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NUMB controls p53 tumour suppressor activity

Nature volume 451, pages 76–80 (2008)Cite this article

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 family1. NUMB is also an endocytic protein2, and the NOTCH–NUMB counteraction has been linked to this function3,4. There might be, however, additional functions of NUMB, as witnessed by its proposed role as a tumour suppressor in breast cancer5. 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 expression5. 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 NOTCH5. 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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Figure 1: NUMB interacts with and regulates p53.
Figure 2: NUMB regulates HDM2-mediated degradation of p53.
Figure 3: NUMB silencing alters the p53-mediated response to DNA damage.
Figure 4: Loss of NUMB in human breast tumours determines decreased p53, enhanced chemoresistance and predicts poor prognosis.

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Acknowledgements

We thank K. Helin for the p53 and HDM2 reagents; L. Van Parijis for the pLL3.7 lentiviral vector; R. Bernard for the p53 shRNA pSUPER vector; G. Matera for technical assistance; P. Maisonneuve and G. Goisis for statistical analysis; the Imaging Service at IEO; and the Real Time PCR Service at IFOM. This work was supported by grants from the Associazione Italiana per la Ricerca sul Cancro and MIUR to S.P. and P.P.D.F., from the European Community (VI Framework), The Ferrari Foundation, the Monzino Foundation and the CARIPLO Foundation to P.P.D.F., and from the G. Vollaro Foundation to S.P.

Author Contributions I.N.C., D.T., F.S.-N. and S.P. performed experimental work. P.N., V.G. and G.V. performed the clinical part of the work (patient selection, histology and data analysis of the patient’s case collection). S.P. and P.P.D.F. planned and supervised the project, performed data analysis and wrote the manuscript.

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Authors and Affiliations

  1. IFOM, the FIRC Institute for Molecular Oncology Foundation, Via Adamello 16, 20139, Milan, Italy ,

    Ivan N. Colaluca, Daniela Tosoni, Paolo Nuciforo, Francesca Senic-Matuglia, Salvatore Pece & Pier Paolo Di Fiore

  2. European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy ,

    Ivan N. Colaluca, Daniela Tosoni, Viviana Galimberti, Giuseppe Viale, Salvatore Pece & Pier Paolo Di Fiore

  3. Dipartimento di Medicina, Chirurgia ed Odontoiatria, Università degli Studi di Milano, 20122 Milan, Italy

    Giuseppe Viale, Salvatore Pece & Pier Paolo Di Fiore

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  1. Ivan N. Colaluca
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Correspondence to Salvatore Pece or Pier Paolo Di Fiore.

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Supplementary Information

This file contains Supplementary Discussion and additional references; Supplementary Table S1 and Supplementary Figures S1-S6 with Legends. (PDF 3132 kb)

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Colaluca, I., Tosoni, D., Nuciforo, P. et al. NUMB controls p53 tumour suppressor activity. Nature 451, 76–80 (2008). https://doi.org/10.1038/nature06412

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