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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
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“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
Cites
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“Recent studies showed that activated chemokine receptor CXCR2 (Acosta et al, 2008), insulin-like growth factor binding protein 7 (Wajapeyee et al, 2008), IL6 receptor (Kuilman et al, 2008) or downregulation of the transcriptional repressor HES1 (Sang et al, 2008) may be required for the establishment and/or maintenanc…”
Ruijtenberg, S., & van den Heuvel, S. (2016) · Cell Cycle · doi:10.1080/15384101.2015.1120925 · Cited by 577
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Posttranscriptional Upregulation by MicroRNAs
Vasudevan, S. (2011) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.121 · Cited by 536
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“Of note, Bmpr1a expression was decreased, whereas Bmpr1b expression was progressively increased upon neuronal differentiation of AH- NSCs (Figure S3).”
BackgroundInfluentialForebrain ependymal cells are Notch-dependent and generate neuroblasts and astrocytes after stroke
Carlén, M., Meletis, K., Göritz, C., Darsalia, V., Evergren, E., Tanigaki, K., Amendola, M., Barnabé‐Heider, F., Yeung, M. S. Y., Naldini, L., et al. (2009) · Nature Neuroscience · doi:10.1038/nn.2268 · Cited by 463
“Notch maintains ependymal cell quiescence and phenotype Maintenance of cellular quiescence is an active proces”
BackgroundDissecting the Unique Role of the Retinoblastoma Tumor Suppressor during Cellular Senescence
Chicas, A., Wang, X., Zhang, C., McCurrach, M., Zhao, Z., Mert, O., Dickins, R. A., Narita, M., Zhang, M., & Lowe, S. W. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.01.023 · Cited by 388
“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).”
DLL4 Blockade Inhibits Tumor Growth and Reduces Tumor-Initiating Cell Frequency
Hoey, T., Yen, W.-C., Axelrod, F. T., Basi, J., Donigian, L., Dylla, S. J., Fitch-Bruhns, M., Lazetic, S., Park, I.-K., Sato, A. K., et al. (2009) · Cell stem cell · doi:10.1016/j.stem.2009.05.019 · Cited by 408
“HES1 expression has been shown to be important in maintaining cells in an undifferentiated, pluripotent state (Sang et al., 2008).”
BackgroundQuiescent Fibroblasts Exhibit High Metabolic Activity
Lemons, J. M. S., Feng, X., Bennett, B. D., Legesse-Miller, A., Johnson, E. L., Raitman, I., Pollina, E. A., RABITZ, H. A., Rabinowitz, J. D., & Coller, H. A. (2010) · PLoS Biology · doi:10.1371/journal.pbio.1000514 · Cited by 394
Self-citationMoore, N., & Lyle, S. R. (2010) · Journal of Oncology · doi:10.1155/2011/396076 · Cited by 378
“Increased expression of Hes1 has been observed in ovarian, breast, and nonsmall cell lung carcinomas, suggesting active regulation of Notch signaling [36].”
BackgroundNR2F1 controls tumour cell dormancy via SOX9- and RARβ-driven quiescence programmes
Sosa, M. S., Parikh, F., Gaspar‐Maia, A., Estrada, Y. D., Bosch, A., Bragado, P., Ekpin, E., George, A. D., Zheng, Y., Lam, H., et al. (2015) · Nature Communications · doi:10.1038/ncomms7170 · Cited by 357
Shea, K. L., Xiang, W., LaPorta, V. S., Licht, J. D., Keller, C., Basson, M. A., & Brack, A. S. (2010) · Cell stem cell · doi:10.1016/j.stem.2009.12.015 · Cited by 351
“The ability of a cell to undergo reversible quiescence is critical for maintenance of the stem cell pool (Sang et al., 2008).”
