The DOI matches its Crossref record; 33 of the 33 references it cites were found in a registry or an index.
NUMB controls p53 tumour suppressor activity
Abstract
NUMB is a cell fate determinant, which, by asymmetrically partitioning at mitosis, controls cell fate choices by antagonising the activity of the plasma membrane receptor of the NOTCH family. NUMB is also an endocytic protein, and the NOTCH-NUMB counteraction has been linked to this function. There might be, however, additional functions of NUMB, as witnessed by its proposed role as a tumour suppressor in breast cancer. Here we describe a previously unknown function for human NUMB as a regulator of tumour protein p53 (also known as TP53). NUMB enters in a tricomplex with p53 and the E3 ubiquitin ligase HDM2 (also known as MDM2), thereby preventing ubiquitination and degradation of p53. This results in increased p53 protein levels and activity, and in regulation of p53-dependent phenotypes. In breast cancers there is frequent loss of NUMB expression. We show that, in primary breast tumour cells, this event causes decreased p53 levels and increased chemoresistance. In breast cancers, loss of NUMB expression causes increased activity of the receptor NOTCH. Thus, in these cancers, a single event-loss of NUMB expression-determines activation of an oncogene (NOTCH) and attenuation of the p53 tumour suppressor pathway. Biologically, this results in an aggressive tumour phenotype, as witnessed by findings that NUMB-defective breast tumours display poor prognosis. Our results uncover a previously unknown tumour suppressor circuitry.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Numb inhibits the degradation of p53 by forming the tricomplex of p53 and Hdm2 where it suppresses the ligase activity of Hdm2 [104].”
From Insights of Endocytosis Signaling in Health and Disease (2023) · cites this paper as [104]
In the citing paper
“Furthermore, a remarkable decline in the levels of Numb expression has been observed in approximately 50% of breast cancer [104].”
From Insights of Endocytosis Signaling in Health and Disease (2023) · cites this paper as [104]
In the citing paper
“Endocytic protein Numb governs the level and activity of tumor suppressive protein p53.”
From Insights of Endocytosis Signaling in Health and Disease (2023) · cites this paper as [104]
In the citing paper
“Numb was recently reported to bind and inhibit Mdm2, leading to stabilization of p53, which is consistent with reports of a Numb tumor suppressor function [93].”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [93]
In the citing paper
“Numb was recently reported to bind and inhibit Mdm2, leading to stabilization of p53, which is consistent with reports of a Numb tumor suppressor function [93].”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [93]
Citations
Cites
p53 Mutations in Human Cancers
Hollstein, M., Sidransky, D., Vogelstein, B., & Harris, C. C. (1991) · Science · doi:10.1126/science.1905840 · Cited by 8,018
DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139
Rogakou, E. P., Pilch, D. R., Orr, A. H., Ivanova, V. S., & Bonner, W. M. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.10.5858 · Cited by 5,438
In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2
Vassilev, L. T., Vu, B. T., Graves, B., Carvajal, D., Podlaski, F., Filipovic, Z., Kong, N., Kammlott, U., Lukacs, C., Klein, C., et al. (2004) · Science · doi:10.1126/science.1092472 · Cited by 4,661
Mdm2 promotes the rapid degradation of p53
Haupt, Y., Maya, R., Kazaz, A., & Oren, M. (1997) · Nature · doi:10.1038/387296a0 · Cited by 4,506
Regulation of p53 stability by Mdm2
Kubbutat, M. H. G., Jones, S. N., & Vousden, K. H. (1997) · Nature · doi:10.1038/387299a0 · Cited by 3,312
