ATF4 (activating transcription factor 4) - Revision history

Dmitry Dzhagarov at 10:36, 21 September 2024

2024-09-21T10:36:24Z

← Older revision		Revision as of 10:36, 21 September 2024
Line 44:		Line 44:

	=== Gadd45a role in longevity ===		=== 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,<ref name="Sensor">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: [https://doi.org/10.1007/978-3-030-94804-7_1 10.1007/978-3-030-94804-7_1]</ref> DNA repair,<ref name="Demethylation">Chandramouly, G. (2022). Gadd45 in DNA Demethylation and DNA Repair. In Gadd45 Stress Sensor Genes (pp. 55-67). Springer, Cham. PMID: 35505162 DOI: [https://doi.org/10.1007/978-3-030-94804-7_4 10.1007/978-3-030-94804-7_4]</ref> and cell survival.<ref>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 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9662138 9662138] DOI: 10.3892/ijmm.2022.5200</ref> 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.<ref name="Demethylation"/> It has been proposed that GADD45A mediates passive DNA demethylation via interaction with the catalytic domain of DNA (cytosine-5)-methyltransferase 1 (DNMT1).<ref>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), [tel:2481-2493 2481-2493]. PMID: 22135303 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3315326 3315326] DOI: 10.1093/nar/gkr1115</ref>		Gadd45a plays a pivotal role as a '''cellular stress sensor''', by interacting with and modulating the function of proteins regulating cell cycle control,<ref name="Sensor">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: [https://doi.org/10.1007/978-3-030-94804-7_1 10.1007/978-3-030-94804-7_1]</ref> DNA repair,<ref name="Demethylation">Chandramouly, G. (2022). Gadd45 in DNA Demethylation and DNA Repair. In Gadd45 Stress Sensor Genes (pp. 55-67). Springer, Cham. PMID: 35505162 DOI: [https://doi.org/10.1007/978-3-030-94804-7_4 10.1007/978-3-030-94804-7_4]</ref> and cell survival.<ref>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 [[Role of JNK in aging\|JNK]]/p38 MAPK and STAT3/VEGF pathways. International Journal of Molecular Medicine, 50(6), 1-11. PMID: 36331027 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9662138 9662138] DOI: 10.3892/ijmm.2022.5200</ref> 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.<ref name="Demethylation"/> It has been proposed that GADD45A mediates passive DNA demethylation via interaction with the catalytic domain of DNA (cytosine-5)-methyltransferase 1 (DNMT1).<ref>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), [tel:2481-2493 2481-2493]. PMID: 22135303 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3315326 3315326] DOI: 10.1093/nar/gkr1115</ref>

	'''Gadd45a might promote epigenetic gene activation by repair-mediated DNA demethylation'''.<ref>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: [https://doi.org/10.1038/nature05515 10.1038/nature05515]</ref> 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 might promote epigenetic gene activation by repair-mediated DNA demethylation'''.<ref>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: [https://doi.org/10.1038/nature05515 10.1038/nature05515]</ref> 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.

