Received for publication March 23, 2006.
Revised July 19, 2006.
Accepted for publication July 20, 2006.

Ras-dependent Recruitment of c-Myc for Transcriptional Activation of Nucleophosmin/B23 in Highly Malignant U1 Bladder Cancer Cells

Abstract

U1 bladder cancer cells of high malignancy exhibited higher proliferation capacity than U4 pre-malignant cells. Higher expression of Ras, c-Myc, and nucleophosmin/B23 as well as greater c-myc transactivation and nucleophosmin/B23 promoter activities were detected in U1 cells as compared to U4 cells. Moreover, c-Myc and nucleophosmin/B23 were increased in U1 but not in U4 cells upon serum stimulation from quiescence. Similarly, only in U1 cells could serum stimulate transcriptional activity of nucleophosmin/B23 promoter and c-Myc response element. The increase of nucleophosmin/B23 promoter activity could be abrogated by MEK inhibitor and was associated with recruitment of c-Myc to the promoter. Constitutive expression of Ras dominant negative (Dn-Ras-U1) reduced the levels of Ras, nucleophosmin/B23 and p-ERK, and consequently abolished the serum-induced up-regulation of nucleophosmin/B23 promoter activity and c-Myc promoter recruitment. Our results have indicated that Ras and c-Myc play important role in the up-regulation of nucleophosmin/B23 during proliferation of cells associated with high degree of malignancy, thus outlining a signaling cascade involving these factors in the cancer cells.

Key words: Ras, MAP Kinase, Promoter analysis, Regulation of gene expression, Regulation - transcriptional