BackgroundDynamic Notch signaling in neural progenitor cells and a revised view of lateral inhibition
Kageyama, R., Ohtsuka, T., Shimojo, H., & Imayoshi, I. (2008) · Nature Neuroscience · doi:10.1038/nn.2208 · Cited by 334
Ehm, O., Göritz, C., Covic, M., Schäffner, I., Schwarz, T. J., Karaca, E., Kempkes, B., Kremmer, E., Pfrieger, F. W., Espinosa, L., et al. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.1567-10.2010 · Cited by 324
“The fact that Hes1 is essential for reversible quiescence in primary cells and tumor cells in vitro (Sang et al., 2008) and the fact that inactivation of RBPJ leads to loss of the quiescent radial glia-like stem cell population and a transient increase in proliferation (this study) raise the…”
BackgroundSkin Cell Heterogeneity in Development, Wound Healing, and Cancer
Rognoni, E., & Watt, F. M. (2018) · Trends in Cell Biology · doi:10.1016/j.tcb.2018.05.002 · Cited by 301
bHLH Factors in Self-Renewal, Multipotency, and Fate Choice of Neural Progenitor Cells
Imayoshi, I., & Kageyama, R. (2014) · Neuron · doi:10.1016/j.neuron.2014.03.018 · Cited by 279
“It has been shown that sustained Hes1 expression is required for the quiescent state of fibroblasts and that, without Hes1, cells become senescent, an irreversible dormant state in which cells never enter the cell cycle (Sang et al., 2008).”
Chapouton, P., Skupien, P., Hesl, B., Coolen, M., Moore, J. C., Madelaine, R., Kremmer, E., Faus-Kessler, T., Blader, P., Lawson, N. D., et al. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.6170-09.2010 · Cited by 259
“One important player in quiescence is the family of Hes or their her orthologs in zebrafish genes (Curry et al., 2006; Sang et al., 2008).”
BackgroundSosa, M. S., Avivar‐Valderas, A., Bragado, P., Wen, H., & Aguirre‐Ghiso, J. A. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-2574 · Cited by 243
“Dormancy of a tumor mass versus dormancy of tumor cells The lack of proliferation markers in surviving DTCs in patients and data from experimental systems suggest that DTC dormancy may be controlled by mechanisms of quiescence (5), a reversible growth arrest that can be brought about by different signals (29).”
BackgroundA GLI1‐p53 inhibitory loop controls neural stem cell and tumour cell numbers
Stecca, B. A., & Altaba, A. R. I. (2009) · The EMBO Journal · doi:10.1038/emboj.2009.16 · Cited by 236
“…the strong upregulation of Hes1 that we detect in vivo and in cerebellar stem cells is consistent with it being a Notch and Gli target (Ingram et al, 2008; V Wallace, personal communication) and is interesting in view of its recent implication in the prevention of senescence (Sang et al, 2008).”
BackgroundValcourt, J. R., Lemons, J. M. S., Haley, E. M., Kojima, M. L., Demuren, O. O., & Coller, H. A. (2012) · Cell Cycle · doi:10.4161/cc.19879 · Cited by 240
Self-citationDamsky, W., Rosenbaum, L. E., & Bosenberg, M. (2010) · Cancers · doi:10.3390/cancers3010126 · Cited by 233
“The HES1 transcription factor, a component of Notch signaling, has been described as an important mediator of the reversibility of quiescence [88] and could theoretically be involved in escape from metastatic dormancy.”
BackgroundVascular niche factor PEDF modulates Notch-dependent stemness in the adult subependymal zone
Andreu-Agulló, C., Morante‐Redolat, J. M., Delgado, A. C., & Fariñas, I. (2009) · Nature Neuroscience · doi:10.1038/nn.2437 · Cited by 218
“Recent evidence indicates that Hes1 prevents permanent cell-cycle exit, allowing for reversibility of the quiescent stat”
BackgroundEpigenomic enhancer annotation reveals a key role for NFIX in neural stem cell quiescencePreprint
Martynoga, B., Mateo, J. L., Zhou, B., Andersen, J., Achimastou, A., Urbán, N., van den Berg, D. L. C., Georgopoulou, D., Hadjur, S., Wittbrodt, J., et al. (2013) · Genes & Development · doi:10.1101/gad.216804.113 · Cited by 215
“Moreover, Hes1 is essential for the maintenance of fibroblast quiescence (Sang et al. 2008).”
BackgroundFramework models of tumor dormancy from patient-derived observations
Klein, C. A. (2010) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2010.10.011 · Cited by 207
“Interestingly, quiescence, activated via different mechanisms such as growth factor withdrawal or loss of adhesion, is not simply equivalent to exit from the cell cycle but includes suppression of differentiation and, unlike senescence, is reversible [55 ,56 ,57].”
