| Summary: | Simultaneous genetic inactivation of the key Notch signaling mediator RBP-Jk and p53 leads to the formation of forebrain tumors in mice, suggesting a tumor suppressor role of the Notch pathway in this context. However, the contribution of individual Notch receptors to the tumor-suppressive activity of Notch signaling in the brain remains elusive. Here, we show that simultaneous <i>Notch1</i> and <i>Notch2</i> deletion, similar to complete ablation of canonical Notch signaling by <i>Rbpj</i> inactivation, cooperates with <i>Trp53</i> deletion to promote tumor growth in the adult forebrain. We also demonstrate that inactivation of <i>Notch1</i> and <i>Trp53</i> in cells with active Notch signaling is sufficient to induce brain tumor or hyperplasia formation. Analysis of tumor location suggests a multifocal origin and shows that ventral forebrain regions and olfactory bulbs are the most affected sites. Hence, Notch1 cooperates with p53 to repress malignant transformation in the adult mouse forebrain.
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