Suwei Wang

Date of Graduation

2001

Document Type

Thesis

Abstract

Although Cr(VI)-containing compounds have been widely recognized as carcinogens for over 100 years, the mechanisms of their actions are not fully understood. The overall objective of this study is to investigate the role of reactive oxygen species (ROS) in Cr(VI)-induced carcinogenesis, focusing on tumor suppressor protein p53 and regulatory signal transduction pathways. In the present study, the role of ROS in p53 activation was investigated and the following conclusions were obtained: (a) Cr(VI) is able to activate p53 protein; (b) ROS, especially ·OH radical, are responsible for the p53 activation induced by Cr(VI). In addition, we presented a mechanism of cellular ROS generation induced by Cr(VI). After entering the cell, Cr(VI) can be reduced to Cr(V). During the reduction process, molecular oxygen is reduced to O2 ·− radical, which generates H2O2 via dismutation. Cr(V) reacts with H2O2 to generate ·OH radicals via a Fenton-like reaction. For the molecular mechanism of p53 activation induced by Cr(VI), post-translational modifications, including Ser 15 phosphorylation, Lys 382 acetylation, and mdm2 dissociation were found to play a crucial role. Erk, but not p38 kinase, is responsible for the phosphorylation of Ser 15 induced by Cr(VI). The present study also investigated the interaction of NF-κB and p53 protein in Cr(VI)-induced apoptosis. NF-κB activation is capable of diminishing Cr(VI)-induced p53 activation, and protecting cells from apoptosis. These studies on Ras overexpressed cells presented a new scheme for ROS generation from Cr(VI)-induced cells different from the one described above. O2·− radical, which is produced by overexpressed Ras protein, reacts with Cr(VI) to generate Cr(V). The Cr(V) further reacts with H2O2, which is produced by O 2·− radical dismutation, to produce ·OH radical. These results implicate Cr(VI) and O2·− radical into the signal transduction pathways mediated by Ras protein. Since Ras signaling pathway is important in regulating cell proliferation, the involvements of Cr(VI) in Ras signal transduction pathway may be one of the mechanisms for Cr(VI)-induced carcinogenesis. This study provides a molecular basis for the understanding of the mechanisms of Cr(VI)-induced cellular responses, and contributes to a better understanding for the carcinogenic process induced by this metal. These new findings also have the impact on other carcinogens and chemical particles that have a ROS generation machinery similar to Cr(VI).

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