BackgroundHes1: a key role in stemness, metastasis and multidrug resistance
Liu, Z.-H., Dai, X., & Du, B. (2015) · Cancer Biology & Therapy · doi:10.1080/15384047.2015.1016662 · Cited by 198
“However, sustained activation of Notch-p21 contributes to an irreversible senescent phenotype.(8,66) In contrast, cells that express full-length Hes1 genes resume proliferation, after a p21-induced senescent phenotype, as Hes1 transcriptionally represses p21 in a bHLH domain-dependent manner and Hes1 keeps quiescent c…”
BackgroundThe cell cycle and acute kidney injury
Price, P. M., Safirstein, R. L., & Megyesi, J. K. (2009) · Kidney International · doi:10.1038/ki.2009.224 · Cited by 203
Lying low but ready for action: the quiescent muscle satellite cell
Montarras, D., L’honoré, A., & BUCKINGHAM, M. E. (2013) · FEBS Journal · doi:10.1111/febs.12372 · Cited by 221
Acyl-CoA-Binding Protein Drives Glioblastoma Tumorigenesis by Sustaining Fatty Acid Oxidation
Duman, C., Yaqubi, K., Hoffmann, A., Açıkgöz, A. A., Korshunov, A., Bendszus, M., Herold‐Mende, C. C., Liu, H., & Alfonso, J. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.04.004 · Cited by 195
Cell cycle proliferation decisions: the impact of single cell analyses
Matson, J. P., & Cook, J. G. (2016) · FEBS Journal · doi:10.1111/febs.13898 · Cited by 183
Kusumbe, A. P., & Bapat, S. A. (2009) · Cancer Research · doi:10.1158/0008-5472.can-09-2802 · Cited by 184
“In contrast to other nonproliferative states (terminal differentiation/senescence), only quiescent stem cells retain the ability to resume proliferation (31).”
BackgroundSueda, R., Imayoshi, I., Harima, Y., & Kageyama, R. (2019) · Genes & Development · doi:10.1101/gad.323196.118 · Cited by 184
“Interestingly, these quiescent fibroblasts lost their ability to resume proliferation and entered senescence when Hes1 was knocked down, whereas high sustained Hes1 was sufficient to prevent these cells from entering senescence associated with prolonged cell cycle arrest (Sang et al. 2008).”
BackgroundHow the cell cycle impacts chromatin architecture and influences cell fate
Ma, Y., Kanakousaki, K., & Buttitta, L. (2015) · Frontiers in Genetics · doi:10.3389/fgene.2015.00019 · Cited by 166
“They find, consistent with the reprogramming studies of others (Egli et al., 2008; Ganier et al., 2011), that transfer of cells with nuclei in late G2 or M-phase confers a dramatic increase in the responsiveness to reprogramming factors and induction of pluripotency genes, up to 100 times faster…”
BackgroundResultModelling mammalian cellular quiescence
Yao, G. (2014) · Interface Focus · doi:10.1098/rsfs.2013.0074 · Cited by 180
“HES1 has been shown to be required for maintaining the reversible quiescent states by preventing premature senescence and differentiation [7,98].”
BackgroundNotch Inhibition as a Promising New Approach to Cancer Therapy
Purow, B. W. (2012) · Advances in experimental medicine and biology · doi:10.1007/978-1-4614-0899-4_23 · Cited by 157
Rao, S. S., O’Neil, J., Liberator, C. D., Hardwick, J. S., Dai, X., Zhang, T., Tyminski, E., Yuan, J., Kohl, N. E., Richon, V. M., et al. (2009) · Cancer Research · doi:10.1158/0008-5472.can-08-4295 · Cited by 153
“A recent report has shown that HES1 is required to prevent irreversible cell cycle exit of quiescent cells (38).”
BackgroundDynamic regulation of Notch signaling in neural progenitor cells
Kageyama, R., Ohtsuka, T., Shimojo, H., & Imayoshi, I. (2009) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2009.08.009 · Cited by 150
Alunni, A., Krecsmarik, M., Bosco, A., Galant, S., Pan, L., Moens, C. B., & Bally‐Cuif, L. (2013) · Development · doi:10.1242/dev.095018 · Cited by 135
“Profiling data in cultured fibroblasts identified Hes1 as quiescence factor that could directly antagonize senescence and differentiation programs, and was upregulated by Notch (Coller et al., 2006; Sang et al., 2008; Sang and Coller, 2009).”
