NUMB controls p53 tumour suppressor activity

Ivan N. Colaluca, et al. 2008. Nature 451, 76-80

Speaker: Shuo-Fu Lin (林碩甫)                                                         Time: 15:00~16:00, Dec 17, 2008

Commentator: Prof. Ming-Derg Lai (賴明德 教授)                Place: Room 601

Abstract:

          P53, a tumor suppressor protein and a transcription factor, can induce the expression of genes involved in cell-cycle arrest, senescence, and apoptosis in response to cellular stresses. P53 is kept inactive in unstressed cells by the E3 ubiquitin ligase HDM2 and subsequent proteasomal degradation. Loss of HDM2 binding or inhibition of its E3 ligase activity allows p53 to be rapidly stabilized and activated that are associated with tumor development and progression. The cell-surface receptor Notch is involved in the regulation of cell-fate specification and may control the balance between proliferation and differentiation in development and homeostasis. Numb functions as an inhibitor of Notch signaling and is involved in the cell-fate decisions (1). Previous studies have shown that Numb can bind to and be ubiquitinated by HDM2 (2). In this study, the authors showed that Numb can actually interact in vivo with endogenous HDM2 and p53, resulting in a trimeric complex between the three proteins. Numb functions by inhibiting the E3 ubiquitin ligase activity of MDM2 towards p53, and these interactions regulate the stability of p53. However, Numbalso can regulate cancer development. Loss of Numb occurs frequently in breast tumors, leading to activation of oncogenic Notch signaling (3). Here, the authors found that loss of Numb causes reduced steady-state levels of p53, resistance to chemotherapeutic drugs, more aggressive neoplastic disease, and poor prognosis. In conclusion, the cell-fate determinant Numb, which has been associated with negative regulation of signaling from the potential oncogene Notch, was shown here to help activate the tumor suppressor protein p53. Loss of Numb in breast cancers would result in both the activation of the potential oncogene Notch and the inhibition of tumor suppression by p53.

References:

1.      Koch U, et al. 2007. Notch and cancer: a double-edged sword. Mol. Life Sci. 64:2746-2762.

2.      Juven-Gershon, T , et al. 1998. The Mdm2 oncoprotein interacts with the cell fateregulator Numb. Mol. Cell. Bio. 18:3974-3982.

3.      Pece S, et al. 2004. Loss of negative regulation by Numb over Notch is relevant to human breast carcinogenesis. J. Cell Biol. 67:215-221.