The DOI matches its Crossref record; 30 of the 30 references it cites were found in a registry or an index.
Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells
Abstract
The 'ataxia telangiectasia mutated' (Atm) gene maintains genomic stability by activating a key cell-cycle checkpoint in response to DNA damage, telomeric instability or oxidative stress. Mutational inactivation of the gene causes an autosomal recessive disorder, ataxia-telangiectasia, characterized by immunodeficiency, progressive cerebellar ataxia, oculocutaneous telangiectasia, defective spermatogenesis, premature ageing and a high incidence of lymphoma. Here we show that ATM has an essential function in the reconstitutive capacity of haematopoietic stem cells (HSCs) but is not as important for the proliferation or differentiation of progenitors, in a telomere-independent manner. Atm-/- mice older than 24 weeks showed progressive bone marrow failure resulting from a defect in HSC function that was associated with elevated reactive oxygen species. Treatment with anti-oxidative agents restored the reconstitutive capacity of Atm-/- HSCs, resulting in the prevention of bone marrow failure. Activation of the p16(INK4a)-retinoblastoma (Rb) gene product pathway in response to elevated reactive oxygen species led to the failure of Atm-/- HSCs. These results show that the self-renewal capacity of HSCs depends on ATM-mediated inhibition of oxidative stress.
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In the citing paper
“other studies have shown the potential of antioxidants to improve the function of old HSCs (76,96).”
From Causes, consequences, and reversal of immune system aging (2013) · cites this paper as [96]
In the citing paper
“in HSCs and neural stem cells (NSCs) of mice, excessive cellular ROS concentrations lead to abnormal proliferation, malignancy and compromised stem cell self-renewal11–14”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [11]
In the citing paper
“experimentally induced genetic disruption of DDR pathways in mice also produces cell-autonomous defects in HSC function, as assayed by in vivo hematopoietic reconstitution and in vitro colony forming assays11,36,52,53.”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [11]
In the citing paper
“age-dependent alterations in regulation of SOD2 by FoxO3 and the DNA damage sensing serine/threonine protein kinase ATM (ataxia-telangiectasia mutated) have been shown to contribute to loss of HSC function with aging11,16, 24.”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [11]
In the citing paper
“Another potential function for ATM in suppressing progeroid phenotypes may be related to reported ATM functions in regulating intracellular ROS levels and sensitivity to these molecules (Barzilai et al., 2002; Ito et al., 2004”
From DNA Repair, Genome Stability, and Aging (2005) · cites this paper as Ito et al., 2004
In the citing paper
“Inactivation of the p16-Rb pathway restores the reproductive function of ATM−/− HSCs, whereas inhibition of the Arf-p53 pathway has no such effect.20,21”
From Total body irradiation causes long-term mouse BM injury via induction of HSC premature senescence in an Ink4a- and Arf-independent manner (2014) · cites this paper as [20]
In the citing paper
“Furthermore, mutation of the ataxia telangiectasia mutated (ATM) gene also results in upregulation of p16 and Arf in HSCs.”
From Total body irradiation causes long-term mouse BM injury via induction of HSC premature senescence in an Ink4a- and Arf-independent manner (2014) · cites this paper as [20]
In the citing paper
“ROS plays an important role in mediating induction of HSC senescence under various pathological conditions, such as mutation of ATM and various Fanconi anemia genes; deletion of Bmi1, FoxOs, Mdm2, and Tsc1; and aging.15,19,20,35-38”
From Total body irradiation causes long-term mouse BM injury via induction of HSC premature senescence in an Ink4a- and Arf-independent manner (2014) · cites this paper as [20]
In the citing paper
“mice lacking Atm show rapid ageing and depletion of their haematopoietic stem cell compartment 34”
From The common biology of cancer and ageing (2007) · cites this paper as [34]
Citations
Cites
Stem cells, cancer, and cancer stem cells
Reya, T., Morrison, S. J., Clarke, M. F., & Weissman, I. L. (2001) · Nature · doi:10.1038/35102167 · Cited by 9,738
A Single Ataxia Telangiectasia Gene with a Product Similar to PI-3 Kinase
Savitsky, K., Bar-Shira, A., Gilad, S., Rotman, G., Ziv, Y., Vanagaite, L., Tagle, D. A., Smith, S., Uziel, T., Sfez, S., et al. (1995) · Science · doi:10.1126/science.7792600 · Cited by 2,785
ATM and related protein kinases: safeguarding genome integrity
Shiloh, Y. (2003) · Nature Reviews Cancer · doi:10.1038/nrc1011 · Cited by 2,577
Long-Term Lymphohematopoietic Reconstitution by a Single CD34-Low/Negative Hematopoietic Stem Cell
Osawa, M., Hanada, K., Hamada, H., & Nakauchi, H. (1996) · Science · doi:10.1126/science.273.5272.242 · Cited by 2,141
Tie2/Angiopoietin-1 Signaling Regulates Hematopoietic Stem Cell Quiescence in the Bone Marrow Niche
Arai, F., Hirao, A., Ohmura, M., Sato, H., Matsuoka, S., Takubo, K., Ito, K., Koh, G. Y., & Suda, T. (2004) · Cell · doi:10.1016/j.cell.2004.07.004 · Cited by 1,958
Self-citationBmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells.