BackgroundControlling Depth of Cellular Quiescence by an Rb-E2F Network Switch
Kwon, J. S., Everetts, N. J., Wang, X., Wang, W., Croce, K. D., Xing, J., & Yao, G. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.09.007 · Cited by 139
“Relatedly, it has been shown that Hes1, a Notch effector, maintains the reversibility of cellular quiescence against senescence (Sang et al., 2008).”
BackgroundDormancy of metastatic melanoma
Ossowski, L., & Aguirre‐Ghiso, J. A. (2009) · Pigment Cell & Melanoma Research · doi:10.1111/j.1755-148x.2009.00647.x · Cited by 135
“The most common mechanism is a G0-G1 arrest with high expression of p21 and p27 (Ducos et al., 2000; Florenes et al., 1996; Marches et al., 1998, 1999; Pelayo et al., 2006; Sang et al., 2008 and our unpublished data).”
BackgroundCell cycle and p53 gate the direct conversion of human fibroblasts to dopaminergic neurons
Jiang, H., Xu, Z., Zhong, P., Ren, Y., Liang, G., Schilling, H. A., Hu, Z., Zhang, Y., Wang, X., Chen, S., et al. (2015) · Nature Communications · doi:10.1038/ncomms10100 · Cited by 133
“To examine the effects of cell quiescence, ANLmp-infected MRC5 cells were maintained for four days in DMEM media with 0.1% FBS to induce quiescence 34,35 .”
InfluentialPutting the brakes on the cell cycle: mechanisms of cellular growth arrest
Pack, L. R., Daigh, L. H., & Meyer, T. (2019) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2019.05.005 · Cited by 139
Liu, Q., Nguyen, D. H. A., Dong, Q., Shitaku, P., Chung, K., Liu, O. Y., Tso, J. L., Liu, J. Y., Konkankit, V., Cloughesy, T. F., et al. (2009) · Journal of Neuro-Oncology · doi:10.1007/s11060-009-9919-z · Cited by 133
“The mechanisms and pathways underlying the spontaneous reentry into active cell cycle from the quiescent state in cultures and in animal experiments remain to be elucidated [57].”
BackgroundGamma Secretase Inhibitors in Cancer: A Current Perspective on Clinical Performance
McCaw, T. R., Inga, E. E., Chen, H., Jaskula‐Sztul, R., Dudeja, V., Bibb, J. A., Ren, B., & Rose, J. B. (2020) · The Oncologist · doi:10.1002/onco.13627 · Cited by 126
“One important downstream effector whose expression is activated by Notch is Hes1, a transcriptional repressor that prevents irreversible cell cycle exit [52].”
BackgroundOuttz, H. H., Wu, J. K., Wang, X., & Kitajewski, J. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.1000720 · Cited by 125
“7 cells are immortalized, and Notch signaling has been reported to interact with proteins that regulate the cell cycle (31, 32), we chose to explore the role of Notch signaling in cultured primary mouse BMM.”
BackgroundA human tRNA methyltransferase 9‐like protein prevents tumour growth by regulating LIN9 and HIF1‐α
Begley, U., Sosa, M. S., Avivar‐Valderas, A., Patil, A., Endres, L., Estrada, Y. D., Chan, C. T. Y., Su, D., Dedon, P. C., Aguirre‐Ghiso, J. A., et al. (2013) · EMBO Molecular Medicine · doi:10.1002/emmm.201201161 · Cited by 123
“…heterochromatin protein 1 g (HP1 g expression and presence of histone-3-tri-methyl-Lysine-9 marks, all senescence markers (Narita et al, 2006; Sang et al, 2008; Xue et al, 2007; Zhang et al, 2007), in SW620-Control (GFP) or SW620-hTRM9L tumour nodules or after their digestion using…”
Tipping, A. J., Pina, C., Castor, A., Hong, D., Rodrigues, N. P., Lazzari, L., May, G. E., Jacobsen, S. E. W., & Enver, T. (2009) · Blood · doi:10.1182/blood-2008-06-161117 · Cited by 126
Cellular senescence: Neither irreversible nor reversible
Reimann, M., Lee, S., & Schmitt, C. A. (2024) · The Journal of Experimental Medicine · doi:10.1084/jem.20232136 · Cited by 125
“…Bouma et al., 2012; Dias et al., 2021; Endo and Inoue, 2019; Ng et al., 2016; Oedekoven et al., 2021; Peeper et al., 2001; Phan and Croucher, 2020; Sage et al., 2000; Sang et al., 2008; Triana-Mart´ ı nez et al., 2020) (see Table 1 for a more detailed comparison of long-term arrest phenotypes).”
