Cited by 313Telomeres, Telomerase, and SenescenceCancer-related Molecular PathwaysDevelopmental Biology and Gene Regulation

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Control of the Reversibility of Cellular Quiescence by the Transcriptional Repressor HES1

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Sang, Liyun, Coller, Hilary A., Roberts, James M.·2008·Science

DOI 10.1126/science.1155998PMC PMC2721335

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Abstract

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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Background
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BackgroundInfluential
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“which was shown to be necessary for maintenance of the quiescent status (Sang et al., 2008).”
BackgroundInfluential
Oxidative Mechanisms in Liver Senescence and Regeneration
Marongiu, F., Serra, M. P., & Laconi, E. (2015) · Oxidative stress in applied basic research and clinical practice · doi:10.1007/978-3-319-15539-5_3
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Immunotherapies Towards Tumor Initiating Cells and Cancer Stem Cells
Rajan, P., & Srinivasan, R. (2008) · The Open Cancer Immunology Journal · doi:10.2174/1876401000801010001
“A recent report indicates that HES1 causes cells to remain in quiescent state without inducing senescence [52].”
Targeting Breast Cancer Recurrence via Hedgehog-Mediated Sensitization of Breast Cancer Stem Cells
DiRenzo, J. (2011) · doi:10.21236/ada560850
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“Several Notch effector genes, including inhibitor of differentiation 4 (ID4) (65), hairy and enhancer of split 1 (HES1) (66), hairy/enhancer-of-split related with YRPW motif 1 (HEY1) (67) and fatty acid binding protein 7 (FABP7) (68), have been detected in GSC by expression microarray analysis, thereby reflecting the…”
Background
Caractérisation des cellules souches cancéreuses de la peau humaine (implication de la voie de signalisation de l'Epidermal Growth Factor Receptor dans le contrôle de la différenciation des cellules souches de l'épiderme)
Roy, H. L., & POLAKOWSKA, R. (2009) · OpenGrey (Institut de l'Information Scientifique et Technique)
Translational Control of Cell Proliferation and Viability in Normal and Neoplastic Cells
Avdulov, S. V., Gómez-García, J. R., Bitterman, P. B., & Polunovsky, V. A. (2014) · Springer eBooks · doi:10.1007/978-94-017-9078-9_18
Back and forth
Heinrichs, A. A. J. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2506
Thrombospondin Inhibits VEGF-Induced Endothelial Survival and Cell Cycle Progression
Gupta, K., Schwartz, R. E., Gupta, P., & Hebbel, R. P. (2009) · The Open Circulation & Vascular Journal · doi:10.2174/1877382600902010001
“Cell cycle regulation by cyclin-dependent kinase inhibitors (CDK-I) such as p21 CIP/WAF-1 and p27 KIP-1 (called p21 and p27) is critical in maintaining cell cycle arrest in serum-starved or quiescent cells [22, 23].”
Ion homeostasis in control of stem cell proliferation
Abdelhady, S. (2015) · Figshare
Notch Pathway Blockade in Human Glioblastoma Stem Cells Defines Heterogeneity and Sensitivity to Neuronal Lineage Commitment
Ling, E. K. M. (2012) · TSpace (University of Toronto)
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MacQuarrie, K. L. (2011) · authors@Fred Hutch (Fred Hutchinson Cancer Research Center)
The role of MITF in the regulation of CDKN2A in melanoma
Andreassen, R. C. (2017) · NORA - Norwegian Open Research Archives
Dormancy of Disseminated Tumor Cells: Reciprocal Crosstalk with the Microenvironment
Bragado, P., Ranganathan, A. C., & Aguirre‐Ghiso, J. A. (2010) · Springer eBooks · doi:10.1007/978-1-4419-6615-5_11
Stochastic model analysis for Hes1/MiR-9 brain cell division system
Sikarwar, V., Chaurasia, V., Yadav, J. S., & Kurmi, Y. (2017) · International Conference on Recent Innovations in Signal Processing and Embedded Systems (RISE) · doi:10.1109/rise.2017.8378208
“As a member of the bHLH family, Hes1 is involved in brain development, cell lineage decision, cell differentiation [3], and cellular senescence [4].”
Background
Peer Review #2 of "Transcriptomic study of the mechanism of anoikis resistance in head and neck squamous carcinoma (v0.1)"
(2019) · PeerJ · doi:10.7287/peerj.6978v0.1/reviews/2
Peer Review #2 of "Transcriptomic study of the mechanism of anoikis resistance in head and neck squamous carcinoma (v0.2)"
(2019) · PeerJ · doi:10.7287/peerj.6978v0.2/reviews/2
Ectopic Notch Activation in Developing Podocytes Impairs Slit Diaphragm Formation and Induces Abnormal Podocyte Differentiation
Waters, A. M. (2009) · TSpace (University of Toronto)
An Introduction to Proliferation and Migration of Stem and Cancer Cells
Pillat, M. M., Glaser, T., Schwindt, T. T., & Ulrich, H. (2013) · Springer eBooks · doi:10.1007/978-94-007-6211-4_1
Dissecting the molecular mechanism and spatiotemporal dynamics controlling senescence entry
Sofiadis, K. (2021) · eDiss (Georg-August-Universität Göttingen) · doi:10.53846/goediss-8409
HES1 expression associates with survival in triple negative breast cancer.Preprint
Mamoor, S. (2021) · doi:10.31219/osf.io/zy5ha
