COOPERATIVE EFFECTS OF VIRAL AND CELLULAR ONCOGENES

一个正常细胞向完全恶性肿瘤的发展是一个多步骤的过程

The progression of a normal cell to a fully malignant tumor is a multistep process involving events of initiation, promotion and progression. The "activation" of a diverse of cellular genes, called oncogenes, is the molecular basis behind several of these events. Two such oncogenes, ras and myc, are activated in certain tumor cell lines and can cooperate to transform primary rodent cells in culture. We have tested whether ras and myc cooperate to cause the transformation of C3H10T1/2 cells, an established cell line of embryonic origin. Myc transfected C3H10T1/2 cells do not form transformed foci; C3H10T1/2 cells transfected with ras show a low incidence of transformation (80 foci/Mug ras). Interestingly, the frequency of focus formation can be increased 15 fold when C3H10T1/2 cells are co-transfected with ras and myc. In addition, comparisons based on morphology and on growth rates in soft agar reveal that ras-myc foci are dramatically different from ras foci. The proposed study will examine the contributions of the ras and myc oncogene products, as separate agents and in cooperation with each other, to the transformation of C3H10T1/2 cells. We will establish (1) the parameters governing ras transformation and how these parameters change when ras and myc cooperate to cause a distinctly different phenotype, (2) the role of the myc protein in the cooperation event and whether the timing of myc expression is critical to that role and (3) the structural domains of the myc protein involved in cooperation with gas and whether these overlap with the structural domains governing the nuclear localization of the myc protein, the DNA binding properties of the myc protein or the ability of the myc protein to transform avian cells. The data obtained from this investigation will form the core of future studies aimed at identifying exogenous and/or endogenous cellular factors that participate with the ras and myc oncogene products in the cascade of events leading to in vivo tumor formation.