Jan 4, 2008

NUMB controls p53 tumour suppressor activity

Nature
Ivan N ColalucaPier Paolo Di Fiore

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, t...Continue Reading

  • References32
  • Citations182

Citations

Mentioned in this Paper

TP53 gene
Biochemical Pathway
MDM2 protein, human
MDM2 gene
Cell Fate
Antibiotic Resistance, Neoplasm
Notch
Neoplasms
Tumor Lysis Syndrome
Plasma Protein Binding Capacity

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