Oncogenic KRAS provides a uniquely powerful and variable oncogenic contribution among RAS family members in the colonic epithelium

• Published in: Journal of cellular physiology 2007-03, Vol.210 (3), p.740-749
• Main Authors: Keller, Jeffrey W., Franklin, Jeffrey L., Graves-Deal, Ramona, Friedman, David B., Whitwell, Corbin W., Coffey, Robert J.
• Format: Article
• Language: English
• Subjects: Cell Line, Tumor; Cell Transformation, Neoplastic - genetics; Colon - metabolism; Colon - pathology; Colorectal Neoplasms - genetics; Colorectal Neoplasms - physiopathology; Gene Expression Regulation, Neoplastic; Genes, ras - genetics; Genes, ras - physiology; Humans; Intestinal Mucosa - metabolism; Intestinal Mucosa - pathology; Isoenzymes; MAP Kinase Kinase Kinases - genetics; MAP Kinase Kinase Kinases - metabolism; Mitogen-Activated Protein Kinase 3 - genetics; Mitogen-Activated Protein Kinase 3 - metabolism; rap1 GTP-Binding Proteins - genetics; rap1 GTP-Binding Proteins - metabolism; Signal Transduction - physiology
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.20898

Activating mutations of the RAS family of small GTPases are among the most common genetic events in human tumorigenesis. Constitutive activation of the three canonical family members, KRAS, NRAS, and HRAS segregate strongly by tissue type. Of these, KRAS mutations predominate in human tumors, including those arising from the colon and lung. We sought to compare the oncogenic contributions of different RAS isoforms in a comparable genetic setting and to explore downstream molecular changes that may explain the apparent differential oncogenic effects of the various RAS family members. We utilized colorectal cancer cell lines characterized by oncogenic KRAS in parallel with isogenically derived lines in which the mutant allele has been disrupted. We additionally attempted to reconstitute the isogenic derivatives with oncogenic forms of other RAS family members and analyze them in parallel. Pairwise analysis of HCT 116 and DLD‐1 cell lines as well as their isogenic derivatives reveals distinct K‐RASG13D signatures despite the genetic similarities of these cell lines. In DLD‐1, for example, oncogenic K‐RAS enhances the motility of these cells by downregulation of Rap1 activity, yet is not associated with increased ERK1/2 phosphorylation. In HCT 116, however, ERK1/2 phosphorylation is elevated relative to the isogenic derivative, but Rap1 activity is unchanged. K‐RAS is uniquely oncogenic in the colonic epithelium, though the molecular aspects of its oncogenic contribution are not necessarily conserved across cell lines. We therefore conclude that the oncogenic contribution of K‐RAS is a function of its multifaceted functionality and is highly context‐dependent. J. Cell. Physiol. 210: 740–749, 2007. © 2006 Wiley‐Liss, Inc.