Dmitry Dzhagarov: /* ATF4 as the effector of the ISR */

2023-12-29T15:21:51Z

ATF4 as the effector of the ISR

← Older revision		Revision as of 15:21, 29 December 2023
Line 8:		Line 8:
	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.<ref>Ameri, K., & Harris, A. L. (2008). Activating transcription factor 4. The international journal of biochemistry & cell biology, 40(1), 14-21. PMID: 17466566 DOI: [https://doi.org/10.1016/j.biocel.2007.01.020 10.1016/j.biocel.2007.01.020]</ref><ref>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), [tel:3720-3724 3720-3724]. PMID: 1827203 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC51524 51524] DOI: 10.1073/pnas.88.9.3720</ref> The encoded protein was isolated and characterized as the cAMP-response element binding protein 2 (CREB-2).<ref>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), [tel:4820-4824 4820-4824]. PMID: 1534408 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC49179 49179] DOI: 10.1073/pnas.89.11.4820</ref> 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.<ref name="atrophy">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 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8970988 8970988] DOI:10.1093/jn/nxab440</ref>		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.<ref>Ameri, K., & Harris, A. L. (2008). Activating transcription factor 4. The international journal of biochemistry & cell biology, 40(1), 14-21. PMID: 17466566 DOI: [https://doi.org/10.1016/j.biocel.2007.01.020 10.1016/j.biocel.2007.01.020]</ref><ref>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), [tel:3720-3724 3720-3724]. PMID: 1827203 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC51524 51524] DOI: 10.1073/pnas.88.9.3720</ref> The encoded protein was isolated and characterized as the cAMP-response element binding protein 2 (CREB-2).<ref>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), [tel:4820-4824 4820-4824]. PMID: 1534408 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC49179 49179] DOI: 10.1073/pnas.89.11.4820</ref> 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.<ref name="atrophy">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 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8970988 8970988] DOI:10.1093/jn/nxab440</ref>
	== ATF4 as the effector of the ISR ==		== 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)'''.<ref>Costa-Mattioli, M., & Walter, P. (2020). The integrated stress response: From mechanism to disease. Science, 368(6489), eaat5314. PMID: 32327570 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8997189 8997189] DOI: 10.1126/science.aat5314</ref><ref>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: [https://doi.org/10.1016/s1097-2765(00)00108-8 10.1016/s1097-2765(00)00108-8]</ref> In particular, treatment with ISRIB, an ISR inhibitor, reduced the induction of ATF4 and several of its target genes.<ref>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 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5496626 5496626] DOI: 10.1083/jcb.201702058</ref><ref>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 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685009 7685009] DOI: 10.1042/BSR20201289</ref>		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)'''.<ref>Costa-Mattioli, M., & Walter, P. (2020). The integrated stress response: From mechanism to disease. Science, 368(6489), eaat5314. PMID: 32327570 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8997189 8997189] DOI: 10.1126/science.aat5314</ref><ref>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: [https://doi.org/10.1016/s1097-2765(00)00108-8 10.1016/s1097-2765(00)00108-8]</ref><ref>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 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10743681/ PMC10743681] DOI: 10.3390/ijms242417423</ref> In particular, treatment with ISRIB, an ISR inhibitor, reduced the induction of ATF4 and several of its target genes.<ref>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 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5496626 5496626] DOI: 10.1083/jcb.201702058</ref><ref>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 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685009 7685009] DOI: 10.1042/BSR20201289</ref>

	Prolonged or intense stimulation of the ISR can result in ATF4-driven expression of pro-apoptotic effectors to induce cell death.<ref>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 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9644628 9644628] DOI: 10.1186/s40164-022-00348-0</ref>		Prolonged or intense stimulation of the ISR can result in ATF4-driven expression of pro-apoptotic effectors to induce cell death.<ref>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 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9644628 9644628] DOI: 10.1186/s40164-022-00348-0</ref>

	== Role of ATF4 in the response to hypoxic stress ==		== Role of ATF4 in the response to hypoxic stress ==

Andrea at 01:13, 16 August 2023

2023-08-16T01:13:30Z

← Older revision		Revision as of 01:13, 16 August 2023
Line 3:		Line 3:
	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.<ref>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 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773203 7773203] DOI: 10.1371/journal.pgen.1009252</ref> 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.<ref>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 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951684 5951684] DOI: 10.1016/j.tem.2017.07.003</ref>		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.<ref>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 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773203 7773203] DOI: 10.1371/journal.pgen.1009252</ref> 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.<ref>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 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951684 5951684] DOI: 10.1016/j.tem.2017.07.003</ref>

