Evasion from oncogene-induced senescence and apoptosis has recently emerged as being crucial for promoting tumorigenesis in vivo. The basic helix-loop-helix transcription factors Twist1 and Twist2 have been found to abrogate oncogene-induced apoptosis and Twist1 overexpression has been reported in a large variety of human solid cancers including carcinomas, sarcomas, melanomas and neuroblastomas. We show that both Twist proteins also override Ras- and ErbB2-induced senescence in murine and human cells, by simultaneously shutting-down p53- and RB-dependent pathways. In addition, like Twist1, Twist2 has an altered expression in a set of primary tumours and tumour cell lines, indicating that both genes might similarly contribute to tumour progression. Our results suggest the existence of a novel class of proteins whose oncogenic potential specifically derives from their ability to antagonize gatekeepers and which we propose to name “gate-jumpers”.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA