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Control of the Reversibility of Cellular Quiescence by the Transcriptional Repressor HES1
Open accessAbstract
The mechanisms by which quiescent cells, including adult stem cells, preserve their ability to resume proliferation after weeks or even years of cell cycle arrest are not known. We report that reversibility is not a passive property of nondividing cells, because enforced cell cycle arrest for a period as brief as 4 days initiates spontaneous, premature, and irreversible senescence. Increased expression of the gene encoding the basic helix-loop-helix protein HES1 was required for quiescence to be reversible, because HES1 prevented both premature senescence and inappropriate differentiation in quiescent fibroblasts. In some human tumors, the HES1 pathway was activated, which allowed these cells to evade differentiation and irreversible cell cycle arrest. We conclude that HES1 safeguards against irreversible cell cycle exit both during normal cellular quiescence and pathologically in the setting of tumorigenesis.
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“However, interruption of this pathway is no longer sufficient to rescue growth once the cells have progressed towards an established senescent phenotype (d'Adda di Fagagna et al, 2003; Sang et al, 2008).”
From Feedback between p21 and reactive oxygen production is necessary for cell senescence (2010) · cites this paper as Sang et al, 2008
Experimental — accuracy not yet measuredIn the citing paper
“The apparent discrepancy in our results may relate to cell type or species differences or the status of the helix-loop-helix protein HES1, which may play a crucial role in determining the reversibility of the quiescent state (Sang et al., 2008).”
From Dissecting the Unique Role of the Retinoblastoma Tumor Suppressor during Cellular Senescence (2010) · cites this paper as Sang et al., 2008
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Citations
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Her9 represses neurogenic fate downstream of Tbx1 and retinoic acid signaling in the inner ear
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Marthandan, S., Priebe, S., Hemmerich, P. H., Klement, K., & Diekmann, S. (2014) · PLoS ONE · doi:10.1371/journal.pone.0115597 · Cited by 55
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Belyea, B., Naini, S., Bentley, R. C., & Linardic, C. M. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-1004 · Cited by 54
“This is consistent with the known role of Hey1 in binding the myogenin promoter and blocking its transcription (31), and also consistent with previous published data showing that both dnHes1 and GSI treatment increase myosin heavy chain mRNA, another marker of commitment to the myogenic lineage, in the presence of fus…”
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Joh, R. I., Khanduja, J. S., Calvo, I. A., Mistry, M., Palmieri, C. M., Savol, A. J., Sui, S. J. H., Sadreyev, R. I., Aryee, M. J., & Motamedi, M. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.11.020 · Cited by 48
BTG2 antagonizes Pin1 in response to mitogens and telomere disruption during replicative senescence
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“This is unlike p21, which is capable of arresting cells at any point during their replicative lifespan (Sang et al., 2008).”
BackgroundIsolation, characterization, and molecular regulation of muscle stem cells
Fukada, S., Ma, Y., Ohtani, T., Watanabe, Y., Murakami, S., & Yamaguchi, M. (2013) · Frontiers in Physiology · doi:10.3389/fphys.2013.00317 · Cited by 48
Cellular Senescence, Neurological Function, and Redox State
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“Quiescent cells are in a reversible cell cycle arrest, able to respond to mitotic stimuli; the expression of the transcriptional repressor HES1 inhibits the acquisition of the senescent phenotype (142).”
Alternative polyadenylation factors link cell cycle to migration
Mitra, M., Johnson, E. L., Swamy, V. S., Nersesian, L., Corney, D. C., Robinson, D. G., Taylor, D. G., Ambrus, A., Jelínek, D., Wang, W., et al. (2018) · Genome biology · doi:10.1186/s13059-018-1551-9 · Cited by 42
Self-citationThe roles and mechanism of ultradian oscillatory expression of the mouse Hes genes
Harima, Y., Imayoshi, I., Shimojo, H., Kobayashi, T., & Kageyama, R. (2014) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2014.04.038 · Cited by 42
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“In this regard, it has been reported that Hes1 prevented irreversible cell cycle exit in human fibroblast and rhabdomyosarcoma cells [49].”