Faculty Opinions recommendation of Dissecting the unique role of the retinoblastoma tumor suppressor during cellular senescence.
Kaldis, P. (2010) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.3090956.2774054
Faculty Opinions recommendation of Quiescent fibroblasts exhibit high metabolic activity.
Huber, B. T. (2010) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.6131956.7173054
Notch Signaling in Cancer Metastasis
Zhang, P., & Zweidler‐McKay, P. A. (2010) · Cancer metastasis · doi:10.1007/978-90-481-9522-0_9
“The Notch target gene HES1 was reported as a key regulator for the maintenance of the quiescent status of adult stem cell and tumor stem cells [ 87 ].”
Background
Peer Review #1 of "Transcriptomic study of the mechanism of anoikis resistance in head and neck squamous carcinoma (v0.1)"
(2019) · PeerJ · doi:10.7287/peerj.6978v0.1/reviews/1
Faculty Opinions recommendation of Sprouty1 regulates reversible quiescence of a self-renewing adult muscle stem cell pool during regeneration.
Rawlins, E. (2012) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.2384956.793463448
Peer Review #1 of "Transcriptomic study of the mechanism of anoikis resistance in head and neck squamous carcinoma (v0.2)"
(2019) · PeerJ · doi:10.7287/peerj.6978v0.2/reviews/1
Pten is a disconnecting node in the molecular landscape of the proliferation/quiescence decision during mammary gland acinogenesisPreprint
Tomasin, R., Rodrigues, A. M., Manucci, A. C., & Bruni‐Cardoso, A. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.03.13.532403
Data from Inhibition of the Notch-Hey1 Axis Blocks Embryonal Rhabdomyosarcoma Tumorigenesis
Belyea, B., Naini, S., Bentley, R. C., & Linardic, C. M. (2023) · doi:10.1158/1078-0432.c.6519921
Data from Inhibition of the Notch-Hey1 Axis Blocks Embryonal Rhabdomyosarcoma Tumorigenesis
Belyea, B., Naini, S., Bentley, R. C., & Linardic, C. M. (2023) · doi:10.1158/1078-0432.c.6519921.v1
Dynamic Transcriptional Control of Neural Stem Cells
Kageyama, R., & Shimojo, H. (2023) · Wiley eBooks · doi:10.1002/9781119860914.ch6
HES1 revitalizes the functionality of aged adipose-derived stem cells by inhibiting the transcription of STAT1
Li, C., Ren, S., Yan, C., Wang, C., Jiang, T., Kang, Y., Chen, J., Xiong, H., Guo, J., Jiang, G., et al. (2024) · Stem Cell Research & Therapy · doi:10.1186/s13287-024-04002-w
“Its expression is widespread across various tissues and cell types, particularly in quiescent and stem cells, where it plays a critical role in inhibiting differentiation [28].”
Background
An Agent-Based Model of Avascular Tumor Growth
Pompa, M., Gaetano, A. D., Borri, A., D’Orsi, L., & Panunzi, S. (2024) · IEEE International Symposium on Computational Intelligence and Informatics (CINTI) · doi:10.1109/cinti63048.2024.10830867
Latrophilin-2 mediates flow activation of Notch to control vascular endothelial phenotype and atherosclerosisPreprint
Tanaka, K., Chen, M., Joshi, D., Chanduri, M. V. L., Zhang, H., Fernandez-Hernando, C. F., Koh, Y.-M., & Schwartz, M. A. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.07.01.662676
“This canonical Notch signaling pathway inhibits VEGF receptor expression and angiogenesis, induces quiescence and promotes arterial identity 17-19 .”
Defective collagen VI-NG2 axis impairs pericyte balance between proliferation and quiescence in COLVI-related myopathies
Fazio, A., Sabatelli, P., Faldini, C., Martino, A. C. D., Marvi, M. V., Neri, I., Koufi, F., Merlini, L., Manzoli, L., Ratti, S., et al. (2025) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2025.168012
Proteome profiling reveals HES1-driven mitotic catastrophe in ovarian serous carcinomaPreprint
Bao, J., Pikkusaari, S., Dai, J., Leppiniemi, S., Huang, W., Yang, W., Anil, A., Pääkkönen, M., Lei, C., Ortiz, E. D. M., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.08.20.671256
“This HES1-induced cell cycle arrest has been considered as irreversible senescence [64], reinforcing HES1 as a promising anti-cancer target.”
Importance of ultradian oscillations in neurogenesis during development and its implications for spinal cord regeneration
Leino, S. A., & Soto, X. (2025) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2025.1680322
Drug target proteome profiling identifies HES1-driven mitotic catastrophe in ovarian serous carcinoma
Bao, J., Pikkusaari, S., Dai, J., Leppiniemi, S., Huang, W., Yang, W., Anil, A., Pääkkönen, M., Lei, C., Ortiz, E. D. M., et al. (2025) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2025.118716

Authors: Sang, L., Coller, H. A., & Roberts, J. M.
Affiliations: Princeton University (US)
Corresponding author: Roberts, James M.
ORCID: Coller, Hilary A.
Roberts, James M.
Venue: Science
Publisher: American Association for the Advancement of Science (AAAS)
Published: 2008-08-22
Volume: 321
Issue: 5892
Pages: 1095-1100
ISSN: 0036-8075 (ISSN-L)
1095-9203
DOI: 10.1126/science.1155998
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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Control of the Reversibility of Cellular Quiescence by the Transcriptional Repressor HES1

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