Park, I.-K., Qian, D., Kiel, M., Becker, M. W., Pihalja, M., Weissman, I. L., Morrison, S. J., & Clarke, M. F. (2003) · Nature · doi:10.1038/nature01587 · Cited by 1,871
Jacobs, J. J. L., Kieboom, K., Marino, S., DePinho, R. A., & van Lohuizen, M. (1999) · Nature · doi:10.1038/16476 · Cited by 1,580
Atm-Deficient Mice: A Paradigm of Ataxia Telangiectasia
Barlow, C., Hirotsune, S., Paylor, R. E., Liyanage, M., Eckhaus, M., Collins, F. S., Shiloh, Y., Crawley, J. N., Ried, T., Tagle, D. A., et al. (1996) · Cell · doi:10.1016/s0092-8674(00)80086-0 · Cited by 1,465
Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells.
Lessard, J., & Sauvageau, G. (2003) · Nature · doi:10.1038/nature01572 · Cited by 1,452
Hematopoietic Stem Cell Quiescence Maintained by p21 cip1/waf1
Cheng, T., Rodrigues, N., Shen, H., Yang, Y.-G., Dombkowski, D., Sykes, M., & Scadden, D. T. (2000) · Science · doi:10.1126/science.287.5459.1804 · Cited by 1,339
Cited by
Sorted by citations
Items 601–700 of 1,000
Tang, S., Yang, L., Tang, X., & Liu, M. (2014) · Cancer Letters · doi:10.1016/j.canlet.2014.07.028 · Cited by 33
Rizvanov, A. A., YALVAÇ, M. E., Shafigullina, A. K., Salafutdinov, I. I., Blatt, N. L., Şahi̇n, F., Kiyasov, A. P., & Palotás, A. (2010) · European Journal of Pharmaceutics and Biopharmaceutics · doi:10.1016/j.ejpb.2010.05.012 · Cited by 32
Li, J., Sejas, D. P., Burma, S., Chen, D. J., & Pang, Q. (2007) · Carcinogenesis · doi:10.1093/carcin/bgm025 · Cited by 32
Neuronal Nitric Oxide Synthase Contributes to the Regulation of Hematopoiesis
Krasnov, P. A., Michurina, T. V., Packer, M. A., Stasiv, Y., Nakaya, N., Moore, K. A., Drazan, K. E., & Enikolopov, G. (2008) · Molecular Medicine · doi:10.2119/2007-00011.krasnov · Cited by 32
“Hematopoietic stem cells are highly sensitive to reactive oxygen species (ROS) (46,48,49), and nNOS-produced NO, a potent antioxidant, may contribute to the defense against ROS by scavenging superoxides, preventing heme oxidation, suppressing Fenton chemistry, and attenuating lipid peroxidation (7,15,17); furthermore,…”
BackgroundSinha, S., Dwivedi, T. R., Yengkhom, R., Bheemsetty, V. A., Abe, T., Kiyonari, H., VijayRaghavan, K., & Inamdar, M. S. (2019) · Blood · doi:10.1182/blood.2019000530 · Cited by 32
Fine-tuning the ubiquitin code at DNA double-strand breaks: deubiquitinating enzymes at work
Citterio, E. (2015) · Frontiers in Genetics · doi:10.3389/fgene.2015.00282 · Cited by 30
“Oxidative stress, accumulation of DNA damage and p53 activation are frequently associated with HSC deficiency and BM failure syndromes (Ito et al., 2004; Niedernhofer, 2008; Liu et al., 2009; Ceccaldi et al., 2012).”
BackgroundWeiss, C. N., & Ito, K. (2015) · International Journal of Molecular Sciences · doi:10.3390/ijms16036183 · Cited by 33
“Additionally, Atm−/− mice have a reduced reconstitution capacity of HSCs, and elevated levels of the Rb and p53 activators p16INK4A (cyclin-dependent kinase inhibitor 2A) and p19ARF (alternate reading frame tumor suppressor), which contribute to the loss of HSCs—both observations can be rescued with NAC treatment, dem…”
BackgroundSelf-citationThe ups and downs of p53 regulation in hematopoietic stem cells
Abbas, H. A., Pant, V., & Lozano, G. (2011) · Cell Cycle · doi:10.4161/cc.10.19.17721 · Cited by 33
The Role of the MAPK Signaling, Topoisomerase and Dietary Bioactives in Controlling Cancer Incidence
Selim, K. A., Abdelrasoul, H., Aboelmagd, M., & Tawila, A. M. (2017) · Diseases · doi:10.3390/diseases5020013 · Cited by 31
Li, X., Erden, O., Li, L., Ye, Q., Wilson, A., & Du, W. (2013) · Antioxidants and Redox Signaling · doi:10.1089/ars.2013.5600 · Cited by 31
“It has been considered as an important pathogenic factor in leukemia-prone bone marrow (BM) diseases by inducing a variety of responses in hematopoietic stem cells (HSCs), such as stem cell differentiation and apoptosis (1, 14, 15, 32).”
