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p53-Dependent Nestin Regulation Links Tumor Suppression to Cellular Plasticity in Liver Cancer
Open accessAbstract
The p53 tumor suppressor coordinates a series of antiproliferative responses that restrict the expansion of malignant cells, and as a consequence, p53 is lost or mutated in the majority of human cancers. Here, we show that p53 restricts expression of the stem and progenitor-cell-associated protein nestin in an Sp1/3 transcription-factor-dependent manner and that Nestin is required for tumor initiation in vivo. Moreover, loss of p53 facilitates dedifferentiation of mature hepatocytes into nestin-positive progenitor-like cells, which are poised to differentiate into hepatocellular carcinomas (HCCs) or cholangiocarcinomas (CCs) in response to lineage-specific mutations that target Wnt and Notch signaling, respectively. Many human HCCs and CCs show elevated nestin expression, which correlates with p53 loss of function and is associated with decreased patient survival. Therefore, transcriptional repression of Nestin by p53 restricts cellular plasticity and tumorigenesis in liver cancer.
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“NF-Y77 and Sp178, 79 are the coactivators most commonly linked to p53-dependent gene downregulation through a mechanism of p53 interference.”
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Cites
A System for Stable Expression of Short Interfering RNAs in Mammalian Cells
Brummelkamp, T. R., Bernards, R., & Agami, R. (2002) · Science · doi:10.1126/science.1068999 · Cited by 4,295
Blinded by the Light: The Growing Complexity of p53
Vousden, K. H., & Prives, C. (2009) · Cell · doi:10.1016/j.cell.2009.04.037 · Cited by 3,163
Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas
Xue, W., Zender, L., Miething, C., Dickins, R. A., Hernando, E., Krizhanovsky, V., Cordon-Cardo, C., & Lowe, S. W. (2007) · Nature · doi:10.1038/nature05529 · Cited by 2,473
Self-citationElucidation of a universal size-control mechanism in Drosophila and mammals
Dong, J., Feldmann, G., Huang, J., Wu, S., Zhang, N., Comerford, S. A., Gayyed, M. F., Anders, R. A., Maitra, A., & Pan, D. (2007) · Cell · doi:10.1016/j.cell.2007.07.019 · Cited by 2,370
A restricted cell population propagates glioblastoma growth after chemotherapy
Chen, J., Li, Y., Yu, T.-S., McKay, R. M., Burns, D. K., Kernie, S. G., & Parada, L. F. (2012) · Nature · doi:10.1038/nature11287 · Cited by 2,354
Vousden, K. H., & Lane, D. P. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2147 · Cited by 2,351
Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways
Grimm, D., Streetz, K. L., Jopling, C. L., Storm, T. A., Pandey, K., Davis, C. R., Marion, P., Salazar, F., & Kay, M. A. (2006) · Nature · doi:10.1038/nature04791 · Cited by 1,677
Suppression of induced pluripotent stem cell generation by the p53–p21 pathway
Hong, H., Takahashi, K., Ichisaka, T., Aoi, T., Kanagawa, O., Nakagawa, M., Okita, K., & Yamanaka, S. (2009) · Nature · doi:10.1038/nature08235 · Cited by 1,301
Bond, G. L., Hu, W., Bond, E. E., Robins, H., Lutzker, S. G., Arva, N. C., Bargonetti, J., Bartel, F., Taubert, H., Wuerl, P., et al. (2004) · Cell · doi:10.1016/j.cell.2004.11.022 · Cited by 1,265
Linking the p53 tumour suppressor pathway to somatic cell reprogramming
Kawamura, T., Suzuki, J., Wang, Y. V., Menendez, S., Morera, L. B., Raya, A., Wahl, G. M., & Belmonte, J. C. I. (2009) · Nature · doi:10.1038/nature08311 · Cited by 1,115
Intestinal Tumorigenesis Initiated by Dedifferentiation and Acquisition of Stem-Cell-like Properties
Schwitalla, S., Fingerle, A. A., Cammareri, P., Nebelsiek, T., Göktuna, S. İ., Ziegler, P. K., Canli, Ö., Heijmans, J., Huels, D. J., Moreaux, G., et al. (2012) · Cell · doi:10.1016/j.cell.2012.12.012 · Cited by 1,098
Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach
Zender, L., Spector, M. S., Xue, W., Flemming, P., Cordon-Cardo, C., Silke, J., Fan, S.-T., Luk, J. M., Wigler, M., Hannon, G. J., et al. (2006) · Cell · doi:10.1016/j.cell.2006.05.030 · Cited by 1,065
Self-citationA p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity
Marión, R. M., Strati, K., Li, H., Murga, M., Blanco, R., Ortega, S., Fernandez-Capetillo, O., Serrano, M., & Blasco, M. A. (2009) · Nature · doi:10.1038/nature08287 · Cited by 1,028
Direct cell reprogramming is a stochastic process amenable to acceleration
Hanna, J., Saha, K., Pando, B., van Zon, J., Lengner, C. J., Creyghton, M. P., van Oudenaarden, A., & Jaenisch, R. (2009) · Nature · doi:10.1038/nature08592 · Cited by 938
p53 induces differentiation of mouse embryonic stem cells by suppressing Nanog expression
Lin, T., Chao, C., Saito, S., Mazur, S. J., Murphy, M. E., Appella, E., & Xu, Y. (2004) · Nature Cell Biology · doi:10.1038/ncb1211 · Cited by 859
Non-Cell-Autonomous Tumor Suppression by p53
Lujambio, A., Akkari, L., Simon, J., Grace, D., Tschaharganeh, D. F., Bolden, J. E., Zhao, Z., Thapar, V., Joyce, J. A., Krizhanovsky, V., et al. (2013) · Cell · doi:10.1016/j.cell.2013.03.020 · Cited by 766
Self-citationBoulter, L., Govaere, O., Bird, T. G., Radulescu, S., Ramachandran, P., Pellicoro, A., Ridgway, R. A., Seo, S. S., Spee, B., Van Rooijen, N., et al. (2012) · Nature Medicine · doi:10.1038/nm.2667 · Cited by 747
Sherr, C. J., & DePinho, R. A. (2000) · Cell · doi:10.1016/s0092-8674(00)00046-5 · Cited by 745
Neural stem and progenitor cells in nestin‐GFP transgenic mice
Mignone, J., Kukekov, V. G., Chiang, A., Steindler, D. A., & Enikolopov, G. (2004) · The Journal of Comparative Neurology · doi:10.1002/cne.10964 · Cited by 707
Self-citationDedifferentiation of committed epithelial cells into stem cells in vivo
Tata, P. R., Mou, H., Pardo–Saganta, A., Zhao, R., Prabhu, M., Law, B. M., Vinarsky, V., Cho, J. L., Breton, S., Sahay, A., et al. (2013) · Nature · doi:10.1038/nature12777 · Cited by 679
Hussain, S. P., Schwank, J., Staib, F., Wang, X. W., & Harris, C. C. (2007) · Oncogene · doi:10.1038/sj.onc.1210279 · Cited by 643
Dedifferentiation of Neurons and Astrocytes by Oncogenes Can Induce Gliomas in Mice
Friedmann‐Morvinski, D., Bushong, E. A., Ke, E., Soda, Y., Marumoto, T., Singer, O., Ellisman, M. H., & Verma, I. M. (2012) · Science · doi:10.1126/science.1226929 · Cited by 566
Andersen, J. B., Spee, B., Blechacz, B. R. A., Avital, I., Komuta, M., Barbour, A. P., Conner, E. A., Gillen, M. C., Roskams, T., Roberts, L. R., et al. (2011) · Gastroenterology · doi:10.1053/j.gastro.2011.12.005 · Cited by 564
Self-citationDistinct p53 Transcriptional Programs Dictate Acute DNA-Damage Responses and Tumor Suppression
Brady, C. A., Jiang, D., Mello, S. S., Johnson, T. M., Jarvis, L. A., Kozak, M. M., Broz, D. K., Basak, S., Park, E. J., McLaughlin, M. E., et al. (2011) · Cell · doi:10.1016/j.cell.2011.03.035 · Cited by 533
Cholangiocarcinomas can originate from hepatocytes in mice
Fan, B., Malato, Y., Calvisi, D. F., Naqvi, S., Razumilava, N., Ribback, S., Gores, G. J., Dombrowski, F., Evert, M., Chen, X., et al. (2012) · Journal of Clinical Investigation · doi:10.1172/jci63212 · Cited by 529
Self-citationYant, S. R., Meuse, L. A., Chiu, W. S., Ivics, Z., Izsvák, Z., & Kay, M. A. (2000) · Nature Genetics · doi:10.1038/75568 · Cited by 509
Godár, S., Ince, T. A., Bell, G. W., Feldser, D. M., Donaher, J. L., Bergh, J. C. S., Liu, A. Y., Miu, K., Watnick, R. S., Reinhardt, F., et al. (2008) · Cell · doi:10.1016/j.cell.2008.06.006 · Cited by 455
Harvey, D. M., & Levine, A. J. (1991) · Genes & Development · doi:10.1101/gad.5.12b.2375 · Cited by 453
