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

Abstract

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.

• Authors: Verline Justilien, Syed A Ali, Lee Jamieson, Ning Yin, Adrienne D Cox, Channing J Der, Nicole R Murray, Alan P Fields
• Journal: Cancer cell (Cancer Cell) Vol. 31 Issue 2 Pg. 256-269 (02 13 2017) ISSN: 1878-3686 [Electronic] United States
• PMID: 28110998 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier Inc. All rights reserved.

Chemical References

• ECT2 protein, human
• Isoenzymes
• KRAS protein, human
• NPM1 protein, human
• Nuclear Proteins
• Proto-Oncogene Proteins
• RAC1 protein, human
• RNA, Ribosomal
• TP53 protein, human
• Tumor Suppressor Protein p53
• Nucleophosmin
• Auranofin
• Protein Kinase C
• protein kinase C lambda
• Proto-Oncogene Proteins p21(ras)
• rac1 GTP-Binding Protein

Topics

• Adenocarcinoma (etiology)
• Adenocarcinoma of Lung
• Animals
• Auranofin (pharmacology)
• Cell Line, Tumor
• Cell Nucleolus (metabolism)
• Cytokinesis
• Humans
• Isoenzymes (physiology)
• Lung Neoplasms (etiology)
• Mice
• Nuclear Proteins (physiology)
• Nucleophosmin
• Protein Kinase C (physiology)
• Proto-Oncogene Proteins (physiology)
• Proto-Oncogene Proteins p21(ras) (physiology)
• RNA, Ribosomal (biosynthesis)
• Signal Transduction (physiology)
• Tumor Suppressor Protein p53 (physiology)
• rac1 GTP-Binding Protein (physiology)