Deregulated E2F activity: Novel targets and therapeutic potential in cancer treatment
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Abstract
The transcription factor E2F is the principal target of the tumour suppressor pRB. E2F plays essential roles in cell proliferation by activating a group of growth-promoting genes. E2F also plays crucial roles in tumor suppression by activating pro-apoptotic and growth-suppressive genes. It is yet to be elucidated how E2F discriminates its targets, which have opposite roles in cell fate determination.
We previously reported that some growth-suppressive E2F targets such as the tumor suppressor ARF and TAp73 and the CDK inhibitor p27Kip1 are not activated by growth stimulation unlike growth-promoting E2F targets. These genes are specifically activated by forced inactivation of pRB that causes deregulated E2F activity. Existence of growth-suppressive E2F targets, which are specifically activated by deregulated E2F activity, suggests the presence of differential regulatory mechanisms between growth-promoting and the growth-suppressive E2F targets. Moreover, our studies suggest that the deregulated E2F activity, which activates the growth-suppressive genes, exists in cancer cells but not in normal growing cells as expected from the mechanism of oncogenesis.
We recently explored new targets of deregulated E2F by DNA microarray and identified 9 novel genes (BCL2L11, RASSF1, PPP1R13B, JMY, MOAP1, RBM38, ABTB1, RBBP4 and RBBP7). Most of the new targets are involved in the p53 and RB tumor suppressor pathways. These results underscore important roles of deregulated E2F in tumor suppression. We also tried to utilize deregulated E2F activity to specifically target cancer cells. ARF promoter, which is specifically activated by deregulated E2F activity, showed higher cancer cell specificity than E2F1 promoter, which is activated by both deregulated and physiological E2F activity. Moreover, ARF promoter-driven HSV-TK gene construct killed cancer cells as efficiently as that with E2F1 promoter and was clearly less cytotoxic to normal growing cells. These observations indicate utility of deregulated E2F activity for specifically targeting cancer cells to minimize side effects.
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