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 either activated or repressed via c-Myc, only few of them obviously contribute to Myc's biological effect--the induction of proliferation. We found that in logarithmically growing cells overexpression of Myc specifically induces thymidine kinase (TK) mRNA expression and enzyme activity, whereas loss of one allele of Myc causes downregulation of this enzyme. We show that activation of Myc triggers high levels of this normally strictly S-phase-regulated DNA metabolism enzyme in serum arrested G0 cells and causes high and constant levels of TK expression throughout 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 E2F-site of the TK promoter. We further show that cell growth arrest by the cyclin-dependent kinase inhibitor p16 is abrogated by overexpression of Myc and that co-overexpression of p16 cannot inhibit the Myc-induced up-regulation of TK expression. Our data demonstrate TK to be a cellular target of Myc independently of the status of cell proliferation and provide evidence that the transcription factor E2F might be involved in this process.
Pusch
O
O
Obstetrics and Gynecology, University of Vienna, Department of Prenatal Diagnosis and Therapy, Austria.
Soucek
T
T
Hengstschläger-Ottnad
E
E
Bernaschek
G
G
Hengstschläger
M
M
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000235:genetics; D002460:Cell Line; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D004789:Enzyme Activation / Q000502:physiology; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D056465:Retinoblastoma-Binding Protein 1; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism*; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors; D013937:Thymidine Kinase