Liver stem cells and their implication in hepatocellular and cholangiocarcinoma
Roskams, T. (2006) · Oncogene · doi:10.1038/sj.onc.1209558 · Cited by 434
Sugimoto, K., Gordon, S., & Meyerowitz, E. M. (2011) · Trends in Cell Biology · doi:10.1016/j.tcb.2010.12.004 · Cited by 356
Intrahepatic cholangiocarcinoma can arise from Notch-mediated conversion of hepatocytes
Sekiya, S., & Suzuki, A. (2012) · Journal of Clinical Investigation · doi:10.1172/jci63065 · Cited by 348
A Rapid and Scalable System for Studying Gene Function in Mice Using Conditional RNA Interference
Premsrirut, P. K., Dow, L. E., Kim, S. Y., Camiolo, M., Malone, C. D., Miething, C., Scuoppo, C., Zuber, J., Dickins, R. A., Kogan, S. C., et al. (2011) · Cell · doi:10.1016/j.cell.2011.03.012 · Cited by 315
Self-citationZhang, L., Yu, D., Hu, M., Xiong, S., Lang, A., Ellis, L. M., & Pollock, R. E. (2000) · PubMed · Cited by 230
Lutzker, S. G., & Levine, A. J. (1996) · Nature Medicine · doi:10.1038/nm0796-804 · Cited by 206
Transcriptional repression mediated by the p53 tumour suppressor
Ho, J., & Benchimol, S. (2003) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4401191 · Cited by 203
Molecular classification of prostate cancer using curated expression signatures
Markert, E. K., Mizuno, H., Vázquez, A., & Levine, A. J. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1117029108 · Cited by 182
Deregulation of Hippo kinase signalling in Human hepatic malignancies
Li, H., Wolfe, A. R., Septer, S. S., Edwards, G., Zhong, X., Abdulkarim, A. B., Ranganathan, S., & Apte, U. M. (2011) · Liver International · doi:10.1111/j.1478-3231.2011.02646.x · Cited by 168
A nestin scaffold links Cdk5/p35 signaling to oxidant‐induced cell death
Sahlgren, C., Pallari, H., He, T., Chou, Y.-H., Goldman, R. D., & Eriksson, J. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601366 · Cited by 166
Inactivation of p53 in breast cancers correlates with stem cell transcriptional signatures
Mizuno, H., Spike, B. T., Wahl, G. M., & Levine, A. J. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1017001108 · Cited by 161
p53, Stem Cells, and Reprogramming: Tumor Suppression beyond Guarding the Genome
Spike, B. T., & Wahl, G. M. (2011) · Genes & Cancer · doi:10.1177/1947601911410224 · Cited by 160
Locating the stem cell niche and tracing hepatocyte lineages in human liver #
Fellous, T. G., Islam, S., Tadrous, P. J., Elia, G., Kocher, H. M., Bhattacharya, S., Mears, L., Turnbull, D. M., Taylor, R. W., Greaves, L. C., et al. (2009) · Hepatology · doi:10.1002/hep.22791 · Cited by 157
Genetics of Hepatobiliary Carcinogenesis
Nault, J., & Zucman‐Rossi, J. (2011) · Seminars in Liver Disease · doi:10.1055/s-0031-1276646 · Cited by 157
Methylome analysis and integrative profiling of human HCCs identify novel protumorigenic factors
Neumann, O., Kesselmeier, M., Geffers, R., Pellegrino, R., Radlwimmer, B., Hoffmann, K., Ehemann, V., Schemmer, P., Schirmacher, P., Bermejo, J. L., et al. (2012) · Hepatology · doi:10.1002/hep.25870 · Cited by 152
Self-citationBell, J. B., Podetz-Pedersen, K. M., Aronovich, E. L., Belur, L. R., McIvor, R. S., & Hackett, P. B. (2007) · Nature Protocols · doi:10.1038/nprot.2007.471 · Cited by 144
The atypical E2F family member E2F7 couples the p53 and RB pathways during cellular senescencePreprint
Aksoy, O., Chicas, A., Zeng, T., Zhao, Z., McCurrach, M. E., Wang, X., & Lowe, S. W. (2012) · Genes & Development · doi:10.1101/gad.196238.112 · Cited by 130
Self-citationRegulation of p53 is critical for vertebrate limb regeneration
Yun, M. H., Gates, P. B., & Brockes, J. P. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1310519110 · Cited by 116
Nestin expression in human tumors and tumor cell lines.
