Protein Kinase C in Carcinogenesis: Comparative Expression of Oncogenes and Protein Kinase C in Rhabdomyosarcoma Models

Abstract

In the past several decades, evidence has accumulated that cancer is a multistep, multifactorial process. Two discrete stages, initiation and promotion, were first described in the model of chemical carcinogenesis developed on mouse skin (1). Initiation resulted from the action of potent mutagens likely responsible for activation of protooncogenes or inactivation of growth suppressor genes, whereas promotion was associated with epigenetic alterations. Cooperation between events occurring during these two stages was found to be required for conversion of normal cells to malignant. It has been well documented that transfection of the activated Ha-ras oncogene, which serves as an initiator of mouse skin carcinogenesis, did not lead to tumor formation unless tumor promoters were repeatedly applied to the skin (2,3). Similarly, the expression of oncogenes in transgenic mice carrying specific oncogenes evoked hyperplasia, with tumors arising as a rare clonal outgrowth, presumably as a result of promoting events. Ha-ras transgene also replaced the initiation step in mouse skin, and sensitized transgenic mice to the action of tumor promoters (4). Oncogene products, the functions of which are known, are proteins from growth signalling pathways acting as surface receptors, growth factors, G proteins, transcription factors etc., (as reviewed in ref. 5). Tumor-promoting phorbol esters interact with protein kinase C (PKC), an enzyme which plays a pivotal role in signalling pathways, exerting both positive and negative controls in cell functions and growth (as reviewed in ref. 6). In the present report, we emphasize the role of PKC in carcinogenesis, via tumor promoter-mediated activation and changes in the levels of expression.