integration of growth factor signaling and the cellular stress response. Circulation research, 103(4), 331-333. PMID: 18703783 PMC2747631 DOI: 10.1161/CIRCRESAHA.108.182246
  35. ↑ Duan, X. H., Chang, J. R., Zhang, J., Zhang, B. H., Li, Y. L., Teng, X., ... & Qi, Y. F. (2013). Activating transcription factor 4 is involved in endoplasmic reticulum stress-mediated apoptosis contributing to vascular calcification. Apoptosis, 18(9), 1132-1144. PMID: 23686245 DOI: 10.1007/s10495-013-0861-3
  36. ↑ Dong, J., Jin, S., Guo, J., Yang, R., Tian, D., Xue, H., ... & Wu, Y. (2022). Pharmacological Inhibition of eIF2α Phosphorylation by Integrated Stress Response Inhibitor (ISRIB) Ameliorates Vascular Calcification in Rats. Physiological Research, 71(3), 379-388. PMID: 35616039 PMC9470096 DOI: 10.33549/physiolres.934797
  37. ↑ Md Nesran, Z. N., Shafie, N. H., Ishak, A. H., Mohd Esa, N., Ismail, A., & Md Tohid, S. F. (2019). Induction of endoplasmic reticulum stress pathway by green tea epigallocatechin-3-gallate (EGCG) in colorectal cancer cells: activation of PERK/p-eIF2α/ATF4 and IRE1α. BioMed research international, 2019. PMID: 31930117 PMC6942794 DOI: 10.1155/2019/3480569
  38. ↑ Zhou, L., He, J. N., Du, L., Ho, B. M., Ng, D. S. C., Chan, P. P., ... & Chu, W. K. (2022). Epigallocatechin-3-Gallate Protects Trabecular Meshwork Cells from Endoplasmic Reticulum Stress. Oxidative Medicine and Cellular Longevity, 2022. PMID: 36406768 PMC9671731 DOI: 10.1155/2022/7435754
  39. ↑ Miller, M. J., Marcotte, G. R., Basisty, N., Wehrfritz, C., Ryan, Z. C., Strub, M. D., ... & Adams, C. M. (2023). The transcription regulator ATF4 is a mediator of skeletal muscle aging. GeroScience, 1-19. PMID: 37014538 PMC10071239 DOI: 10.1007/s11357-023-00772-y
  40. ↑ Ebert, S. M., Dyle, M. C., Kunkel, S. D., Bullard, S. A., Bongers, K. S., Fox, D. K., ... & Adams, C. M. (2012). Stress-induced skeletal muscle Gadd45a expression reprograms myonuclei and causes muscle atrophy. Journal of Biological Chemistry, 287(33), 27290-27301. PMID: 22692209 PMC3431665 DOI: 10.1074/jbc.M112.374777
  41. ↑ Adams, C. M., Ebert, S. M., & Dyle, M. C. (2017). Role of ATF4 in skeletal muscle atrophy. Current Opinion in Clinical Nutrition & Metabolic Care, 20(3), 164-168. PMID: 28376050 DOI: 10.1097/MCO.0000000000000362
  42. ↑ Ebert, S. M., Bullard, S. A., Basisty, N., Marcotte, G. R., Skopec, Z. P., Dierdorff, J. M., ... & Adams, C. M. (2020). Activating transcription factor 4 (ATF4) promotes skeletal muscle atrophy by forming a heterodimer with the transcriptional regulator C/EBPβ. Journal of Biological Chemistry, 295(9), 2787-2803. PMID: 31953319 PMC7049960 DOI: 10.1074/jbc.RA119.012095
  43. ↑ 43.0 43.1 43.2 Ebert, S. M., Dyle, M. C., Bullard, S. A., Dierdorff, J. M., Murry, D. J., Fox, D. K., ... & Adams, C. M. (2015). Identification and small molecule inhibition of an activating transcription factor 4 (ATF4)-dependent pathway to age-related skeletal muscle weakness and atrophy. Journal of Biological Chemistry, 290(42), 25497-25511. PMID: 26338703 PMC4646196 DOI: 10.1074/jbc.M115.681445
  44. ↑ 44.0 44.1 Cussonneau, L., Coudy-Gandilhon, C., Deval, C., Chaouki, G., Djelloul-Mazouz, M., Delorme, Y., ... & Combaret, L. (2023). Induction of ATF4-Regulated Atrogenes Is Uncoupled from Muscle Atrophy during Disuse in Halofuginone-Treated Mice and in Hibernating Brown Bears. Int. J. Mol. Sci. 24(1), 621; PMID: 36614063 PMC9820832 DOI: 10.3390/ijms24010621
  45. ↑ Bodanovsky, A., Guttman, N., Barzilai-Tutsch, H., Genin, O., Levy, O., Pines, M., & Halevy, O. (2014). Halofuginone improves muscle-cell survival in muscular dystrophies. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research, 1843(7), 1339-1347. PMID: 24703880 DOI: 10.1016/j.bbamcr.2014.03.025
  46. ↑ 46.0 46.1 Humayun, A., & Fornace Jr, A. J. (2022). GADD45 in stress signaling, cell cycle control, and apoptosis. In Gadd45 Stress Sensor Genes (pp. 1-22). Cham: Springer International Publishing. PMID: 35505159 DOI: 10.1007/978-3-030-94804-7_1
  47. ↑ 47.0 47.1 Chandramouly, G. (2022). Gadd45 in DNA Demethylation and DNA Repair. In Gadd45 Stress Sensor Genes (pp. 55-67). Springer, Cham. PMID: 35505162 DOI: 10.1007/978-3-030-94804-7_4
  48. ↑ Wang, Y., Gao, H., Cao, X., Li, Z., Kuang, Y., Ji, Y., & Li, Y. (2022). Role of GADD45A in myocardial ischemia/reperfusion through mediation of the JNK/p38 MAPK and STAT3/VEGF pathways. International Journal of Molecular Medicine, 50(6), 1-11. PMID: 36331027 PMC9662138 DOI: 10.3892/ijmm.2022.5200
  49. ↑ Lee, B., Morano, A., Porcellini, A., & Muller, M. T. (2012). GADD45α inhibition of DNMT1 dependent DNA methylation during homology directed DNA repair. Nucleic acids research, 40(6), 2481-2493. PMID: 22135303 PMC3315326 DOI: 10.1093/nar/gkr1115
  50. ↑ Barreto, G., Schäfer, A., Marhold, J., Stach, D., Swaminathan, S. K., Handa, V., ... & Niehrs, C. (2007). Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethylation. nature, 445(7128), 671-675. PMID: 17268471 DOI: 10.1038/nature05515
  51. ↑ Diao, D., Wang, H., Li, T., Shi, Z., Jin, X., Sperka, T., ... & Ju, Z. (2018). Telomeric epigenetic response mediated by Gadd45a regulates stem cell aging and lifespan. EMBO reports, 19(10), e45494. PMID: 30126922 PMC6172461 DOI: 10.15252/embr.201745494
  52. ↑ Arab, K., Karaulanov, E., Musheev, M., Trnka, P., Schäfer, A., Grummt, I., & Niehrs, C. (2019). GADD45A binds R-loops and recruits TET1 to CpG island promoters. Nature genetics, 51(2), 217-223. PMID: 30617255 PMC6420098 DOI: 10.1038/s41588-018-0306-6
  53. ↑ Higham, J., Kerr, L., Zhang, Q., Walker, R. M., Harris, S. E., Howard, D. M., ... & Sproul, D. (2022). Local CpG density affects the trajectory and variance of age-associated DNA methylation changes. Genome Biology, 23(1), 1-28. PMID: 36253871 PMC9575273 DOI: 10.1186/s13059-022-02787-8
  54. ↑ Kearsey, J. M., Coates, P. J., Prescott, A. R., Warbrick, E., & Hall, P. A. (1995). Gadd45 is a nuclear cell cycle regulated protein which interacts with p21Cip1. Oncogene, 11(9), 1675-1683. PMID: 7478594
  55. ↑ Bulavin, D. V., Kovalsky, O., Hollander, M. C., & Fornace Jr, A. J. (2003). Loss of oncogenic H-ras-induced cell cycle arrest and p38 mitogen-activated protein kinase activation by disruption of Gadd45a. Molecular and cellular biology, 23(11), 3859-3871. PMID: 12748288 PMC155214 DOI: 10.1128/MCB.23.11.3859-3871.2003