BackgroundMicroenvironments Dictating Tumor Cell Dormancy
Bragado, P., Sosa, M. S., Keely, P. J., Condeelis, J. S., & Aguirre‐Ghiso, J. A. (2012) · Recent results in cancer research/Recent Results in Cancer Research · doi:10.1007/978-3-642-28160-0_3 · Cited by 123
“The lack of proliferation markers in surviving DTCs obtained from patients and experimental studies suggest that solitary DTC dormancy might be controlled by mechanisms of quiescence [1], a reversible growth arrest that can be brought about by different signals [3].”
BackgroundSOX2 maintains the quiescent progenitor cell state of postnatal retinal Müller glia
Surzenko, N., Crowl, T., Bachleda, A., Langer, L., & Pevny, L. (2013) · Development · doi:10.1242/dev.071878 · Cited by 118
McKnight, J. N., Boerma, J. W., Breeden, L. L., & Tsukiyama, T. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.07.014 · Cited by 114
“Indeed, HES1, a component of a complex that recruits Rpd3, is critical for ensuring the reversibility of quiescence in Drosophila and suppressing senescence in human fibroblasts (Chen et al., 1999; Sang et al., 2008).”
Regulation of Tumor Cell Dormancy by Tissue Microenvironments and Autophagy
Sosa, M. S., Bragado, P., Debnath, J., & Aguirre‐Ghiso, J. A. (2012) · Advances in experimental medicine and biology · doi:10.1007/978-1-4614-1445-2_5 · Cited by 111
“The lack of proliferation markers in surviving DTCs obtained from patients and findings from experimental studies suggest that solitary DTC dormancy may be controlled by mechanisms of quiescence [1], a reversible growth arrest that can be induced by different signals [3].”
BackgroundClancy, H. A., Sun, H., Passantino, L., Kluz, T., Muñoz, A. B., Zavadil, J., & Costa, M. (2012) · Metallomics · doi:10.1039/c2mt20074k · Cited by 109
Cellular quiescence in budding yeast
Sun, S., & Gresham, D. (2020) · Yeast · doi:10.1002/yea.3545 · Cited by 108
Zhang, Y., Xu, W., Guo, H., Zhang, Y., He, Y., Lee, S. H., Song, X., Li, X., Guo, Y., Zhao, Y., et al. (2017) · Cancer Research · doi:10.1158/0008-5472.can-16-1633 · Cited by 104
Cellular senescence and its role in white adipose tissue
Smith, U., Li, Q., Rydén, M., & Spalding, K. L. (2021) · International Journal of Obesity · doi:10.1038/s41366-021-00757-x · Cited by 109
Hijacking HES1: how tumors co-opt the anti-differentiation strategies of quiescent cells
Sang, L., Roberts, J. M., & Coller, H. A. (2009) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2009.11.001 · Cited by 101
“Introduction of HES1 into proliferating fibroblasts made them resistant to a muscle differentiation program, whereas inhibition of HES1 in quiescent cells made them more responsive to differentiation-inducing transcription factors [12].”
InfluentialSelf-citationColler, H. A. (2011) · Science · doi:10.1126/science.1216242 · Cited by 100
Self-citationExpression Dynamics and Functions of Hes Factors in Development and Diseases
Kobayashi, T., & Kageyama, R. (2014) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/b978-0-12-405943-6.00007-5 · Cited by 98
Baumgart, A., Seidl, S., Vlachou, P., Michel, L., Mitova, N., Schatz, N., Specht, K., Koch, I., Schuster, T., Grundler, R., et al. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-3763 · Cited by 96
“It has been shown that Notch1 and HES1 are necessary for H-RasV12– induced tumorigenesis in fibroblasts (44, 45).”