	~~'''~~ATF-4 is hypothesized to mediate the lifespan extension effects of mTORC1 inhibition (target of [[rapamycin]]) and of translation inhibition.~~'''~~<ref>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). <nowiki>https://doi.org/10.1038/s41467-022-28599-9</nowiki></ref> ~~'''~~In fact, mTORC1 inhibition requires ATF-4 activation, which promotes hydrogen sulphide production and cooperates with lifespan regulators [[FOXO longevity genes\|FOXO]], [[Heat-shock response\|Heat-Shock]] Factor 1 (HSF-1) and Nuclear Receptor Factor 1 (NRF-1).~~'''~~<ref>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). <nowiki>https://doi.org/10.1038/s41467-022-28599-9</nowiki></ref> ~~'''~~ATF-4 additionally regulates stress responses in [[mitochondria]], up-regulating cytoprotective genes.<ref>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.</ref>~~'''~~		ATF-4 is hypothesized to mediate the lifespan extension effects of mTORC1 inhibition (target of [[rapamycin]]) and of translation inhibition.<ref>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). <nowiki>https://doi.org/10.1038/s41467-022-28599-9</nowiki></ref> In fact, mTORC1 inhibition requires ATF-4 activation, which promotes hydrogen sulphide production and cooperates with lifespan regulators [[FOXO longevity genes\|FOXO]], [[Heat-shock response\|Heat-Shock]] Factor 1 (HSF-1) and Nuclear Receptor Factor 1 (NRF-1).<ref>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). <nowiki>https://doi.org/10.1038/s41467-022-28599-9</nowiki></ref> ATF-4 additionally regulates stress responses in [[mitochondria]], up-regulating cytoprotective genes.<ref>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.</ref>

	== Identification of ATF4 ==		== Identification of ATF4 ==

Dmitry Dzhagarov: /* Role of ATF4 in skeletal muscle weakness and atrophy */

2023-04-11T13:50:41Z

Role of ATF4 in skeletal muscle weakness and atrophy

← Older revision		Revision as of 13:50, 11 April 2023
Line 36:		Line 36:
	== Role of ATF4 in skeletal muscle weakness and atrophy ==		== 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.<ref name="atrophy"/>		ATF4 induction by skeletal muscle stresses such as fasting, muscle immobilization, and muscle denervation, results in muscle wasting.<ref name="atrophy"/>
	ATF4 as 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.<ref>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 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10071239 10071239] DOI: 10.1007/s11357-023-00772-y</ref> '''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).'''<ref>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), [tel:27290-27301 27290-27301]. PMID: 22692209 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3431665 3431665] DOI: 10.1074/jbc.M112.374777</ref><ref>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: [https://doi.org/10.1097/MCO.0000000000000362 10.1097/MCO.0000000000000362]</ref> 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.<ref>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), [tel:2787-2803 2787-2803]. PMID: 31953319 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049960 7049960] DOI: 10.1074/jbc.RA119.012095</ref><ref name="small">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), [tel:25497-25511 25497-25511]. PMID: 26338703 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4646196 4646196] DOI: 10.1074/jbc.M115.681445</ref><ref name="atrophy"/>		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.<ref>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 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10071239 10071239] DOI: 10.1007/s11357-023-00772-y</ref> '''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).'''<ref>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), [tel:27290-27301 27290-27301]. PMID: 22692209 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3431665 3431665] DOI: 10.1074/jbc.M112.374777</ref><ref>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: [https://doi.org/10.1097/MCO.0000000000000362 10.1097/MCO.0000000000000362]</ref> 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.<ref>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), [tel:2787-2803 2787-2803]. PMID: 31953319 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049960 7049960] DOI: 10.1074/jbc.RA119.012095</ref><ref name="small">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), [tel:25497-25511 25497-25511]. PMID: 26338703 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4646196 4646196] DOI: 10.1074/jbc.M115.681445</ref><ref name="atrophy"/>

	'''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.<ref name="Halofuginone">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 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9820832 9820832] DOI: 10.3390/ijms24010621</ref>		'''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.<ref name="Halofuginone">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 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9820832 9820832] DOI: 10.3390/ijms24010621</ref>

Dmitry Dzhagarov: /* Role of ATF4 in skeletal muscle weakness and atrophy */

2023-04-11T13:48:30Z

Role of ATF4 in skeletal muscle weakness and atrophy

← Older revision		Revision as of 13:48, 11 April 2023
Line 35:		Line 35:

