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.

Mdm2-mediated ubiquitylation: p53 and beyond

“…The physical interaction has been confirmed at endogenous levels of protein expression. 88 Sequential coimmunoprecipitation assays further demonstrate the existence of a p53-Mdm2-Numb trimeric complex in cells, whereby Numb prevents Mdm2-mediated p53 ubiquitylation and subsequent degradation (Figure 2). The ability of purified recombinant NUMB to interfere with Mdm2-dependent p53 ubiquitylation was confirmed in in vitro ubiquitylation assays.…”

“…Consistently, NUMB expression is frequently lost in breast cancers and is associated with decreased p53 levels and increased chemoresistance. 88 Loss of NUMB expression also enhances the activity of the oncogenic receptor NOTCH. Hence, a single event -loss of NUMB expression -leads to an activation of an oncogene and attenuation of the p53 tumor suppressor pathway.…”

p53-family proteins and their regulators: hubs and spokes in tumor suppression

“…54 In line with this antagonism, the endocytic protein Numb, which is asymmetrically partitioned at mitosis to control cell fate by antagonizing the activity of Notch, binds to both MDM2 and p53, counteracting MDM2-dependent p53 ubiquitination and promoting p53 stabilization and activity. 55 The p53-MDM2 core circuit also mediates a functional link between p53 and the Hedgehog signaling pathway. In fact, constitutive activation of the Hedgehog pathway downregulates p53 by promoting MDM2 phosphorylation and association with p53.…”

L-GILZ binds p53 and MDM2 and suppresses tumor growth through p53 activation in human cancer cells

“…By binding to p53 and MDM2, L-GILZ behaves in a manner similar to Numb and TSC-22; 50,51 however, unlike TSC-22, which does not interfere with the formation of p53/MDM2 complexes, 50 L-GILZ prevents p53/MDM2 complex formation, similar to Numb. 51 Using overexpression models, we also showed the cytoplasmic co-localization of p53 and L-GILZ, whereas ectopic expression of L-GILZ or p53 alone was associated with cytoplasmic and mostly nuclear localization, respectively. Furthermore, blocking nuclear export by leptomycin prevented binding between L-GILZ and p53 but not between L-GILZ and MDM2 or p53 and MDM2 (Figure 4).…”