BackgroundHes1 suppresses acute myeloid leukemia development through FLT3 repression
Kato, T., Sakata‐Yanagimoto, M., Nishikii, H., Ueno, M., Miyake, Y., Yokoyama, Y., Asabe, Y., Kamada, Y., Muto, H., Obara, N., et al. (2014) · Leukemia · doi:10.1038/leu.2014.281 · Cited by 42
Hes1deficiency causes hematopoietic stem cell exhaustion
Ma, Z., Xu, J., Wu, L., Wang, J., Lin, Q., Chowdhury, F. A., Mazumder, M. H. H., Hu, G., Li, X., & Du, W. (2020) · Stem Cells · doi:10.1002/stem.3169 · Cited by 43
“of stem/progenitor cells, by controlling the reversibility of cellular quiescence, and by regulating cell fate decision.(1,61,62) Deletion of Hes1 in mice results in severe defects in multiple organs and is lethal in late embryogenesis.”
BackgroundDulic, V. (2013) · Methods in Molecular Biology · doi:10.1007/978-1-62703-239-1_2 · Cited by 42
Head and Neck Squamous Cell Carcinoma: New Translational Therapies
Prince, A., Aguirre‐Ghizo, J., Genden, E., Posner, M. R., & Sikora, A. (2010) · Mount Sinai Journal of Medicine A Journal of Translational and Personalized Medicine · doi:10.1002/msj.20216 · Cited by 42
Differential cell-cycle control by oscillatory versus sustained Hes1 expression via p21
Maeda, Y., Isomura, A., Masaki, T., & Kageyama, R. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112520 · Cited by 40
Phase correlation imaging of unlabeled cell dynamics
Ma, L., Gannavarpu, R., Wang, R., Bhaduri, B., Sridharan, S., Mir, M., Chakraborty, A., Iyer, R., Prasanth, S. G., Millet, L. J., et al. (2016) · Scientific Reports · doi:10.1038/srep32702 · Cited by 40
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“It has previously been demonstrated that interference with HES1 contributes to RMS proliferation [27], and the HES/HEY family is known to be Notch responsive [28], a signaling pathway with myogenic inhibitory effects [29-31].”
BackgroundSturrock, M., Terry, A. J., Xirodimas, D. P., Thompson, A. M., & Chaplain, M. A. J. (2012) · Bulletin of Mathematical Biology · doi:10.1007/s11538-012-9725-1 · Cited by 39
“It has been found to be deregulated in some forms of cancer (Sang et al. 2008) and is known to play a role in somitogenesis, the developmental process responsible for segmentation of the vertebrate embryo.”
BackgroundLi, H., Zhang, W., Niu, C., Lin, C., Wu, X., Jian, Y., Li, Y., Ye, L., Dai, Y., Ouyang, Y., et al. (2019) · International Journal of Cancer · doi:10.1002/ijc.32293 · Cited by 40
“Hes1 is a well-known direct transcriptional target of Notch3, and it plays an important role in the maintenance of cancer stem cells and tumor drug resistance.(19,20) Changes in NR2F6 expression had no impact on the expression of Jagged1 at either the protein or the mRNA level (Fig.”
BackgroundQuiescent fibroblasts are protected from proteasome inhibition–mediated toxicity
Legesse-Miller, A., Raitman, I., Haley, E. M., Liao, A., Sun, L., Wang, J., Krishnan, N., Lemons, J. M. S., Suh, E. J., Johnson, E. L., et al. (2012) · Molecular Biology of the Cell · doi:10.1091/mbc.e12-03-0192 · Cited by 41
“Although this protected state can be beneficial for long-lived cells, the evocation of such pathways in tumor cells may allow them to survive by avoiding apoptosis or differentiation that is normally induced by anticancer agents (Sang et al., 2008; Schewe and Aguirre-Ghiso, 2008).”
Self-citationIdentification of new genes associated with melanoma
Mauerer, A., Roesch, A., Hafner, C. M., Stempfl, T., Wild, P. J., Meyer, S., Landthaler, M., & VOGT, T. M. (2011) · Experimental Dermatology · doi:10.1111/j.1600-0625.2011.01254.x · Cited by 40
“arrest [52, 59].”
Interactions between nematodes and other factors on plants.
