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.
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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
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A Randomized Comparison of Sentinel-Node Biopsy with Routine Axillary Dissection in Breast Cancer
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Cited by
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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
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