腫瘍抑制遺伝子E2F標的遺伝子プロモーターエレメントのがん細胞特異的遺伝子発現駆動における有用性

The transcription factor E2F is the principal target of the tumor suppressor pRB. In almost all cancers, pRB function is disabled due to oncogenic changes, leading to enhanced E2F activity, thereby facilitating aberrant cell proliferation. Enhanced E2F activity has been utilized to drive gene expression preferentially in cancer cells using E2F target promoters, such as the E2F1 promoter. However, these promoters are also activated by physiological E2F activity in normal proliferating cells, resulting in gene expression in normal proliferating cells. In contrast, promoters of tumor suppressor genes, such ARF and TAp73, are activated by deregulated E2F activity, induced by loss of pRB control, but not by physiological E2F activity, induced by growth stimulation, thereby providing a mechanism to drive expression specifically in cancer cells. Here we show artificial promoters, in which E2F-responsive elements of the TAp73 gene are tandemly connected to the ARF core promoter, exhibited higher cancer cell specificity than E2F1, hTERT, or ARF promoters. Moreover, adenoviruses driving a cytotoxic gene using these artificial promoters showed cancer cell-specific cytotoxicity and inhibited tumor growth in a xenograft mouse model. These results indicate utility of tumor suppressor gene promoter elements to drive gene expression specifically in cancer cells.