Wallace, H. R. (1983) · PubMed Central · Cited by 38
Cell dormancy plasticity: quiescence deepens into senescence through a dimmer switch
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“Consistent with the notion that quiescence is distinct from senescence, quiescent cells 47 exhibit unique gene expression (13, 32, 58, 65) that is considered necessary to actively maintain 48 their reversible phenotype against irreversible arrest (13, 51).”
BackgroundTransitional dynamics of cancer stem cells in invasion and metastasis
Richard, V., Kumar, T. R. S., & Pillai, R. M. (2020) · Translational Oncology · doi:10.1016/j.tranon.2020.100909 · Cited by 34
Zhao, H., Faltermeier, C. M., Mendelsohn, L., Porter, P. L., Clurman, B. E., & Roberts, J. M. (2014) · Oncotarget · doi:10.18632/oncotarget.2871 · Cited by 35
“Retroviral and lentiviral infections were performed as previously described [35].”
MethodSelf-citationhCLP46 regulates U937 cell proliferation via Notch signaling pathway
Ma, W., Du, J., Chu, Q., Wang, Y., Liu, L., Song, M., & Wang, W. (2011) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2011.03.124 · Cited by 35
Acute kidney injury: can we improve prognosis?
Hsu, C. W., & Symons, J. M. (2010) · Pediatric Nephrology · doi:10.1007/s00467-010-1508-z · Cited by 35
“Simultaneously, the transcription of p21, a cell cycle inhibitor, is upregulated [72].”
BackgroundPfeuty, B. (2015) · Development · doi:10.1242/dev.112649 · Cited by 34
“…(Kageyama et al., 2007), whereas it is steadily expressed at high level in boundary areas of the developing nervous system (Baek et al., 2006), in quiescent fibroblasts (Sang et al., 2008), in contact-inhibited 3T3-L1 cells (Noda et al., 2011) and in some differentiated cells (Wu et al., 2003).”
BackgroundNotch signalling is off and is uncoupled from HES1 expression in Ewing's sarcoma
Bennani-Baı̈ti, I. M., Aryee, D. N. T., Ban, J., Machado, I., Kauer, M. O., Muehlbacher, K., Amann, G., Llombart‐Bosch, A., & Kovar, H. (2011) · The Journal of Pathology · doi:10.1002/path.2966 · Cited by 34
“In parallel to this meta-analysis, we ran two controls: first, we carried out an ESFT genome-wide HEY1 covariance analysis as a positive control for a Notch effector that is efficiently regulated by Notch in ESFT [13]; second, we ran both HEY1 and HES1 analyses in RMS, wherein HES1 is an active component of the Notch…”
MethodHes1 Oscillations Contribute to Heterogeneous Differentiation Responses in Embryonic Stem Cells
Kobayashi, T., & Kageyama, R. (2011) · Genes · doi:10.3390/genes2010219 · Cited by 34
“For example, it has been reported that Hes1 is mostly absent during early G1 phase and mainly expressed during late G1, S and G2 phase in neural progenitors [10], Hes1 directly or indirectly represses the transcription of cell cycle related genes, p21Cip1, p27Kip1 and p57Kip2 in various types of cells [36–38], and Hes…”
BackgroundRegulation of cellular chromatin state
Srivastava, S., Mishra, R. K., & Dhawan, J. (2010) · Organogenesis · doi:10.4161/org.6.1.11337 · Cited by 34
“The ability of quiescent cells to actively maintain the option of cell cycle re-entry may in part be governed by the transcriptional repressor Hairy and Enhancer of Split1 (HES1), which is associated with a chromatin-modifying complex.(65,66) A global reorganization of the epigenetic chromatin state including heteroch…”
BackgroundMicroRNAs and epigenetic mechanisms of rhabdomyosarcoma development
Cieśla, M., Dulak, J., & Józkowicz, A. (2014) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2014.05.003 · Cited by 32
The Role of Dimerisation and Nuclear Transport in the Hes1 Gene Regulatory Network
Sturrock, M., Hellander, A., Aldakheel, S., Petzold, L. R., & Chaplain, M. A. J. (2013) · Bulletin of Mathematical Biology · doi:10.1007/s11538-013-9842-5 · Cited by 33
“Finally, we compare and contrast the two different modelling scenarios using numerical experiments that simulate dimer disruption, and suggest a biological experiment that could distinguish which model more faithfully captures the Hes1 GRN. M. Sturrock · S. Aldakheel · M.A.J. Chaplain University of…”
Cancer Stem Cells in Squamous Cell Carcinoma
Jian, Z., Strait, A. A., Jimeno, A., & Wang, X. (2016) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2016.07.033 · Cited by 35
“Quiescence in normal SCs limits proliferation and protects genomic integrity (Coller et al., 2006; Sang et al., 2008; Viatour et al., 2008; White et al., 2014).”
