Negative regulation of the mammalian UV response by Myc through association with Miz-1.
The Myc oncoprotein represses initiator-dependent transcription through the POZ domain transcription factor Miz-1. We now show that transactivation by Miz-1 is negatively regulated by association with topoisomerase II binding protein (TopBP1); UV irradiation downregulates expression of TopBP1 and releases Miz-1. Miz-1 binds to the p21Cip1 core promoter in vivo and is required for upregulation of p21Cip1 upon UV irradiation. Using both c-myc(-/-) cells and a point mutant of Myc that is deficient in Miz-1 dependent repression, we show that Myc negatively regulates transcription of p21Cip1 upon UV irradiation and facilitates recovery from UV-induced cell cycle arrest through binding to Miz-1. Our data implicate Miz-1 in a pathway that regulates cell proliferation in response to UV irradiation.
Herold
Steffi
S
Institute for Molecular Biology and Tumor Research, 35033 Marburg, Germany.
Wanzel
Michael
M
Beuger
Vincent
V
Frohme
Carsten
C
Beul
Dorothee
D
Hillukkala
Tomi
T
Syvaoja
Juhani
J
Saluz
Hans-Peter
HP
Haenel
Frank
F
Eilers
Martin
M
D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000502:physiology / Q000528:radiation effects; D002478:Cells, Cultured; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D017930:Genes, Reporter; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000502:physiology / Q000528:radiation effects; D051741:Kruppel-Like Transcription Factors; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009687:Nuclear Proteins; D017434:Protein Structure, Tertiary; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000528:radiation effects*; D015533:Transcriptional Activation; D025521:Tumor Suppressor Proteins; D020798:Two-Hybrid System Techniques; D014466:Ultraviolet Rays
C493956:CDKN1A protein, human; C493966:CDKN2B protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D011993:Recombinant Fusion Proteins; C110513:TOPBP1 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C107961:ZBTB17 protein, human