  56. ↑ Tront, J. S., Huang, Y., Fornace, A. A., Hoffman, B., & Liebermann, D. A. (2010). Gadd45a Functions as a Promoter or Suppressor of Breast Cancer Dependent on the Oncogenic StressGadd45a in Breast Tumorigenesis. Cancer research, 70(23), 9671-9681. PMID: 21098706 PMC3199142 DOI: 10.1158/0008-5472.CAN-10-2177
  57. ↑ Magimaidas, A., Madireddi, P., Maifrede, S., Mukherjee, K., Hoffman, B., & Liebermann, D. A. (2016). Gadd45b deficiency promotes premature senescence and skin aging. Oncotarget, 7(19), 26935. PMID: 27105496 PMC5053623 DOI: 10.18632/oncotarget.8854
  58. ↑ Zaidi, M. R., & Liebermann, D. A. (2022). Gadd45 in Senescence. In Gadd45 Stress Sensor Genes (pp. 109-116). Springer, Cham. PMID: 35505166 DOI: 10.1007/978-3-030-94804-7_8
  59. ↑ Zhan, Q. (2005). Gadd45a, a p53-and BRCA1-regulated stress protein, in cellular response to DNA damage. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 569(1-2), 133-143. PMID: 15603758 DOI: 10.1016/j.mrfmmm.2004.06.055
  60. ↑ Oyabu, M., Takigawa, K., Mizutani, S., Hatazawa, Y., Fujita, M., Ohira, Y., ... & Kamei, Y. (2022). FOXO1 cooperates with C/EBPδ and ATF4 to regulate skeletal muscle atrophy transcriptional program during fasting. The FASEB Journal, 36(2), e22152. PMID: 35061305 DOI: 10.1096/fj.202101385RR
  61. ↑ Wu, Y., Wang, J., Zhao, T., Wei, Y., Han, L., Shen, L., ... & Wei, G. (2021). LncRNAs activate longevity regulation pathway due to aging of Leydig cells caused by DEHP exposure: A transcriptome-based study. Ecotoxicology and Environmental Safety, 209, 111798. PMID: 33360214 DOI: 10.1016/j.ecoenv.2020.111798
  62. ↑ Ji, J., Liu, R., Tong, T., Song, Y., Jin, S., Wu, M., & Zhan, Q. (2007). Gadd45a regulates β-catenin distribution and maintains cell–cell adhesion/contact. Oncogene, 26(44), 6396-6405. PMID: 17452974 DOI: 10.1038/sj.onc.1210469
  63. ↑ Dyle, M. C., Ebert, S. M., Cook, D. P., Kunkel, S. D., Fox, D. K., Bongers, K. S., ... & Adams, C. M. (2014). Systems-based discovery of tomatidine as a natural small molecule inhibitor of skeletal muscle atrophy. Journal of Biological Chemistry, 289(21), 14913-14924. PMID: 24719321 PMC4031541 DOI: 10.1074/jbc.M114.556241
  64. ↑ 64.0 64.1 Fang, E. F., Waltz, T. B., Kassahun, H., Lu, Q., Kerr, J. S., Morevati, M., ... & Becker, K. G. (2017). Tomatidine enhances lifespan and healthspan in C. elegans through mitophagy induction via the SKN-1/Nrf2 pathway. Scientific reports, 7(1), 1-13. PMID: 28397803 PMC5387417 DOI: 10.1038/srep46208
  65. ↑ Zolfaghari, M., Faramarzi, M., Hedayati, M., & Ghaffari, M. (2022). The effect of resistance and endurance training with ursolic acid on atrophy‐related biomarkers in muscle tissue of diabetic male rats induced by streptozotocin and a high‐fat diet. Journal of Food Biochemistry, 46(8), e14202. PMID: 35593021 DOI: 10.1111/jfbc.14202
Retrieved from ‘https://en.longevitywiki.org/index.php?title=ATF4_(activating_transcription_factor_4)&oldid=3387’
Creative Commons Attribution-ShareAlike
Powered by MediaWiki