BackgroundEvolving Roles of Notch Signaling in Cortical Development
Nian, F., & Hou, P. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.844410 · Cited by 33
Tian, C., Zheng, G., Cao, Z., Li, Q., Ju, Z., Wang, J., Yuan, W., & Cheng, T. (2013) · Cell Cycle · doi:10.4161/cc.23160 · Cited by 30
Quiescence and γH2AX in neuroblastoma are regulated by ouabain/Na,K-ATPase
Hiyoshi, H., Abdelhady, S., Segerström, L., Sveinbjørnsson, B., Nuriya, M., Lundgren, K. C., Desfrere, L., Miyakawa, A., Yasui, M., Kogner, P., et al. (2012) · British Journal of Cancer · doi:10.1038/bjc.2012.159 · Cited by 31
“However, it was recently shown that a reduction in p21 per se was not sufficient to push arrested cells back into the cell cycle (Sang et al, 2008).”
BackgroundInfluentialControl of hair cell development by molecular pathways involving Atoh1, Hes1 and Hes5
Su, Y., Hou, C.-C., & Yang, W. (2014) · Gene · doi:10.1016/j.gene.2014.12.054 · Cited by 31
Désarnaud, F., Geck, P., Parkin, C. D., Carpinito, G., & Makarovskiy, A. N. (2011) · Cancer Biology & Therapy · doi:10.4161/cbt.11.2.13750 · Cited by 29
Mimicking Muscle Stem Cell Quiescence in Culture: Methods for Synchronization in Reversible Arrest
Arora, R., Rumman, M., Venugopal, N., Gala, H., & Dhawan, J. (2017) · Methods in molecular biology · doi:10.1007/978-1-4939-6771-1_15 · Cited by 28
Unraveling the Big Sleep: Molecular Aspects of Stem Cell Dormancy and Hibernation
Dias, I. B., Bouma, H. R., & Henning, R. H. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.624950 · Cited by 28
“…through alteration of chromatin recruiting histone deacetylases (HDACs) (Sang and Coller, 2009), promoting tight packaging of DNA into heterochromatin and downregulation of p21 (Yu et al., 2006; Sang et al., 2008), p27 (Murata et al., 2005), and E2F-dependent proteins (Hartman et al., 2004).”
BackgroundImpaired 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
“The Drosophila hairy and enhancer of split (HES) 1 basic helix-loop-helix protein is a major downstream effector in the canonical Notch pathway, which is surmised to play a role in the self-renewal and maintenance of HSC, and in the control of quiescence (40,41).”
BackgroundMelanoma in the liver: Oxidative stress and the mechanisms of metastatic cell survival
Obrador, E., Salvador, R., López‐Blanch, R., Jihad-Jebbar, A., Alcácer, J., Benlloch, M., Pellicer, J. A., & Estrela, J. M. (2020) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2020.05.001 · Cited by 27
The histone- and PRMT5-associated protein COPR5 is required for myogenic differentiation
Paul, C., Sardet, C., & Fabbrizio, E. (2011) · Cell Death and Differentiation · doi:10.1038/cdd.2011.193 · Cited by 27
“, differentiation) associated with permanent cell cycle withdrawal.(2) Skeletal muscle formation is characterized by the fusion of myoblasts into myotubes and increased synthesis of muscle contractile proteins.”
BackgroundCorlu, A., & Loyer, P. (2012) · International Journal of Hepatology · doi:10.1155/2012/689324 · Cited by 27
“However, recent reports evinced differences between “arrested” cells in various conditions [7, 8].”
ResultRegulation of Cell Cycle Entry and Exit: A Single Cell Perspective
Coller, H. A. (2019) · Comprehensive physiology · doi:10.1002/cphy.c190014 · Cited by 33
“Quiescent cells have been shown to activate genes that protect them from differentiation and senescence (83, 426).”