Tug of War between Survival and Death: Exploring ATM Function in Cancer
Stagni, V., Oropallo, V., Fianco, G., Antonelli, M., Cinà, I., & Barilà, D. (2014) · International Journal of Molecular Sciences · doi:10.3390/ijms15045388 · Cited by 32
“normal haematopoietic stem cells (HSCs) [82].”
BackgroundReactive oxygen species in eradicating acute myeloid leukemic stem cells.
Zhang, H., Fang, H., & Wang, K. (2014) · Europe PMC (PubMed Central) · doi:10.3978/j.issn.2306-9759.2014.04.03 · Cited by 32
“Mice lacking the ataxia telangiectasia mutated (ATM) can develop bone marrow failure that is correlated with increased levels of ROS (64).”
BackgroundPremature ageing of the immune system underlies immunodeficiency in ataxia telangiectasia
Exley, A. R., Buckenham, S., Hodges, E., Hallam, R., Byrd, P., Last, J., Trinder, C., Harris, S., Screaton, N., Williams, A. P., et al. (2011) · Clinical Immunology · doi:10.1016/j.clim.2011.03.007 · Cited by 30
Bhattarai, G., Shrestha, S. K., Sim, H., Lee, J., & Kook, S. (2024) · Experimental & Molecular Medicine · doi:10.1038/s12276-023-01149-z · Cited by 30
Rac1 drives intestinal stem cell proliferation and regeneration
Myant, K., Scopelliti, A., Haque, S., Vidal, M., Sansom, O. J., & Cordero, J. B. (2013) · Cell Cycle · doi:10.4161/cc.26031 · Cited by 30
mTOR Signaling as a Regulator of Hematopoietic Stem Cell Fate
Fernandes, H., Moura, J., & Carvalho, E. (2021) · Stem Cell Reviews and Reports · doi:10.1007/s12015-021-10131-z · Cited by 31
DNA damage and repair in the hematopoietic system
Li, N., Chen, H., & Wang, J. (2022) · Acta Biochimica et Biophysica Sinica · doi:10.3724/abbs.2022053 · Cited by 33
“In line with this hypothesis, hematopoietic abnormalities have been observed in mice models deficient of Atm [33,34], Mre11 [98], Rad50 [99], and Nbs1 [100,101], respectively.”
BackgroundInfluentialPullarkat, V. A., Sehgal, A., Li, L., Meng, Z., Lin, A., Forman, S. J., & Bhatia, R. (2012) · Leukemia Research · doi:10.1016/j.leukres.2012.03.018 · Cited by 30
Reactive Oxygen Species Adversely Impacts Bone Marrow Microenvironment in Diabetes
Mangialardi, G., Spinetti, G., Reni, C., & Madeddu, P. R. (2014) · Antioxidants and Redox Signaling · doi:10.1089/ars.2014.5944 · Cited by 33
“Along with FOXO3a and Nrf2, the ataxia telangiectasia mutated (ATM) gene exerts a protective role in HSCs against oxidative stress, as it maintains genomic stability by activating cell-cycle checkpoint, as demonstrated in ATM - / - mice (2, 48, 64).”
BackgroundExpansion of hematopoietic stem/progenitor cells
Wu, H., Xin‐Na, D., & Duan, H. (2008) · American Journal of Hematology · doi:10.1002/ajh.21262 · Cited by 30
“Besides, several other new cell cycle-related factors have been reported: butyric acid [44], ‘‘ataxia telangiectasia mutated’’ (Atm) gene [45], HTm4 gene [46], RUNX family [47], Jak2 with the V617F point mutation [48], nucleophosmin [49], RhoAN19 GTPase [50], neurokinin-A [51], Hedgehog (Hh) proteins [52].”
Iron loading and oxidative stress in theAtm−/−mouse liver
McDonald, C. J., Ostini, L., Wallace, D. F., John, A. N., Watters, D. J., & Subramaniam, V. N. (2011) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00486.2010 · Cited by 30
Xie, G., Zhan, J., Tian, Y., Liu, Y., Chen, Z., Ren, C., Sun, Q., Lian, J., Chen, L., Ruan, J., et al. (2011) · Cancer Letters · doi:10.1016/j.canlet.2011.10.018 · Cited by 30
“It has recently been shown that normal stem/progenitor cells [24–28] and cancer stem cells [29] contain lower levels of ROS than their more mature progeny and that lower ROS appear to be critical for maintaining stem-like cell function and mediating the resistance to chemotherapy and radiotherapy.”
BackgroundInfluentialHiguchi, M., Kawamura, H., Matsuki, H., Hara, T., Takahashi, M., Saito, S., Saito, K., Jiang, S. S., Naito, M., Kiyonari, H., et al. (2016) · Stem Cell Reports · doi:10.1016/j.stemcr.2016.11.003 · Cited by 30
“Augmented ROS production in HSCs is the frequent cause of HSC depletion in multiple gene-KO mice (Amrani et al., 2011; Chen et al., 2008; Ito et al., 2004; Liu et al., 2010; Miyamoto et al., 2007; Tothova et al., 2007).”