BackgroundATRX is a regulator of therapy induced senescence in human cells
Kovatcheva, M., Liao, W., Klein, M. E., Robine, N., Geiger, H., Crago, A. M., Dickson, M. A., Tap, W. D., Singer, S., & Koff, A. (2017) · Nature Communications · doi:10.1038/s41467-017-00540-5 · Cited by 89
Crosstalk between the Rb pathway and AKT signaling forms a quiescence-senescence switch.
Imai, Y., Takahashi, A., Hanyu, A., Hori, S., Sato, S., Naka, K., Hirao, A., Ohtani, N., & Hara, E. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.03.006 · Cited by 84
Diao, Y., Guo, X. H., Jiang, L., Wang, G., Zhang, C., Wan, J., Jin, Y. J., & Wu, Z. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.494716 · Cited by 86
Rani, A., Greenlaw, R., Smith, R. A., & Galustian, C. (2016) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2016.03.010 · Cited by 84
“HES1 maintains cell quiescence by inhibiting p21 and thus preventing senescence [49].”
BackgroundDentin and dental pulp regeneration by the patient's endogenous cells
Kim, S. G., Zheng, Y., Zhou, J. P., Chen, M., Embree, M. C., Song, K., Jiang, N., & Mao, J. J. (2013) · Endodontic Topics · doi:10.1111/etp.12037 · Cited by 84
“Cell quiescence is critical in maintaining stem cell populations in a tissue without exhausting their proliferative potentials (37,38).”
BackgroundZacharioudaki, E., Magadi, S. S., & Delidakis, C. (2012) · Development · doi:10.1242/dev.071779 · Cited by 78
“Analogous experiments to address the role of dpn in Notchinduced overproliferation used a different activated Notch (UASNicd) (Seugnet et al., 1997) for technical reasons (see Materials and methods).”
MethodThe paradox of metabolism in quiescent stem cells
Coller, H. A. (2019) · FEBS Letters · doi:10.1002/1873-3468.13608 · Cited by 82
Self-citationMühleder, S., Fernández-Chacón, M., García-Gónzalez, I., & Benedito, R. (2020) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-020-03664-y · Cited by 84
“It has been demonstrated that short-term expression of p21 leads to a reversible growth arrest, while only a sustained and high expression of p21 induces irreversible cell cycle exit [171].”
BackgroundTranscriptional control of vertebrate neurogenesis by the proneural factor Ascl1
Vasconcelos, F. F., & Castro, D. S. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00412 · Cited by 81
“There is evidence that Hes1 activity both promotes and inhibits the cell cycle and therefore its oscillation may be required for cell proliferation (Castella et al., 2000; Hartman et al., 2004; Sang et al., 2008).”
Fibroblast Memory in Development, Homeostasis and Disease
Kirk, T., Ahmed, A., & Rognoni, E. (2021) · Cells · doi:10.3390/cells10112840 · Cited by 80
“While most fibroblasts are proliferative during development, in homeostasis adult fibroblasts generally exist in a quiescent state with a distinct metabolic programme [34], which is actively maintained by repressing proliferation and the transition into senescence or terminal differentiation [95,96].”
BackgroundViales, R. R., Diotel, N., Ferg, M., Armant, O., Eich, J., Alunni, A., März, M., Bally‐Cuif, L., Rastegar, S., & Strähle, U. (2014) · Stem Cells · doi:10.1002/stem.1883 · Cited by 73
Nakahara, F., Sakata-Yanagimoto, M., Komeno, Y., Kato, N., Uchida, T., Haraguchi, K., Kumano, K., Harada, Y., Harada, H., Kitaura, J., et al. (2010) · Blood · doi:10.1182/blood-2009-05-222836 · Cited by 38
Chapouton, P., Webb, K. J., Stigloher, C., Alunni, A., Adolf, B., Hesl, B., Topp, S., Kremmer, E., & Bally‐Cuif, L. (2011) · The Journal of Comparative Neurology · doi:10.1002/cne.22599 · Cited by 73
“…of Comparative Neurology | Research in Systems Neuroscience 1749 brain context is not known, Hes1 expression was shown to permit quiescence of hematopoietic stem cells (Yu et al., 2006) and to control the reversibility of the quiescent state in cultured fibroblast cell lines (Sang et al., 2008).”