Self-citationSP promotes cell proliferation in esophageal squamous cell carcinoma through the NK1R/Hes1 axis
Wang, F., Liu, S., Liu, J., Feng, F., Guo, Y., Zhang, W., Zheng, G., Wang, Q., Cai, L., Guo, M., et al. (2019) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2019.05.092 · Cited by 26
Notch signaling in pediatric soft tissue sarcomas
Rota, R., Ciarapica, R., Miele, L., & Locatelli, F. (2012) · BMC Medicine · doi:10.1186/1741-7015-10-141 · Cited by 25
“[68], these results strongly indicate that the in vitro antidifferentiative and pro-tumorigenic role of Notch3 in RMS is, at least in part, due to the induction of HES1 expression.”
BackgroundResultInfluentialSabherwal, N., Rowntree, A., Marinopoulou, E., Pettini, T., Hourihane, S., Thomas, R., Soto, X., Kursawe, J., & Papalopulu, N. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2113527118 · Cited by 25
Quiescence, an individual journey
Sagot, I., & Laporte, D. (2019) · Current Genetics · doi:10.1007/s00294-018-00928-w · Cited by 26
Cellular Quiescence in Mammary Stem Cells and Breast Tumor Stem Cells: Got Testable Hypotheses?
Harmes, D. C., & DiRenzo, J. (2009) · Journal of Mammary Gland Biology and Neoplasia · doi:10.1007/s10911-009-9111-2 · Cited by 26
“Additionally Hes1 a transcriptional target of Notch signaling has recently been identified as a factor that is sufficient to maintain cellular quiescence [7].”
InfluentialYamada, K., Tso, J. L., Ye, F., Choe, J., Liu, Y., Liau, L. M., & Tso, C.-L. (2011) · Cancers · doi:10.3390/cancers3021975 · Cited by 24
“Notch signaling has been implicated in the maintenance of cellular quiescence in many adult stem cell pools by retaining self-renewal potential, inhibiting differentiation, and protecting them from exhaustion of their proliferative capacity [15-17].”
BackgroundThe significance of gene expression dynamics in neural stem cell regulation
Kageyama, R., Ochi, S., Sueda, R., & Shimojo, H. (2020) · Proceedings of the Japan Academy Series B · doi:10.2183/pjab.96.026 · Cited by 24
Hes1 is required for contact inhibition of cell proliferation in 3T3-L1 preadipocytes
Noda, N., Honma, S., & Ohmiya, Y. (2011) · Genes to Cells · doi:10.1111/j.1365-2443.2011.01518.x · Cited by 23
“Additionally, the expression of dominant negative Hes1 caused multinucleation in rhabdomyosarcoma cells (Sang et al. 2008).”
BackgroundInfluentialZheng, X., Narayanan, S., Zheng, X., Luecke-Johansson, S., Gradin, K., Catrina, S., Poellinger, L., & Pereira, T. (2017) · Experimental Cell Research · doi:10.1016/j.yexcr.2017.06.006 · Cited by 24
Zenitani, M., Nojiri, T., Uehara, S., Miura, K., Hosoda, H., Kimura, T., Nakahata, K., Miyazato, M., Okuyama, H., & Kangawa, K. (2016) · Cancer Medicine · doi:10.1002/cam4.642 · Cited by 23
“In RMS cells, several signaling pathways including Notch [17, 18], Wnt [19], Hedgehog [20], phosphoinositide 3- kinase (PI3K)/AKT/mTOR [21, 22], and MAPK/ERK [23, 24] are involved in promoting cell proliferation.”
BackgroundHoare, M., & Narita, M. (2018) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-89512-3_15 · Cited by 23
Jin, H., Tan, X.-Z., Liu, X., & Ding, Y. (2010) · International Journal of Colorectal Disease · doi:10.1007/s00384-010-1047-x · Cited by 22
“The HES1 and JAG1 genes correlated with the development and maturation of the nervous system as well as the development, differentiation of stem cells involved in the renewal of the colonic epithelium [13, 14].”