BackgroundViswanathan, P., Sharma, Y., Gupta, P., & Gupta, S. K. (2018) · Cell Proliferation · doi:10.1111/cpr.12445 · Cited by 31
Wang, Q., Qian, W., Han, Y., Mao, Y., Gao, Z., Chen, Y., Zeng, X., Lu, H., Jiang, L., Li, J., et al. (2025) · Nature Nanotechnology · doi:10.1038/s41565-025-01907-2 · Cited by 33
The telomere binding protein Pot1 maintains haematopoietic stem cell activity with age
Hosokawa, K., MacArthur, B. D., Ikushima, Y. M., Toyama, H., Masuhiro, Y., Hanazawa, S., Suda, T., & Arai, F. (2017) · Nature Communications · doi:10.1038/s41467-017-00935-4 · Cited by 32
Self-citationmicroRNAs Tune Oxidative Stress in Cancer Therapeutic Tolerance and Resistance
Zhang, W. C. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20236094 · Cited by 29
“Tumor-initiating cells protect their genomes from ROS-mediated damage [122] via increased production of free radical scavengers [123] leading to low ROS levels [124].”
BackgroundSchraml, E., Fuchs, R., Kotzbeck, P., Grillari, J., & Schauenstein, K. (2008) · Stem Cells and Development · doi:10.1089/scd.2008.0072 · Cited by 29
“Similarly, it was shown that loss of either ataxia telangiec-tasia mutated (ATM) or a forkhead-related FOXO transcription factor followed by serial bone marrow transplantation elevates ROS in HPCs and disrupts self-renewal activity [52,53].”
Bensimon, J., Biard, D. S. F., Paget, V., Goislard, M., Altmeyer‐Morel, S., Konge, J. C., Chevillard, S., & Lebeau, J. (2015) · Molecular Carcinogenesis · doi:10.1002/mc.22273 · Cited by 29
“In agreement with a low metabolic activity and quiescent state, normal and cancer stem cells were shown to exhibit reducedROS levels in several tissues,mostly through enhancement of ROS-controlling pathways [5,11,36,37].”
BackgroundMantel, C., Messina‐Graham, S., & Broxmeyer, H. E. (2011) · Current Opinion in Hematology · doi:10.1097/moh.0b013e3283475ffe · Cited by 29
Hypercholesterolemia Tunes Hematopoietic Stem/Progenitor Cells for Inflammation and Atherosclerosis
Ma, X., & Feng, Y. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms17071162 · Cited by 29
“Although it is hard to discriminate whether increased ROS production in HSPC is the cause or consequence of HSPC proliferation, inhibition of ROS production rescues HSPC exhaustion and senescence and regains the self-renewal capacity of HSPC [77].”
BackgroundPpm1d truncating mutations promote the development of genotoxic stress-induced AML
Burócziová, M., Daněk, P., Oravetzova, A., Chalupova, Z., Alberich-Jordà, M., & Macůrek, L. (2023) · Leukemia · doi:10.1038/s41375-023-02030-8 · Cited by 28
Losdat, S., Helfenstein, F., Blount, J. D., & Richner, H. (2014) · Journal of Evolutionary Biology · doi:10.1111/jeb.12454 · Cited by 28
Stem cell mitochondria during aging
Min‐Wen, J. C., Jun‐Hao, E. T., & Shyh‐Chang, N. (2016) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2016.02.005 · Cited by 28
“Mutator mice closely resembled other mouse models of progeria, previously connected to defects in DNA repair during stem cell aging [91-92].”
Fancb deficiency impairs hematopoietic stem cell function
Du, W., Amarachintha, S. P., Erden, O., Wilson, A., Meetei, A. R., Andreassen, P. R., Namekawa, S. H., & Pang, Q. (2015) · Scientific Reports · doi:10.1038/srep18127 · Cited by 28
Liang, R. H.-S., & Ghaffari, S. (2017) · Journal of Bioenergetics and Biomembranes · doi:10.1007/s10863-017-9719-7 · Cited by 28
“In many of these models, the in vivo administration of N-acetyl-cysteine (NAC) - a glutathione precursor that reduces ROS levels - rescues HSC ability to reconstitute all blood cells for a long period of time in a mouse in which blood is ablated (Rimmele et al. 2015), also known as long-term competitive repopulation a…”
InfluentialYeo, A. J., Henningham, A., Fantino, E., Galbraith, S., Krause, L., Wainwright, C. E., Sly, P. D., & Lavin, M. F. (2019) · Scientific Reports · doi:10.1038/s41598-019-38901-3 · Cited by 28
The Anti-oxidative Role of ABCG2 in Corneal Epithelial Cells
Kubota, M., Shimmura, S., Miyashita, H., Kawashima, M., Kawakita, T., & Tsubota, K. (2010) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.10-5463 · Cited by 28
A pathway from leukemogenic oncogenes and stem cell chemokines to RNA processing via THOC5
Griaud, F., Pierce, A., Gonzalez-Sanchez, M.-B., Scott, M. T., Abraham, S. A., Holyoake, T. L., Tran, D. D. H., Tamura, T., & Whetton, A. D. (2012) · Leukemia · doi:10.1038/leu.2012.283 · Cited by 28
Wang, Y., Tan, H., Xu, D., Ma, A., ZHANG, L., Sun, J., Yang, Z., Liu, Y., & Shi, G. (2014) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2014.1774 · Cited by 28
“In this study, we showed that 15d-PGJ 2 , the natural ligand of PPAR-γ , impaired the maintenance and function of TICs in bladder cancer cells.”