BackgroundSturrock, M., Hellander, A., Anastasios Matzavinos, A., & Chaplain, M. A. J. (2013) · Journal of The Royal Society Interface · doi:10.1098/rsif.2012.0988 · Cited by 74
“The Hes1 GRN plays a central role in the timing of somitogenesis [1] and can become deregulated in human cancer [5].”
BackgroundGiovannini, C., Gramantieri, L., Minguzzi, M., Fornari, F., Chieco, P., Grazi, G. L., & Bolondi, L. (2012) · American Journal Of Pathology · doi:10.1016/j.ajpath.2012.04.019 · Cited by 71
Suh, E. J., Remillard, M., Legesse-Miller, A., Johnson, E. L., Lemons, J. M. S., Chapman, T. R., Forman, J. J., Kojima, M. L., Silberman, E., & Coller, H. A. (2012) · Genome biology · doi:10.1186/gb-2012-13-12-r121 · Cited by 70
“that preserves the reversibility of quiescence [14].”
Self-citationOchi, S., Imaizumi, Y., Shimojo, H., Miyachi, H., & Kageyama, R. (2020) · Development · doi:10.1242/dev.182204 · Cited by 72
“Furthermore, it has been shown that high and sustained levels of Hes1 repress the expression of cell cycle regulators and lead to G1 arrest in cultured fibroblasts, NPCs and hematopoietic stem cells (Baek et al. 2006; Yu et al., 2006; Sang et al., 2008), suggesting that high and sustained Hes1 is a general feature of…”
BackgroundLi, L., Miles, S., Melville, Z., Prasad, A., Bradley, G. T., & Breeden, L. L. (2013) · Molecular Biology of the Cell · doi:10.1091/mbc.e13-05-0241 · Cited by 69
“Multicellular organisms depend on the persistence and genetic stability of quiescent stem cells for their controlled growth, development, and tissue renewal (Tothova and Gilliland, 2007; Sang et al., 2008).”
BackgroundMacQuarrie, K. L., Yao, Z., Fong, A. P., Diede, S. J., Rudzinski, E. R., Hawkins, D. S., & Tapscott, S. J. (2012) · Molecular and Cellular Biology · doi:10.1128/mcb.00916-12 · Cited by 66
“implicated in the control of cellular senescence (21), and HES1, a bHLH protein involved 477 in the control of the quiescence-senescence decision in cells, contributes to the failure of 478 terminal differentiation in RMS cells (29).”
BackgroundA cell cycle centric view of tumour dormancy
Weston, W. A., & Barr, A. R. (2023) · British Journal of Cancer · doi:10.1038/s41416-023-02401-z · Cited by 68
“There is signi fi cant heterogeneity among quiescent cells depending on the induction signal and cellular context but all share the common feature of retaining proliferative potential [10, 11].”
BackgroundDeubiquitinating enzymes regulate Hes1 stability and neuronal differentiation
Kobayashi, T., Iwamoto, Y., Takashima, K., Isomura, A., Kosodo, Y., Kawakami, K., Nishioka, T., Kaibuchi, K., & Kageyama, R. (2015) · FEBS Journal · doi:10.1111/febs.13290 · Cited by 62
KSHV Manipulates Notch Signaling by DLL4 and JAG1 to Alter Cell Cycle Genes in Lymphatic Endothelia
Emuss, V., Lagos, D., Pizzey, A. R., Gratrix, F., Henderson, S. R., & Boshoff, C. (2009) · PLoS Pathogens · doi:10.1371/journal.ppat.1000616 · Cited by 62
A Novel Notch–YAP Circuit Drives Stemness and Tumorigenesis in Embryonal Rhabdomyosarcoma
Slemmons, K. K., Crose, L. E. S., Riedel, S., Sushnitha, M., Belyea, B., & Linardic, C. M. (2017) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-17-0004 · Cited by 62
SET Domain–Containing Protein 4 Epigenetically Controls Breast Cancer Stem Cell Quiescence
Ye, S., Ding, Y.-F., Jia, W.-H., Liu, X., Feng, J., Zhu, Q., Cai, S.-L., Yang, Y.-S., Lu, Q.-Y., Huang, X.-T., et al. (2019) · Cancer Research · doi:10.1158/0008-5472.can-19-1084 · Cited by 63