BackgroundAnti-tumor effects of the Notch pathway in gastrointestinal stromal tumors
Dumont, A. G., Yang, Y., Reynoso, D., Katz, D., Trent, J. C., & Hughes, D. P. M. (2012) · Carcinogenesis · doi:10.1093/carcin/bgs221 · Cited by 22
Johnson, E. L., Robinson, D. G., & Coller, H. A. (2017) · BMC Genomics · doi:10.1186/s12864-017-3521-0 · Cited by 22
“Transcriptional repressors such as HES1 and FOXC1 that can control the expression of clusters of genes involved in maintaining the reversibility of quiescence have been shown to account for some of these observed expression changes [5, 7, 8].”
BackgroundSelf-citationBiomimetic generation of the strongest known biomaterial found in limpet tooth
Rumney, R. M. H., Robson, S. C., Kao, A. P., Barbu, E., Bożycki, Ł., Smith, J. R., Cragg, S. M., Couceiro, F., Parwani, R., Tozzi, G., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-31139-0 · Cited by 21
Bitterman, P. B., & Polunovsky, V. A. (2012) · Cell Cycle · doi:10.4161/cc.11.6.19610 · Cited by 23
ΔNp63α promotes cellular quiescence via induction and activation of Notch3
Kent, S. S., Hutchinson, J. A., Balboni, A., DeCastro, A., Cherukuri, P., & DiRenzo, J. (2011) · Cell Cycle · doi:10.4161/cc.10.18.17300 · Cited by 22
“Additionally, Hes1 is required to preserve the reversibility associated with quiescence.(25) In addition to Hes1, N3 also induced mRNA levels of Mxi1, a negative regulator of c-myc activity recently identified as a serum deprivation early response gene (SDERG) and shown to be essential for quiescence.”
BackgroundNovel therapeutic strategies and targets in advanced uveal melanoma
Chua, V. Y. L., & Aplin, A. E. (2017) · Current Opinion in Oncology · doi:10.1097/cco.0000000000000425 · Cited by 21
Dahlberg, A. E., Brashem‐Stein, C., Delaney, C. S., & Bernstein, I. D. (2014) · Leukemia · doi:10.1038/leu.2014.181 · Cited by 20
Zhao, H., Chen, X., Gurian-West, M., & Roberts, J. M. (2012) · Molecular and Cellular Biology · doi:10.1128/mcb.06721-11 · Cited by 21
Self-citationThe oncogenic effects of HES1 on salivary adenoid cystic carcinoma cell growth and metastasis
Huang, X., Gan, R.-H., Xie, J. W., She, L., Zhao, Y., Ding, L.-C., Su, B.-H., Zheng, D.-L., & Lu, Y. (2018) · BMC Cancer · doi:10.1186/s12885-018-4350-5 · Cited by 20
Morizet, D., Foucher, I., Alunni, A., & Bally‐Cuif, L. (2024) · Nature Communications · doi:10.1038/s41467-024-47484-1 · Cited by 26
“Some of these are likely part of a core quiescent stem cell gene set such as HES1 which has been proposed to be a general marker of stemness 51 , or those encoding the exosomal proteins CD9 and CD81 which are enriched in several types of quiescent cells 52 .”
BackgroundBoulestreau, J., Maumus, M., Bertolino, G. M., Toupet, K., Jørgensen, C., & Noël, D. (2024) · Journal of Nanobiotechnology · doi:10.1186/s12951-024-02509-1 · Cited by 22
“HES-1 expression is sufficient to prevent senescence in naturally quiescent cells, thereby playing a role in stem cell lineages and tissue regeneration [30].”
BackgroundHistone deacetylase inhibition as an anticancer telomerase‐targeting strategy
Rahman, R., & Grundy, R. G. (2011) · International Journal of Cancer · doi:10.1002/ijc.26241 · Cited by 21
“This is consistent with evidence suggesting that quiescence may play an important role in protecting stem cells from exhausting their proliferative capacity, inhibiting differentiation, and limiting accumulation of mutations.(87,88) Label-retaining studies have shown that slow cycling stem cells (e.”
BackgroundExpression and clinical significance of Notch signaling genes in colorectal cancer
Jin, H., Zhang, H., Wang, X., Xu, J., & Ding, Y. (2012) · Tumor Biology · doi:10.1007/s13277-011-0301-3 · Cited by 20
“Notch-IC then translocates into the nucleus and binds to the transcription factor CSL, inhibiting the transcription of target genes, such as HES1 [5, 12–16].”