InfluentialTumorigenic Potential of Mononucleated Small Cells of Hodgkin Lymphoma Cell Lines
Ikeda, J., Mamat, S., Tian, T., Wang, Y., Rahadiani, N., Aozasa, K., & Morii, E. (2010) · American Journal Of Pathology · doi:10.2353/ajpath.2010.100089 · Cited by 29
Impaired functionality and homing of Fancg-deficient hematopoietic stem cells
Barroca, V., Mouthon, M., Lewandowski, D., de la Grange, P. B., Gauthier, L., Pflumio, F., Boussin, F. D., Arwert, F., Riou, L., Allemand, I., et al. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr447 · Cited by 34
“Impaired function of HSC is frequently associated with the loss of quiescence and excessive proliferation (23,24).”
BackgroundSignaling Pathways Regulating Hematopoietic Stem Cell and Progenitor Aging
Singh, A. K., Althoff, M. J., & Cancelas, J. A. (2018) · Current Stem Cell Reports · doi:10.1007/s40778-018-0128-6 · Cited by 27
Yan, M., Shen, J., Person, M. D., Kuang, X., Lynn, W. S., Atlas, D., & Wong, P. K. Y. (2008) · Neoplasia · doi:10.1593/neo.07935 · Cited by 28
“All rights reserved 1522-8002/08/$25.00 DOI 10.1593/neo.07935 are markedly increased, and the resultant progressive bone marrow failure is prevented by treatment with the antioxidant N-acetylcysteine (NAC) [4].”
BackgroundInfluentialCho, J. S., Kook, S. H., Robinson, A. R., Niedernhofer, L. J., & Lee, B.-C. (2013) · Stem Cells · doi:10.1002/stem.1261 · Cited by 27
Isoda, T., Takagi, M., Piao, J., Nakagama, S., Sato, M., Masuda, K., Ikawa, T., Azuma, M., Morio, T., Kawamoto, H., et al. (2012) · Blood · doi:10.1182/blood-2012-02-413195 · Cited by 27
Epigenetic Erosion in Adult Stem Cells: Drivers and Passengers of Aging
Kosan, C., Heidel, F. H., Godmann, M., & Bierhoff, H. (2018) · Cells · doi:10.3390/cells7120237 · Cited by 29
Yang, Z., Shah, K. K., Khodadadi‐Jamayran, A., & Jiang, H. (2019) · Stem Cell Reports · doi:10.1016/j.stemcr.2019.05.023 · Cited by 28
“Mice deficient of components in either recognition (Ito et al., 2004) or repair (Nijnik et al.”
BackgroundIkonomi, N., Werle, S. D., Schwab, J. D., & Kestler, H. A. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.00848 · Cited by 29
“This might explain the normal hematopoiesis seen in the FOXO3A and ATM mouse models (Ito et al., 2004; Yalcin et al., 2008).”
BackgroundThe Role of Iron in Benign and Malignant Hematopoiesis
Sinha, S., Pereira-Reis, J., Guerra, A., Rivella, S., & Duarte, D. (2020) · Antioxidants and Redox Signaling · doi:10.1089/ars.2020.8155 · Cited by 29
“Ultimately, excessive ROS levels may lead to HSC exhaustion and apoptosis (74).”
Li, M., Lin, Y., Palchik, G. A., Matsunaga, S., Wang, D., & Chen, B. P. C. (2014) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2014.08.019 · Cited by 27
“It was reported that there is an age-dependent loss of hematopoietic stem cells (HSCs) in older ATM / mice due to an elevation of ROS, and that treatment with free radical scavenger NAC was able to alleviate the oxidative stress response in ATM / mice [34].”
Han, X., Xue, X., Zhao, Y., Li, Y., Liu, W., Zhang, J., & Fan, S. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18050942 · Cited by 27
“in several studies to be responsible for the loss of self-renewing ability and premature exhaustion of hematopoietic stem cells [9,10].”
BackgroundGRK6 regulates ROS response and maintains hematopoietic stem cell self-renewal
Le, Q., Yao, W., Chen, Y., Yan, B., Cao, L., Yuan, M., Zhou, Y., & Ma, L. (2016) · Cell Death and Disease · doi:10.1038/cddis.2016.377 · Cited by 27
Li, Q., Liu, Q., Cai, H., & Tan, W. (2006) · Cellular & Molecular Biology Letters · doi:10.2478/s11658-006-0039-x · Cited by 27
“It was recently reported that the interaction of the transcription factor FOXO and β-Catenin of the Wnt signaling was enhanced to tolerate the condition of oxidative stress [17], which is detrimental to stem cell self-renewal [18].”
BackgroundSurvival responses to oxidative stress and aging
Miura, Y., & Endo, T. (2010) · Geriatrics and gerontology international/Geriatrics & gerontology international · doi:10.1111/j.1447-0594.2010.00597.x · Cited by 26
Oxidants, metabolism, and stem cell biology
Liu, J., Cao, L., & Finkel, T. (2011) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2011.10.434 · Cited by 26
“For instance, defects in HSCs from Atm−/− mice can be rescued by overexpression of Bmi1 [16].”