Krupkova_Jr, O., Loja, T., Zambo, I. S., & Veselská, R. (2010) · Neoplasma · doi:10.4149/neo_2010_04_291 · Cited by 107
Disruption of Trp53 in Livers of Mice Induces Formation of Carcinomas With Bilineal Differentiation
Katz, S., Lechel, A., Obenauf, A. C., Begus‐Nahrmann, Y., Kraus, J. M., Hoffmann, E. M., Duda, J., Eshraghi, P., Hartmann, D., Liss, B., et al. (2012) · Gastroenterology · doi:10.1053/j.gastro.2012.02.009 · Cited by 96
Self-citationIn vivo analysis of p53 tumor suppressor function using genetically engineered mouse models
Brož, D. K., & Attardi, L. D. (2010) · Carcinogenesis · doi:10.1093/carcin/bgp331 · Cited by 92
Zhao, Y., Zhang, W., Guo, Z., Ma, F., Yao, W., Bai, Y., Gong, W., Chen, Y., Cheng, T., Zhi, F., et al. (2013) · Oncology Reports · doi:10.3892/or.2013.2627 · Cited by 90
Regulation of Sp1 by cell cycle related proteins
Tapias, A., Ciudad, C. J., Roninson, I. B., & Noé, V. (2008) · Cell Cycle · doi:10.4161/cc.7.18.6671 · Cited by 82
Saborowski, A. L., Saborowski, M., Davare, M. A., Druker, B. J., Klimstra, D. S., & Lowe, S. W. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1311707110 · Cited by 73
Self-citationExpression of nestin–green fluorescent protein transgene marks oval cells in the adult liver
Gleiberman, A. S., Encinas, J. M., Mignone, J., Michurina, T. V., Rosenfeld, M. G., & Enikolopov, G. (2005) · Developmental Dynamics · doi:10.1002/dvdy.20536 · Cited by 66
Self-citationWild-type p53 gene expression induces granulocytic differentiation of HL-60 cells
Soddu, S., Blandino, G., Citro, G., Scardigli, R., Piaggio, G., Ferber, A., Calabretta, B., & Sacchi, A. (1994) · Blood · doi:10.1182/blood.v83.8.2230.2230 · Cited by 61
Characterization and promoter analysis of the mouse nestin gene
Cheng, L., Jin, Z., Liu, L., Yan, Y., Li, T., Zhu, X., & Jing, N. (2004) · FEBS Letters · doi:10.1016/j.febslet.2004.03.097 · Cited by 42
Functional analysis of two Sp1/Sp3 binding sites in murine Nanog gene promoter
Wu, D. Y., & Yao, Z. (2006) · Cell Research · doi:10.1038/sj.cr.7310040 · Cited by 36
Lu, W. J., Lan, F., He, Q., Lee, A. S., Tang, C. Z., Dong, L., Lan, B., Ma, X., Wu, J. C., & Li, S. (2010) · International Journal of Cancer · doi:10.1002/ijc.25586 · Cited by 32
Involvement of intermediate filament nestin in cell growth of small-cell lung cancer
Takakuwa, O., Maeno, K., Kunii, E., Ozasa, H., Hijikata, H., Uemura, T., Kasai, D., Ohkubo, H., Miyazaki, M., Oguri, T., et al. (2013) · Lung Cancer · doi:10.1016/j.lungcan.2013.04.022 · Cited by 27
Rumsby, P. C., DAVIES, M. J., & Evans, J. G. (1994) · Molecular Carcinogenesis · doi:10.1002/mc.2940090204 · Cited by 19
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Metadata
- Authors
- Tschaharganeh, D. F., Xue, W., Calvisi, D. F., Evert, M., Michurina, T. V., Dow, L. E., Banito, A., Katz, S. F., Kastenhuber, E. R., Weissmueller, S., Huang, C.-H., Lechel, A., Andersen, J. B., Capper, D., Zender, L., Longerich, T., Enikolopov, G., & Lowe, S. W.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Cold Spring Harbor Laboratory (US)
- Universitätsmedizin Greifswald (DE)
- Universität Ulm (DE)
- University of Copenhagen (DK)
- German Cancer Research Center (DE)
- University Hospital Heidelberg (DE)
- Corresponding author
- Lowe, Scott W.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2014-07
- Volume
- 158
- Issue
- 3
- Pages
- 579-592
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4221237
- OpenAlex
- W1980168406
- Cited by
- 227
- References
- 60
- Citations by year
- 2026: 10 · 2025: 13 · 2024: 15 · 2023: 22 · 2022: 21 · 2021: 25 · 2020: 21 · 2019: 24 · 2018: 23 · 2017: 15 · 2016: 20 · 2015: 11 · 2014: 6
- FWCI
- 8.36
- Type
- journal article
- Language
- en
- Update notices
- erratum (2016-06-02)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (5p30ca045508-35)
- National Cancer Institute (P01CA087497, P30-CA045508, P01CA013106, P30CA008748)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- p53, nestin, hepatocellular carcinoma, cholangiocarcinoma, liver cancer, cellular plasticity, dedifferentiation, progenitor-like cells, Wnt signaling, Notch signaling, tumor suppression, transcriptional repression, patient survival
- MeSH terms
- Animals, Cell Transformation, Neoplastic, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Prognosis, Transcription, Genetic, Tumor Suppressor Protein p53, Sp1 Transcription Factor, Hepatocytes, Mice, Sp3 Transcription Factor, Nestin
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