Momand, J., Zambetti, G. P., Olson, D. C., George, D., & Levine, A. J. (1992) · Cell · doi:10.1016/0092-8674(92)90644-r · Cited by 3,113
p53-dependent apoptosis modulates the cytotoxicity of anticancer agents
Lowe, S. W., Ruley, H. E., Jacks, T., & Housman, D. E. (1993) · Cell · doi:10.1016/0092-8674(93)90719-7 · Cited by 2,911
A Randomized Comparison of Sentinel-Node Biopsy with Routine Axillary Dissection in Breast Cancer
Veronesi, U., Paganelli, G., Viale, G., Luini, A., Zurrida, S., Galimberti, V. E., Intra, M., Veronesi, P., Robertson, C., Maisonneuve, P., et al. (2003) · New England Journal of Medicine · doi:10.1056/nejmoa012782 · Cited by 2,204
A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage
Paull, T. T., Rogakou, E. P., Yamazaki, V., Kirchgessner, C. U., Gellert, M., & Bonner, W. M. (2000) · Current Biology · doi:10.1016/s0960-9822(00)00610-2 · Cited by 2,098
Amplification of a gene encoding a p53-associated protein in human sarcomas
Oliner, J. D., Kinzler, K. W., Meltzer, P. S., George, D. L., & Vogelstein, B. (1992) · Nature · doi:10.1038/358080a0 · Cited by 1,949
Zhang, Y., Xiong, Y., & Yarbrough, W. G. (1998) · Cell · doi:10.1016/s0092-8674(00)81401-4 · Cited by 1,626
Rubinson, D. A., Dillon, C. P., Kwiatkowski, A. V., Sievers, C., Yang, L., Kopinja, J. E., Rooney, D. L., Zhang, M., Ihrig, M. M., McManus, M. T., et al. (2003) · Nature Genetics · doi:10.1038/ng1117 · Cited by 1,499
Tumor surveillance via the ARF–p53 pathwayPreprint
Sherr, C. J. (1998) · Genes & Development · doi:10.1101/gad.12.19.2984 · Cited by 718
The INK4A/ARF locus and its two gene products.
Sharpless, N. E., & DePinho, R. A. (1999) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(99)80004-5 · Cited by 533
Telomeres, stem cells, senescence, and cancer
Sharpless, N. E., & DePinho, R. A. (2004) · Journal of Clinical Investigation · doi:10.1172/jci20761 · Cited by 488
Loss of negative regulation by Numb over Notch is relevant to human breast carcinogenesis
Pece, S., Serresi, M., Santolini, E., Capra, M. C., Hulleman, E., Galimberti, V. E., Zurrida, S., Maisonneuve, P., Viale, G., & Fiore, P. P. D. (2004) · The Journal of Cell Biology · doi:10.1083/jcb.200406140 · Cited by 483
The Endocytic Protein α-Adaptin Is Required for Numb-Mediated Asymmetric Cell Division in Drosophila
Berdnik, D., Tőrők, T., González‐Gaitán, M., & Knoblich, J. A. (2002) · Developmental Cell · doi:10.1016/s1534-5807(02)00215-0 · Cited by 366
Santolini, E., Puri, C., Salcini, A. E., Gagliani, M. C., Pelicci, P. G., Tacchetti, C., & Di Fiore, P. P. (2000) · The Journal of Cell Biology · doi:10.1083/jcb.151.6.1345 · Cited by 331
Somatic mutations in the p53 gene and prognosis in breast cancer: a meta-analysis
Pharoah, P. D. P., Day, N. E., & Caldas, C. (1999) · British Journal of Cancer · doi:10.1038/sj.bjc.6690628 · Cited by 306
Vousden, K. H., & Prives, C. L. (2005) · Cell · doi:10.1016/j.cell.2004.12.027 · Cited by 259
Roegiers, F., & Jan, Y. N. (2004) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2004.02.010 · Cited by 223
Molecular mechanisms of coupled monoubiquitination
Woelk, T., Oldrini, B., Maspero, E., Confalonieri, S., Cavallaro, E. C., Fiore, P. P. D., & Polo, S. (2006) · Nature Cell Biology · doi:10.1038/ncb1484 · Cited by 198
The Mdm2 Oncoprotein Interacts with the Cell Fate Regulator Numb
Juven‐Gershon, T., Shifman, O., Unger, T., Elkeles, A., Haupt, Y., & Oren, M. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.7.3974 · Cited by 135
Hutterer, A., & Knoblich, J. A. (2005) · EMBO Reports · doi:10.1038/sj.embor.7400500 · Cited by 129
Negative Regulation of dE2F1 by Cyclin-Dependent Kinases Controls Cell Cycle Timing
Reis, T., & Edgar, B. A. (2004) · Cell · doi:10.1016/s0092-8674(04)00247-8 · Cited by 127