BackgroundMethodInfluentialXie, F., Xu, W., Yin, C., Zhang, G., Zhong, Y., & Gao, J. (2016) · World Journal of Gastrointestinal Oncology · doi:10.4251/wjgo.v8.i10.735 · Cited by 26
The Periostin/Integrin-αv Axis Regulates the Size of Hematopoietic Stem Cell Pool in the Fetal Liver
Biswas, A., Roy, I. M., Babu, P., Manesia, J. K., Schouteden, S., Vijayakurup, V., Anto, R. J., Huelsken, J., Lacy‐Hulbert, A., Verfaillie, C. M., et al. (2020) · Stem Cell Reports · doi:10.1016/j.stemcr.2020.06.022 · Cited by 24
“In addition, in a number of mouse models with defective DDRs, pre-mature aging of HSCs was observed (Ito et al., 2004).”
BackgroundThe nexus between redox state and intermediary metabolism
Zoccarato, A., Nabeebaccus, A., Oexner, R. R., Santos, C. X. C., & Shah, A. M. (2021) · FEBS Journal · doi:10.1111/febs.16191 · Cited by 27
Simple Measurement of IgA Predicts Immunity and Mortality in Ataxia-Telangiectasia
Zielen, S., Duecker, R. P., Woelke, S., Donath, H., Bakhtiar, S., Buecker, A., Kreyenberg, H., Huenecke, S., Bader, P., Mahlaoui, N., et al. (2021) · Journal of Clinical Immunology · doi:10.1007/s10875-021-01090-8 · Cited by 26
Targeting Mitochondria to Control Ageing and Senescence
Protasoni, M., & Serrano, M. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15020352 · Cited by 30
Aldehyde dehydrogenase activity is necessary for beta cell development and functionality in mice
Anastasiou, V., Ninou, E., Alexopoulou, D., Stertmann, J., Müller, A., Dahl, A., Solimena, M., Speier, S., Serafimidis, I., & Gavalas, A. (2015) · Diabetologia · doi:10.1007/s00125-015-3784-4 · Cited by 26
“Availability of low ROS concentrations appears to be critical for self-renewal of some tissue stem cells [45, 46].”
BackgroundLorenzo, L. P. E., Chen, H., Shatynski, K. E., Clark, S. M., Yuan, R., Harrison, D. E., Yarowsky, P., & Williams, M. S. (2011) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3798 · Cited by 24
“HSC quiescence has been shown to be required for HSC function, therefore, the oxidative stress in the HSCs of Ts65Dn mice may be inducing a loss of quiescence, resulting in decreased function as measured by repopulating activity (5, 13, 14, 45).”
Tokar, E. J., Kojima, C., & Waalkes, M. P. (2013) · Archives of Toxicology · doi:10.1007/s00204-013-1141-2 · Cited by 26
“Reduced ROS level, partly due to an elevated level of ROS scavenging factors, is a key mechanism for resistance in normal stem cells and cancer stem cells in various tissues (Ito et al. 2004; Diehn et al. 2009).”
BackgroundDNA asymmetry and cell fate regulation in stem cells
Yennek, S., & Tajbakhsh, S. (2013) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2013.05.008 · Cited by 34
Impaired hepatocyte survival and liver regeneration in Atm-deficient mice
Lu, S., Shen, K. C., Wang, Y., Brooks, S. C., & Wang, Y. (2005) · Human Molecular Genetics · doi:10.1093/hmg/ddi333 · Cited by 26
“Furthermore, it was recently demonstrated that the ability of Atm-deficient hematopoietic cells to reconstitute bone marrow was improved greatly with the administration of antioxidants (34).”
BackgroundLekli, I., Gurusamy, N., Ray, D., Tósaki, Á., & Das, D. K. (2009) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/y09-102 · Cited by 28
“Ito et al. (2004) have also show that ATM-mediated inhibition of oxidative stress potentiates the self-renewal capacity of hematopoietic stem cells.”
BackgroundCheng, T. (2007) · Gene Therapy · doi:10.1038/sj.gt.3303066 · Cited by 26
Gene therapy approaches for stem cell protection
Greenberger, J. S. (2007) · Gene Therapy · doi:10.1038/sj.gt.3303004 · Cited by 25
Adaptive and Pathogenic Responses to Stress by Stem Cells during Development
Mansouri, L., Xie, Y., & Rappolee, D. A. (2012) · Cells · doi:10.3390/cells1041197 · Cited by 24
“progenitors but inhibits the repopulating of stem cells [67].”
BackgroundNayler, S., Powell, J. E., Vanichkina, D., Korn, O., Wells, C. A., Kanjhan, R., Sun, J., Taft, R. J., Lavin, M. F., & Wolvetang, E. J. (2017) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2017.00321 · Cited by 26
“It is worth noting also that ROS levels have been shown to negatively impact stem cell expansion in the bone marrow in an Atm-dependent fashion (Ito et al., 2004; D’Souza et al., 2012).”
BackgroundChen, Y., Li, J., & Zhao, Z. (2021) · Cells · doi:10.3390/cells10051218 · Cited by 25
“inhibits the self-renewal capacity of HSCs [28,47].”