BackgroundKowalewski, A., Durślewicz, J., Zdrenka, M., Grzanka, D., & Szylberg, Ł. (2020) · Targeted Oncology · doi:10.1007/s11523-020-00735-9 · Cited by 20
Dormancy, Quiescence, and Diapause: Savings Accounts for Life
Ozguldez, H. O., & Bulut-Karslıoğlu, A. (2024) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-112122-022528 · Cited by 17
Label retaining cells in cancer – The dormant root of evil?
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“In addition, quiescence may limit the accumulation of mutations during numerous rounds of DNA synthesis [30–32] and therefore prevent the accumulation of mutations in stem cells [33].”
BackgroundFOXOs Maintaining the Equilibrium for Better or for Worse
van Doeselaar, S., & Burgering, B. M. T. (2018) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/bs.ctdb.2017.10.003 · Cited by 17
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“Notably, the Notch pathway target, HES1, which actively maintains quiescence (Moriyama et al., 2008; Sang et al., 2008), is upregulated across”
BackgroundTremblay, C. S., Huard, C., Huang, F., Habi, O., Bourdages, V., Lévesque, G., & Carreau, M. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m807921200 · Cited by 19
Kang, S., Xie, J., Miao, J., Li, R., Liao, W., & Luo, R. (2012) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-012-1318-1 · Cited by 17
“The knockdown effectively repressed the cyclin-dependent kinase inhibitors p16, p21, p27, and p57, resulting in decreased cell proliferation and senescence [14, 17, 27].”
BackgroundEberhardt, K., Matthäus, C., Marthandan, S., Diekmann, S., & Popp, J. (2018) · PLoS ONE · doi:10.1371/journal.pone.0207380 · Cited by 18
Recent considerations in regenerative endodontic treatment approaches
Aksel, H., & Serper, A. (2014) · Journal of Dental Sciences · doi:10.1016/j.jds.2013.12.007 · Cited by 16
“Stem cells generally remain in a quiescent state to protect their proliferative potentials in vivo.(6) Quiescent stem cells may be activated by microenvironmental changes such as tissue injury or disease.”
BackgroundCarlier, G., Maugein, A., Cordier, C., Pechberty, S., Garfa‐Traoré, M., Martin, P., Scharfmann, R., & Albagli, O. (2014) · PLoS ONE · doi:10.1371/journal.pone.0108202 · Cited by 15
Programmed Cell Senescence in the Mouse Developing Spinal Cord and Notochord
Domínguez-Bautista, J. A., Acevo-Rodríguez, P. S., & Castro‐Obregón, S. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.587096 · Cited by 18
“Molecularly, the transcriptional repressor HES1 safeguards against irreversible cell cycle exit during cellular quiescence, and prevents senescence (Sang et al., 2008; Sueda et al., 2019).”
BackgroundInfluentialSaad, N., Alberio, R., Johnson, A. D., Emes, R. D., Giles, T. C., Clarke, P. A., Grabowska, A. M., & Allegrucci, C. (2018) · Oncotarget · doi:10.18632/oncotarget.24664 · Cited by 17
“Two important epigenetic regulators, MLL5 and HES1 [48, 49], were identified among the common quiescencerelated genes, suggesting a link between AOE-induced growth arrest and epigenetic reprogramming.”
BackgroundInfluentialTranscription factor networks in cellular quiescence
Mitra, M., Batista, S., & Coller, H. A. (2025) · Nature Cell Biology · doi:10.1038/s41556-024-01582-w · Cited by 16
“104), a Notch target gene that maintains quiescence reversibility 23 .”
Self-citationImpaired innate immune cells in cystic fibrosis: Is it really a surprise?
Bonfield, T. L., & Chmiel, J. F. (2017) · Journal of Cystic Fibrosis · doi:10.1016/j.jcf.2017.06.001 · Cited by 15
Tanke, N. T., Liu, Z., Gore, M. T., Bougaran, P., Linares, M. B., Marvin, A., Sharma, A., Oatley, M., Yu, T., Quigley, K., et al. (2024) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.124.320671 · Cited by 14
“64 Senescent arterial endothelial cells often express a senescence-associated secretory phenotype 65 characterized by inflammatory cytokine expression that contributes to endothelial dysfunction, leading to cardiovascular disease.”
