The c-jun protooncogene encodes a protein, cJun, that is part of the AP-1 complex, originally identified as a mediator of gene induction by tumor promoters. AP-1 is also stimulated by growth factors and transforming oncoproteins. The same agents induce c-jun transcription by posttranslationally stimulating preexisting cJun that binds to an AP-1 site in the c-Jun promoter. Upon overexpression, cJun can transform rodent fibroblasts either by itself or in collaboration with activated Ha-ras. Since Ha-ras does not transform normal diploid fibroblasts by itself and requires cooperation with exogenously introduced c-jun, it is likely that normal cells have negative regulatory mechanisms for preventing overexpression of endogenous c-jun. One negative mechanism may directly act on the c-jun promoter. To elucidate this mechanism the cis-element within the c-jun promoter and the trans-acting factor which mediate negative control will be characterized. Additional attenuation of AP-1 activity is achieved by transcriptional interference between AP-1 and members of the nuclear receptor family. The contribution of this interference to the control of cell proliferation will be studied, as well as its biochemical basis. AP-1 and c-jun are also inhibited by the anti-tumor promoter curcumin. The mechanism of this inhibition will be investigated as it will provide us with new insights to the control of AP-1 activity and c-jun expression. We will also investigate whether the cJun protein serves as a substrate for the cell cycle regulated cdc2 kinase, which could affect its DNA binding activity. Another part of the project will focus on the biological functions of c-jun. Using c-jun- ES cells obtained by homologous recombination, we will test whether their differentiated derivatives are refractory to transformation by Ha-ras. The effect of c-jun under- and over-expression on the differentiation potential of ES cells will be examined as well. The c-jun- ES cells will also be used to investigate the control of AP-1 activity. Finally, we will determine the function of AP-1 in the differentiation and proliferation of PC12 pheochromocytoma cells using cJun dominant negative mutants. This comprehensive program should provide us with new and important information on the control of cJun and AP-1 activity and the biological functions of this central regulator of cell proliferation and differentiation.
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