McCann, A. H., Kirley, A., Carney, D. N., Corbally, N., Magee, H. M., Keating, G., & Dervan, P. A. (1995) · British Journal of Cancer · doi:10.1038/bjc.1995.189 · Cited by 125
Evidence That Dynamin-2 Functions as a Signal-Transducing Gtpase
Fish, K. N., Schmid, S. L., & Damke, H. (2000) · The Journal of Cell Biology · doi:10.1083/jcb.150.1.145 · Cited by 107
Silva, J., Silva, J. M., Domínguez, G., García, J. M., Cantos, B., Rodríguez, R., Larrondo, F. J., Provencio, M., España, P., & Bonilla, F. (2003) · The Journal of Pathology · doi:10.1002/path.1297 · Cited by 107
Requirement of clathrin heavy chain for p53-mediated transcriptionPreprint
Enari, M., Ohmori, K., Kitabayashi, I., & Taya, Y. (2006) · Genes & Development · doi:10.1101/gad.1381906 · Cited by 71
Rambhatla, L., Ram‐Mohan, S., Cheng, J. J., & Sherley, J. L. (2005) · Cancer Research · doi:10.1158/0008-5472.can-04-3161 · Cited by 70
Sherley, J. L., Stadler, P. B., & Johnson, D. R. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.1.136 · Cited by 69
Analysis of genetic and epigenetic processes that influence p14ARF expression in breast cancer
Silva, J., Domínguez, G., Silva, J. M., García, J. M., Gallego, I., Corbacho, C., Provencio, M., España, P., & Bonilla, F. (2001) · Oncogene · doi:10.1038/sj.onc.1204617 · Cited by 50
Vestey, S. B., Sen, C., Calder, C. J., Perks, C. M., Pignatelli, M. N., & Winters, Z. (2004) · Breast Cancer Research · doi:10.1186/bcr912 · Cited by 20
Cited by
Sorted by citations
Notch signaling pathway: architecture, disease, and therapeutics
Zhou, B., Lin, W., Long, Y., Yang, Y., Zhang, H., Wu, K., & Chu, Q. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-00934-y · Cited by 1,216
Notch signaling: simplicity in design, versatility in function
Andersson, E. R., Sandberg, R., & Lendahl, U. (2011) · Development · doi:10.1242/dev.063610 · Cited by 950
Pece, S., Tosoni, D., Confalonieri, S., Mazzarol, G., Vecchi, M., Ronzoni, S., Bernard, L., Viale, G., Pelicci, P. G., & Fiore, P. P. D. (2010) · Cell · doi:10.1016/j.cell.2009.12.007 · Cited by 974
Notch signalling in solid tumours: a little bit of everything but not all the time
Ranganathan, P., Weaver, K. L., & Capobianco, A. J. (2011) · Nature reviews. Cancer · doi:10.1038/nrc3035 · Cited by 841
Derailed endocytosis: an emerging feature of cancer
Mosesson, Y., Mills, G. B., & Yarden, Y. (2008) · Nature reviews. Cancer · doi:10.1038/nrc2521 · Cited by 719
Metadata
- Authors
- Colaluca, I. N., Tosoni, D., Nuciforo, P., Senic-Matuglia, F., Galimberti, V., Viale, G., Pece, S., & Di Fiore, P. P.
- Affiliations
- IFOM (IT)
- European Institute of Oncology (IT)
- University of Milan (IT)
- Corresponding author
- Pece, Salvatore
- ORCID
- Venue
- Nature
- Published
- 2008-01
- Volume
- 451
- Issue
- 7174
- Pages
- 76-80
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2072555538
- Cited by
- 385
- References
- 33
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 9 · 2023: 25 · 2022: 19 · 2021: 19 · 2020: 15 · 2019: 12 · 2018: 18 · 2017: 19 · 2016: 22 · 2015: 22 · 2014: 27 · 2013: 25 · 2012: 36
- FWCI
- 18.16
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Fondazione Cariplo
- Ministero dell’Istruzione, dell’Università e della Ricerca
- Associazione Italiana per la Ricerca sul Cancro
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- Numb, p53, MDM2, tumour suppressor, breast cancer, Notch receptor, ubiquitination, protein stability, chemoresistance, prognosis, asymmetric cell division, endocytosis, oncogene activation
- MeSH terms
- Breast Neoplasms, Cells, Cultured, DNA Damage, Humans, Membrane Proteins, Nerve Tissue Proteins, Prognosis, Protein Binding, Tumor Suppressor Protein p53, Drug Resistance, Neoplasm, Gene Silencing, Cell Line, Tumor, Proto-Oncogene Proteins c-mdm2, Ubiquitination
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