BackgroundBittig, A. T., & Uhrmacher, A. M. (2016) · IEEE Transactions on Computational Biology and Bioinformatics · doi:10.1109/tcbb.2016.2598162 · Cited by 14
“Malfunction in the Hes1 feedback loop has been implicated in cancer development [42].”
BackgroundTranscriptomic study of the mechanism of anoikis resistance in head and neck squamous carcinoma
Guo, C., Xu, L., Li, H., Wang, W., Guo, J., Jia, M., Jia, R., & Jia, J. (2019) · PeerJ · doi:10.7717/peerj.6978 · Cited by 14
Hyper-Activation of Notch3 Amplifies the Proliferative Potential of Rhabdomyosarcoma Cells
Salvo, M. D., Raimondi, L., Vella, S., Adesso, L., Ciarapica, R., Verginelli, F., Pannuti, A., Citti, A., Boldrini, R., Milano, G. M., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0096238 · Cited by 14
“[17], this function was, at least in part, related to the Notch3dependent induction of HES1.”
BackgroundKeeping Them Quiet: BMPs Maintain Adult Neural Stem Cell Quiescence
Johnston, M. A., & Lim, D. A. (2010) · Cell stem cell · doi:10.1016/j.stem.2010.06.006 · Cited by 14
“For instance, in fibroblasts, enforced expression of Hes1, a target of SMAD signaling, prevents senescence induced by the p21 cell cycle inhibitor, thus allowing cell cycle re-entry (Sang et al., 2008).”
BackgroundXhairy2 functions in Xenopus lens development by regulating p27xic1 expression
Murato, Y., & Hashimoto, C. (2009) · Developmental Dynamics · doi:10.1002/dvdy.21883 · Cited by 14
“Moreover, a recent report showed that Hes1 actively safeguarded against terminal differentiation and permanent cell cycle arrest in quiescent cells (Sang et al., 2008).”
BackgroundFXR1a-associated microRNP: A driver of specialized non-canonical translation in quiescent conditions
Bukhari, S. I. A., & Vasudevan, S. (2016) · RNA Biology · doi:10.1080/15476286.2016.1265197 · Cited by 14
“from differentiation and apoptosis, and is implicated in cancer progression.(59,121,129-133) Consistently, components of the”
BackgroundTonquèze, O. L., Lee, J., & Vasudevan, S. (2012) · RNA Biology · doi:10.4161/rna.20806 · Cited by 16
“G0 cells demonstrate a switch to expression of specific genes that resist tumor-negative conditions, differentiation and cell death to maintain the quiescent state and secure the abilities of the cell to be restored to the proliferative state.(27,54) Maintenance of the G0 state can extend from a few hours to several m…”
BackgroundInfluential
Metadata
- Authors
- Sang, L., Coller, H. A., & Roberts, J. M.
- Affiliations
- Princeton University (US)
- Corresponding author
- Roberts, James M.
- Venue
- Science
- Published
- 2008-08-22
- Volume
- 321
- Issue
- 5892
- Pages
- 1095-1100
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC2721335
- OpenAlex
- W2018341322
- Cited by
- 313
- References
- 29
- Citations by year
- 2026: 9 · 2025: 12 · 2024: 12 · 2023: 10 · 2022: 7 · 2021: 10 · 2020: 12 · 2019: 16 · 2018: 14 · 2017: 16 · 2016: 13 · 2015: 17 · 2014: 25 · 2013: 23 · 2012: 33
- FWCI
- 18.74
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Cancer Institute (R01CA118043)
- National Institute of General Medical Sciences (P50GM071508)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- quiescent cells, Hes1, bHLH transcription factors, cell cycle arrest, premature senescence, fibroblasts, adult stem cells, carcinogenesis, cell cycle exit
- MeSH terms
- Transcription Factor HES-1, Cell Cycle, Cell Differentiation, Cell Line, Fibroblasts, Humans, Recombinant Fusion Proteins, Repressor Proteins, Rhabdomyosarcoma, Transduction, Genetic, Signal Transduction, Cellular Senescence, MyoD Protein, Homeodomain Proteins, Muscle Development, Cell Line, Tumor, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p21, Basic Helix-Loop-Helix Proteins, Receptors, Notch, Co-Repressor Proteins
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