Authors:
Silvia Licciulli, Jacqueline L. Avila, Linda Hanlon, Scott Troutman, Matteo Cesaroni, Smitha Kota, Brian Keith, M. Celeste Simon, Ellen Pure, Fred Radtke, Anthony J. Capobianco, and Joseph L. Kissil
Summary:
Over the last few years, the Notch pathway has been implicated in a number of malignancies with different roles that are cell and tissue-type dependent. Notch1 is a putative oncogene in NSCLC and activation of the pathway represents a negative prognostic factor. To establish the role of Notch1 in lung adenocarcinoma we directly assessed its requirement in K-ras-induced tumorigenesis in vivo, employing an autochthonous model of lung adenocarcinoma with concomitant expression of oncogenic K-ras and deletion of Notch1. We find that Notch1 function is required for lung tumor initiation via suppression of p53-mediated apoptosis in vivo, through the regulation of p53 stability. These findings implicate Notch1 as a critical effector in K-ras-driven lung adenocarcinoma and as a regulator of p53 at a post-translational level. Moreover, our study provides new insights to explain, at a molecular level, the correlation between Notch1 activity and poor prognosis in NSCLC patients carrying wild type p53. This information is critical for the design and implementation of new therapeutic strategies in this cohort of patients representing 50% of all NSCLC cases.
Source:
Cancer Research; (08/13/13)