Extensive characterization of sphere models established from colorectal cancer cell lines
Collura, A., Marisa, L., Trojan, D., Buhard, O., Lagrange, A., Saget, A., Bombled, M., Méchighel, P., Ayadi, M., Muleris, M., et al. (2012) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-012-1160-9 · Cited by 25
“These data agree with other recent studies demonstrating widespread plasticity and dedifferentiation processes that affect some tumor cells under specific environmental conditions, particularly CRC cells [4, 31–35].”
Result“Nutrient-sensing” and self-renewal: O-GlcNAc in a new role
Sharma, N., Saluja, A. K., & Banerjee, S. (2017) · Journal of Bioenergetics and Biomembranes · doi:10.1007/s10863-017-9735-7 · Cited by 25
“thereby maintaining the genomic and protein integrity (Ito et al. 2004).”
BackgroundIshibashi, T., Yokota, T., Satoh, Y., Ichii, M., Sudo, T., Doi, Y., Ueda, T., Nagate, Y., Hamanaka, Y., Tanimura, A., et al. (2017) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2017.12.117 · Cited by 26
INK4a/ARF Expression Impairs Neurogenesis in the Brain of Irradiated Mice
Lê, O., Palacio, L., Bernier, G., Batinic̈‐Haberle, I., Hickson, G. R. X., & Beausejour, C. M. (2018) · Stem Cell Reports · doi:10.1016/j.stemcr.2018.03.025 · Cited by 26
“…Growth Ex Vivo but Not In Vivo Expression of INK4a/ARF is delayed following exposure to IR, suggesting that it does not increase as a direct effect but rather as a consequence of IR, for example following replicative exhaustion or in response to increased levels of ROS (Ito et al., 2004, 2006).”
BackgroundInfluentialNonsenescent Hsp27-Upregulated MSCs Implantation Promotes Neuroplasticity in Stroke Model
Liu, S., Ding, D., Wang, H.-J., Su, C.-Y., Lin, S., Li, H., & Shyu, W. (2010) · Cell Transplantation · doi:10.3727/096368910x507204 · Cited by 25
Bera, R., Chiu, M.-C., Huang, Y., Liang, D., Lee, Y., & Shih, L. (2018) · Neoplasia · doi:10.1016/j.neo.2018.08.013 · Cited by 27
Henry, E., & Arcangeli, M.-L. (2020) · Experimental Hematology · doi:10.1016/j.exphem.2020.12.001 · Cited by 24
Innate immunity dysregulation in aging eye and therapeutic interventions
Das, S., Ahmad, Z., Suryawanshi, A. S., & Kumar, A. (2022) · Ageing Research Reviews · doi:10.1016/j.arr.2022.101768 · Cited by 24
Stem cells and aging: a chicken-or-the-egg issue?
Smith, J. A., & Daniel, R. (2012) · Europe PMC (PubMed Central) · Cited by 23
A Role for Vascular Deficiency in Retinal Pathology in a Mouse Model of Ataxia-Telangiectasia
Raz-Prag, D., Galron, R., Segev‐Amzaleg, N., Solomon, A., Shiloh, Y., Barzilai, A., & Frenkel, D. (2011) · American Journal Of Pathology · doi:10.1016/j.ajpath.2011.05.026 · Cited by 24
Ramachandran, S., Tran, D. D. H., Klebba-Färber, S., Kardinal, C., Whetton, A. D., & Tamura, T. (2011) · RNA · doi:10.1261/rna.2820911 · Cited by 24
“A consequence of ATM kinase loss is a variety of effects, including extinction of hematopoietic stem cells (Ito et al. 2004).”
BackgroundMethodBagley, J., Singh, G., & Iacomini, J. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.178.8.4757 · Cited by 24
“Increasing evidence also indicates that Atm is critically involved in prevention of oxidative damage caused by ROS (11, 13, 25, 27, 28).”
BackgroundMethodReplication stress in hematopoietic stem cells in mouse and man
Flach, J., & Milyavsky, M. (2017) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/j.mrfmmm.2017.10.001 · Cited by 23
Molecular and Cellular Aspects of Macrophage Aging
Sebastián, C., Lloberas, J., & Celada, A. (2009) · Springer eBooks · doi:10.1007/978-1-4020-9063-9_46 · Cited by 24
Genetic Interactions of STAT3 and Anticancer Drug Development
Fang, B. (2014) · Cancers · doi:10.3390/cancers6010494 · Cited by 25
“angiogenesis [236,237], and maintenance of stem cell status [238,239].”
BackgroundRegulation of the Atm promoter in vivo
Gueven, N., Fukao, T., Luff, J., Paterson, C. A., Kay, G. F., Kondo, N., & Lavin, M. F. (2005) · Genes Chromosomes and Cancer · doi:10.1002/gcc.20267 · Cited by 24
“There is accumulating evidence that A-T cells and some tissues in Atm-mutant mice are in a constant state of oxidative stress presumably because of persistent chromosomal breaks and alterations in transcriptional activity (Kamsler et al., 2001; Barzilai et al., 2002; Chen et al., 2003; Barzilai and Yamamoto, 2004; Ito…”
BackgroundAldehyde dehydrogenases in acute myeloid leukemia
Smith, C. A., Gasparetto, M., Humphries, R. K., Pollyea, D. A., Vasiliou, V., & Jordan, C. T. (2014) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.12414 · Cited by 23
Shao, L., Feng, W., Lee, K. J., Chen, B. P. C., & Zhou, D. (2012) · PLoS ONE · doi:10.1371/journal.pone.0033499 · Cited by 27
“failure and a high incidence of lymphoma [4,5].”
