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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Interruption of the DDR pathway is no longer sufficient to rescue growth once cells have progressed towards an established senescent phenotype.
“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
The passage describing the p21-removal experiment (indexed under Abstract; page unavailable) reports that fibroblasts remained unable to reenter the cell cycle and displayed senescence markers after p21 returned to baseline. Another passage says activating HES1 did not reverse senescence after the phenotypic transition. These findings support the claim that established senescence was not rescued, but the paper does not report interruption of the DDR pathway. (LLM, conf=0.82)
Experimental — accuracy not yet measuredThe discrepancy in our results may relate to cell type or species differences or to HES1 status, which may determine quiescence reversibility (Sang et al., 2008).
“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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“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).”
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“HES1 has been shown to be required for maintaining the reversible quiescent states by preventing premature senescence and differentiation [7,98].”
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“A recent report has shown that HES1 is required to prevent irreversible cell cycle exit of quiescent cells (38).”
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“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).”
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“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
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BackgroundCell cycle and p53 gate the direct conversion of human fibroblasts to dopaminergic neurons
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InfluentialPutting the brakes on the cell cycle: mechanisms of cellular growth arrest
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“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
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“One important downstream effector whose expression is activated by Notch is Hes1, a transcriptional repressor that prevents irreversible cell cycle exit [52].”
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“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 122 · see citing works
“…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…”
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Cellular senescence: Neither irreversible nor reversible
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“…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 117 · see citing works
“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 117 · see citing works
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“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 109 · see citing works
“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 · see citing works
Cellular quiescence in budding yeast
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Cellular senescence and its role in white adipose tissue
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Hijacking HES1: how tumors co-opt the anti-differentiation strategies of quiescent cells
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“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 · see citing works
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 · see citing works
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“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 · see citing works
Crosstalk between the Rb pathway and AKT signaling forms a quiescence-senescence switch.
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“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 · see citing works
“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 · see citing works
“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 · see citing works
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 79 · see citing works
“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 79 · see citing works
“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 78 · see citing works
“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 · see citing works
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“…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 71 · see citing works
“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 · see citing works
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 67 · see citing works
“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 69 · see citing works
“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 68 · see citing works
“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 · see citing works
“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 64 · see citing works
“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 · see citing works
KSHV Manipulates Notch Signaling by DLL4 and JAG1 to Alter Cell Cycle Genes in Lymphatic Endothelia
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A Novel Notch–YAP Circuit Drives Stemness and Tumorigenesis in Embryonal Rhabdomyosarcoma
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SET Domain–Containing Protein 4 Epigenetically Controls Breast Cancer Stem Cell Quiescence
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Gasiewicz, T. A., Singh, K. P., & Casado, F. L. (2009) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2009.10.019 · Cited by 61 · see citing works
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 · see citing works
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 · see citing works
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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 59 · see citing works
“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).”
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“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 · see citing works
“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 58 · see citing works
Hes1 Increases the Invasion Ability of Colorectal Cancer Cells via the STAT3-MMP14 Pathway
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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 58 · see citing works
“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 · see citing works
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 57 · see citing works
- 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
- Health Sciences › Medicine › Physiology › 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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