Poster Sessions

CANCER-1

Kantima Leelahavanichkul

K. Leelahavanichkul, Y. Huang, Y. Lussier, A. Molinolo, J.S. Gutkind

Activation of a Novel p38-MK2 Network Controlling mRNA Stability by Ras in Cancer

The ras oncogene is one of the most frequently mutated genes involved in human cancers. Its protein product, Ras, activate multiple MAPK kinase cascades, thereby regulating cell proliferation, growth, survival and migration. However, to understand the complex process of tumorigenesis, we need to study the earliest possible events heralding the neoplastic conversion, and to investigate the nature of the molecular mechanisms. For these efforts, we have established of a K5tet-on expressing a K-ras oncogene which rapidly leads to SCC of the skin. By immunohistochemistry, we found high level of p-p38MAPK and p-Elk1 in hyperplasia and SCC, and moderate level of p-JNK activity in hyperplasia. The activation of p38MAPK was further demonstrated by the accumulation of active MAPKAPK2 (MK2). This activation pattern was confirmed in a large collection of human SCC tissues. We hypothesize that the p38-MK2 pathway regulates HuR, and that stabilizes ARE-containing mRNAs which in turn enhances the expression of chemokines and cytokines that stimulate p38MAPK pathway. Indeed, in a recent gene expression profile analysis, we found identified 6,260 genes which are highly distinct within the normal, hyperplasia, and SCC, and that the vast majority of the changes occurred in the transition from normal to hyperplasia. These included multiple chemokines and cytokines exhibiting ARE sequences. We are currently investigating the contribution of this novel p38, MK2 and HuR pathway controlling mRNA stability in ras-induced tumorigenesis in animal models and in clinical samples harboring ras mutations and their derived cell lines.