Ect2-Dependent rRNA Synthesis Is Required for KRAS-TRP53-Driven Lung Adenocarcinoma

Publication date: Available online 19 January 2017
Source:Cancer Cell
Author(s): Verline Justilien, Syed A. Ali, Lee Jamieson, Ning Yin, Adrienne D. Cox, Channing J. Der, Nicole R. Murray, Alan P. Fields
The guanine nucleotide exchange factor (GEF) epithelial cell transforming sequence 2 (Ect2) has been implicated in cancer. However, it is not clear how Ect2 causes transformation and whether Ect2 is necessary for tumorigenesis in vivo. Here, we demonstrate that nuclear Ect2 GEF activity is required for Kras-Trp53 lung tumorigenesis in vivo and that Ect2-mediated transformation requires Ect2-dependent rDNA transcription. Ect2 activates rRNA synthesis by binding the nucleolar transcription factor upstream binding factor 1 (UBF1) on rDNA promoters and recruiting Rac1 and its downstream effector nucleophosmin (NPM) to rDNA. Protein kinase Cι (PKCι)-mediated Ect2 phosphorylation stimulates Ect2-dependent rDNA transcription. Thus, Ect2 regulates rRNA synthesis through a PKCι-Ect2-Rac1-NPM signaling axis that is required for lung tumorigenesis.

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Teaser

Justilien et al. reveal that the guanine nucleotide exchange factor Ect2 is required for tumor initiation in a non-small-cell lung carcinoma model and uncover a nuclear role for Ect2 in promoting rDNA transcription, which is important for transformation, through a mechanism involving Rac1, NPM, and UBF1.


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