Gasiewicz, T. A., Singh, K. P., & Casado, F. L. (2009) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2009.10.019 · Cited by 64
Dynamic expression and roles of Hes factors in neural development
Kageyama, R., Shimojo, H., & Imayoshi, I. (2014) · Cell and Tissue Research · doi:10.1007/s00441-014-1888-7 · Cited by 60
Hes4 Controls Proliferative Properties of Neural Stem Cells During Retinal Ontogenesis
Yakoubi, W. E., Borday, C., Hamdache, J., Parain, K., Tran, H. T., Vleminckx, K., Perron, M., & Locker, M. (2012) · Stem Cells · doi:10.1002/stem.1231 · Cited by 61
Mews, P., Zee, B. M., Liu, S., Donahue, G., Garcia, B. A., & Berger, S. L. (2014) · Molecular and Cellular Biology · doi:10.1128/mcb.00763-14 · Cited by 60
Cheedipudi, S. M., Puri, D., Saleh, A., Gala, H., Rumman, M., Pillai, M. S., Sreenivas, P., Arora, R., Sellathurai, J., Schrøder, H. D., et al. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv567 · Cited by 60
“The bifurcation of arrest programs appears to be regulated by the Notch pathway, since G0 fibroblasts enter senescence-associated terminal arrest when depleted of the Notch target repressor Hes1, (60), while muscle SCs null for Notch effector RBPJ are diverted to differentiation-associated terminal arrest (9,61).”
BackgroundWang, S., Lin, X., Wang, H., Qin, Y., Chen, L., Li, J., Jia, J.-S., Shen, H.-F., Yang, S., Xie, R., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.5457 · Cited by 59
“As a member of the bHLH family, Hes1 is involved in brain development and cell lineage decision [1–6], self-renewal and differentiation of adult and embryonic stem cells [7–13], cell survival and apoptosis [11, 14], cell differentiation [15–19], and cellular senescence [17].”
BackgroundFiaschetti, G., Abela, L., Nonoguchi, N., Dubuc, A. M., Remke, M., Boro, A., Grunder, E., Siler, U., Ohgaki, H., Taylor, M. D., et al. (2013) · British Journal of Cancer · doi:10.1038/bjc.2013.764 · Cited by 58
“Given the important regulatory function of HES1 in neuronal differentiation (Kabos et al, 2002; Sang et al, 2008), we hypothesised that miR-9-mediated repression of HES1 could trigger the differentiation of MB cells.”
BackgroundFähling, M., Mrowka, R., Steege, A., Kirschner, K. M., Benko, E., Förstera, B., Persson, P. B., Thiele, B. J., Meier, J. C., & Scholz, H. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m807354200 · Cited by 61
Hes1 Increases the Invasion Ability of Colorectal Cancer Cells via the STAT3-MMP14 Pathway
Weng, M., Tsao, P., Lin, H., Tung, C.-C. C.-C., Change, M., Chang, Y., Wong, J., & Wei, S. (2015) · PLoS ONE · doi:10.1371/journal.pone.0144322 · Cited by 58
Intrinsic checkpoint deficiency during cell cycle re-entry from quiescence
Matson, J. P., House, A. M., Grant, G. D., Wu, H., Perez, J., & Cook, J. G. (2019) · The Journal of Cell Biology · doi:10.1083/jcb.201902143 · Cited by 59
“G0 is distinct from a G1 arrest; it is an active state requiring upregulation of anti-apoptotic, anti-senescent, and anti-differentiation genes as well as repression of cell cycle genes (Coller et al., 2006; Sang et al., 2008; Litovchick et al., 2007; Sagot and Laporte, 2019).”
BackgroundEpithelial proliferation and cell cycle dysregulation in kidney injury and disease
Lee, K., Gusella, G. L., & He, C. (2021) · Kidney International · doi:10.1016/j.kint.2021.03.024 · Cited by 56
Casado, F. L., Singh, K. P., & Gasiewicz, T. A. (2010) · Blood Cells Molecules and Diseases · doi:10.1016/j.bcmd.2010.01.005 · Cited by 59
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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