BackgroundTelomere, DNA damage, and oxidative stress in stem cell aging
Zhang, J., & Ju, Z. (2010) · Birth Defects Research Part C Embryo Today Reviews · doi:10.1002/bdrc.20190 · Cited by 25
Yi, W., Zhang, Y., Liu, B., Zhou, Y., Liao, D., Qiao, X., Gao, D., Xie, T., Yao, Q., Zhang, Y., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.108922 · Cited by 23
“Increased reactive oxygen species (ROS) impairs HSC self-renewal capacity (Ito et al., 2004).”
BackgroundTang, X. T., Wang, Z., Wang, J., Cui, S., Xu, R., & Wang, Y. (2023) · Stem Cell Research & Therapy · doi:10.1186/s13287-023-03316-5 · Cited by 24
“Further research shows that the overexpression of these two enzymes can reduce ROS levels, promote DNA repair, reduce apoptosis, and significantly promote the long-term survival of HSC transplantations [118].”
BackgroundThe multifaceted role of mitochondria in HSC fate decisions: energy and beyond
Filippi, M. (2023) · Experimental Hematology · doi:10.1016/j.exphem.2023.10.001 · Cited by 24
Desai, A. B., Qing, Y., & Gerson, S. L. (2013) · Stem Cells · doi:10.1002/stem.1596 · Cited by 23
The Role of Reactive Oxygen Species in Tumor Treatment and its Impact on Bone Marrow Hematopoiesis
Chen, Y., Luo, X., Zou, Z., & Liang, Y. (2019) · Current Drug Targets · doi:10.2174/1389450120666191021110208 · Cited by 24
NAD+ augmentation with nicotinamide riboside improves lymphoid potential of Atm−/− and old mice HSCs
Zong, L., Tanaka-Yano, M., Park, B., Yanai, H., Turhan, F. T., Croteau, D. L., Tian, J., Fang, E. F., Bohr, V. A., & Beerman, I. (2021) · npj Aging and Mechanisms of Disease · doi:10.1038/s41514-021-00078-3 · Cited by 22
Respect the Anaerobic Nature of Stem Cells to Exploit their Potential in Regenerative Medicine
Ivanović, Z. (2013) · Regenerative Medicine · doi:10.2217/rme.13.65 · Cited by 22
Orlando, L., Tanasijevic, B., Nakanishi, M., Reid, J. C., García‐Rodríguez, J. L., Chauhan, K. D., Porras, D. P., Aslostovar, L., Lu, J. D., Shapovalova, Z., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.108818 · Cited by 21
Redox-dependent Igfbp2 signaling controls Brca1 DNA damage response to govern neural stem cell fate
Shahin, W. S., Ebed, S. O., Tyler, S. R., Miljkovic, B., Choi, S. H., Zhang, Y., Zhou, W., Evans, I. A., Yeaman, C. A., & Engelhardt, J. F. (2023) · Nature Communications · doi:10.1038/s41467-023-36174-z · Cited by 22
Metadata
- Authors
- Ito, K., Hirao, A., Arai, F., Matsuoka, S., Takubo, K., Hamaguchi, I., Nomiyama, K., Hosokawa, K., Sakurada, K., Nakagata, N., Ikeda, Y., Mak, T. W., & Suda, T.
- Affiliations
- Keio University (JP)
- Kumamoto University (JP)
- University of Toronto (CA)
- Corresponding author
- Hirao, Atsushi
- Suda, Toshio
- ORCID
- Venue
- Nature
- Published
- 2004-10
- Volume
- 431
- Issue
- 7011
- Pages
- 997-1002
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2041897873
- Cited by
- 1,175
- References
- 30
- Citations by year
- 2026: 15 · 2025: 29 · 2024: 38 · 2023: 31 · 2022: 37 · 2021: 51 · 2020: 44 · 2019: 58 · 2018: 47 · 2017: 59 · 2016: 73 · 2015: 71 · 2014: 75 · 2013: 88 · 2012: 77
- FWCI
- 25.91
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- ATM, oxidative stress, hematopoietic stem cells, self-renewal, reactive oxygen species, ataxia telangiectasia, bone marrow failure, p16INK4a, retinoblastoma protein, DNA damage response, antioxidant therapy
- MeSH terms
- Acetylcysteine, Animals, Antioxidants, Cell Division, DNA-Binding Proteins, Hematopoiesis, Hematopoietic Stem Cells, Mice, Inbred C57BL, RNA, Messenger, Signal Transduction, Retinoblastoma Protein, Protein Serine-Threonine Kinases, Gene Deletion, Reactive Oxygen Species, Mice, Knockout, Oxidative Stress, Cell Cycle Proteins, Cell Lineage, Cyclin-Dependent Kinase Inhibitor p16, Tumor Suppressor Proteins, Mice, Ataxia Telangiectasia Mutated Proteins
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