	== Role of ATF4 in skeletal muscle weakness and atrophy ==		== 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.<ref name="atrophy"/> '''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).'''<ref>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), [tel:27290-27301 27290-27301]. PMID: 22692209 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3431665 3431665] DOI: 10.1074/jbc.M112.374777</ref><ref>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: [https://doi.org/10.1097/MCO.0000000000000362 10.1097/MCO.0000000000000362]</ref> 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.<ref>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), [tel:2787-2803 2787-2803]. PMID: 31953319 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049960 7049960] DOI: 10.1074/jbc.RA119.012095</ref><ref name="small">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), [tel:25497-25511 25497-25511]. PMID: 26338703 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4646196 4646196] DOI: 10.1074/jbc.M115.681445</ref><ref name="atrophy"/>		ATF4 induction by skeletal muscle stresses such as fasting, muscle immobilization, and muscle denervation, results in muscle wasting.<ref name="atrophy"/>
			ATF4 as 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.<ref>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 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10071239 10071239] DOI: 10.1007/s11357-023-00772-y</ref> '''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).'''<ref>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), [tel:27290-27301 27290-27301]. PMID: 22692209 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3431665 3431665] DOI: 10.1074/jbc.M112.374777</ref><ref>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: [https://doi.org/10.1097/MCO.0000000000000362 10.1097/MCO.0000000000000362]</ref> 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.<ref>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), [tel:2787-2803 2787-2803]. PMID: 31953319 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049960 7049960] DOI: 10.1074/jbc.RA119.012095</ref><ref name="small">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), [tel:25497-25511 25497-25511]. PMID: 26338703 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4646196 4646196] DOI: 10.1074/jbc.M115.681445</ref><ref name="atrophy"/>

	'''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.<ref name="Halofuginone">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 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9820832 9820832] DOI: 10.3390/ijms24010621</ref>		'''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.<ref name="Halofuginone">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 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9820832 9820832] DOI: 10.3390/ijms24010621</ref>

Andrea: /* Intro */

2023-03-05T18:18:04Z

Intro

Show changes

Andrea: Reviewed and added content

2023-03-05T17:43:12Z

Reviewed and added content

Show changes

Dmitry Dzhagarov: /* Role of ATF4 in skeletal muscle weakness and atrophy */

2023-01-29T18:31:59Z

Role of ATF4 in skeletal muscle weakness and atrophy

← Older revision		Revision as of 18:31, 29 January 2023
Line 38:		Line 38:
	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.<ref>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 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049960 7049960] DOI: 10.1074/jbc.RA119.012095</ref><ref name="small">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 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4646196 4646196] DOI: 10.1074/jbc.M115.681445</ref><ref name="atrophy"/>		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.<ref>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 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049960 7049960] DOI: 10.1074/jbc.RA119.012095</ref><ref name="small">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 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4646196 4646196] DOI: 10.1074/jbc.M115.681445</ref><ref name="atrophy"/>

	'''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 the two major atrophic inducers, prolonged fasting and physical inactivity up to 5–7 months despite the fact that at the same time Atf4 and ATF4-regulated Gadd45a were upregulated in hibernating brown bear atrophy-resistant muscle compared to the active counterpart.<ref>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 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9820832 9820832] DOI: 10.3390/ijms24010621</ref>		'''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 the two major atrophic inducers, prolonged fasting and physical inactivity up to 5–7 months despite the fact that at the same time Atf4 and ATF4-regulated Gadd45a were upregulated in hibernating brown bear atrophy-resistant muscle compared to the active counterpart.<ref name="Halofuginone">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 PMC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9820832 9820832] DOI: 10.3390/ijms24010621</ref>

			==== Halofuginone improves muscle functions during physical inactivity ====
			Halofuginone, a racemic halogenated derivative of plant alkaloid febrifugine, capable to reduce fibrosis and inflammation and improve muscle functions in muscular dystrophies.<ref>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: [https://doi.org/10.1016/j.bbamcr.2014.03.025 10.1016/j.bbamcr.2014.03.025]</ref>
			'''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.<ref name="Halofuginone"/>

