CELLULAR TARGETS FOR ACTIVATION BY C-MYC INCLUDE THE DNA METABOLISM ENZYME THYMIDINE KINASE

Although a remarkable number of genes has been identified that are eit her activated or repressed via c-Myc, only few of them obviously contr ibute to Myc's biological effect-the induction of proliferation, We fo und that in logarithmically growing cells overexpression of Myc specif ically induces thymidine kinase (TK) mRNA expression and enzyme activi ty, whereas loss of one allele of Myc causes downregulation of this en zyme. We show that activation of Myc triggers high levels of this norm ally strictly S-phase-regulated DNA metabolism enzyme in serum arreste d Go cells and causes high and constant levels of TK expression throug hout the entire ongoing cell cycle. Induction of TK by Myc requires an intact transcriptional activation domain. Myc-induced deregulation of this enzyme is paralleled by alterations of protein binding at the E2 F-site of the TK promoter. We further show that cell growth arrest by the cyclin-dependent kinase inhibitor p16 is abrogated by overexpressi on of Myc and that co-overexpression of p16 cannot inhibit the Myc-ind uced up-regulation of TK expression. Our data demonstrate TK to be a c ellular target of Myc independently of the status of cell proliferatio n and provide evidence that the transcription factor E2F might be invo lved in this process.