	=== Gadd45a role in longevity ===		=== Gadd45a role in longevity ===
Line 52:		Line 56:
	<ref>Zaidi, M. R., & Liebermann, D. A. (2022). Gadd45 in Senescence. In Gadd45 Stress Sensor Genes (pp. 109-116). Springer, Cham. PMID: 35505166 DOI: [https://doi.org/10.1007/978-3-030-94804-7_8 10.1007/978-3-030-94804-7_8]</ref>		<ref>Zaidi, M. R., & Liebermann, D. A. (2022). Gadd45 in Senescence. In Gadd45 Stress Sensor Genes (pp. 109-116). Springer, Cham. PMID: 35505166 DOI: [https://doi.org/10.1007/978-3-030-94804-7_8 10.1007/978-3-030-94804-7_8]</ref>
	Gadd45a (Growth arrest and DNA-damage-inducible protein 45 alpha), a p53- and BRCA1-regulated stress-inducible gene, disruption 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. Gadd45a gene, plays important roles in the control of cell cycle checkpoints, DNA repair and apoptosis. <ref name="Sensor"/><ref>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: [https://doi.org/10.1016/j.mrfmmm.2004.06.055 10.1016/j.mrfmmm.2004.06.055]</ref>		Gadd45a (Growth arrest and DNA-damage-inducible protein 45 alpha), a p53- and BRCA1-regulated stress-inducible gene, disruption 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. Gadd45a gene, plays important roles in the control of cell cycle checkpoints, DNA repair and apoptosis. <ref name="Sensor"/><ref>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: [https://doi.org/10.1016/j.mrfmmm.2004.06.055 10.1016/j.mrfmmm.2004.06.055]</ref>
	[[FOXO longevity genes\|FOXO]] proteins also mainly regulate the longevity regulation pathway via promoting the expression of Gadd45a, Sod2, and Cat. <ref>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: [https://doi.org/10.1016/j.ecoenv.2020.111798 10.1016/j.ecoenv.2020.111798]</ref>		[[FOXO longevity genes\|FOXO]] proteins, such as FOXO1, that enhances the promoter activity of target genes in cooperation with C/EBPδ and ATF4,<ref>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: [https://doi.org/10.1096/fj.202101385RR 10.1096/fj.202101385RR]</ref> also mainly regulate the longevity regulation pathway via promoting the expression of Gadd45a, Sod2, and Cat.<ref>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: [https://doi.org/10.1016/j.ecoenv.2020.111798 10.1016/j.ecoenv.2020.111798]</ref>

	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.<ref>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: [https://doi.org/10.1038/sj.onc.1210469 10.1038/sj.onc.1210469]</ref>		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.<ref>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: [https://doi.org/10.1038/sj.onc.1210469 10.1038/sj.onc.1210469]</ref>

Dmitry Dzhagarov at 18:57, 28 January 2023

2023-01-28T18:57:48Z

Show changes

Dmitry Dzhagarov: /* Gadd45a role in longevity */

2023-01-28T18:08:55Z

Gadd45a role in longevity

← Older revision		Revision as of 18:08, 28 January 2023
Line 52:		Line 52:
	<ref>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</ref>		<ref>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</ref>
	Gadd45a (Growth arrest and DNA-damage-inducible protein 45 alpha), a p53- and BRCA1-regulated stress-inducible gene, disruption 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. Gadd45a gene, plays important roles in the control of cell cycle checkpoints, DNA repair and apoptosis. <ref name="Sensor"/><ref>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</ref>		Gadd45a (Growth arrest and DNA-damage-inducible protein 45 alpha), a p53- and BRCA1-regulated stress-inducible gene, disruption 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. Gadd45a gene, plays important roles in the control of cell cycle checkpoints, DNA repair and apoptosis. <ref name="Sensor"/><ref>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</ref>
	FOXO proteins also mainly regulate the longevity regulation pathway via promoting the expression of Gadd45a, Sod2, and Cat. <ref>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</ref>		[[FOXO longevity genes\|FOXO]] proteins also mainly regulate the longevity regulation pathway via promoting the expression of Gadd45a, Sod2, and Cat. <ref>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</ref>

	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.<ref>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</ref>		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.<ref>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</ref>