Myc-ARF (alternate reading frame) interaction inhibits the functions of Myc.
The tumor suppressor protein ARF (alternate reading frame) inhibits MDM2 to stabilize and activate the functions of p53. Here we provide evidence for an additional activity of ARF that attenuates cell cycle progression independently of p53 activation. We show that ARF interacts with c-Myc independently of MDM2 or p53. Consequently, ARF relocalizes c-Myc from the nucleoplasm to the nucleolus. Binding and relocalization by ARF correlate with an inhibition of the c-Myc-activated transcription in both p53-positive and -negative cells. Using inducible cell lines, we show that the wild type ARF, but not a mutant, inhibits expression of the c-Myc-induced genes before inhibiting S phase. Moreover, ARF inhibits Myc-induced progression into S phase in cells lacking p53 or expressing a defective p53, indicating that ARF inhibits the S phase stimulatory function of c-Myc independently of p53. Our results strongly suggest that cMyc is a bona fide target of ARF and that ARF attenuates c-Myc independently of the ARF-p53 axis.
Datta
Abhishek
A
Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, 900 S. Ashland Avenue, Chicago, IL 60607, USA.
Nag
Alo
A
Pan
Wei
W
Hay
Nissim
N
Gartel
Andrei L
AL
Colamonici
Oscar
O
Mori
Yasuji
Y
Raychaudhuri
Pradip
P
D017398:Alternative Splicing; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D001973:Bromodeoxyuridine / Q000494:pharmacology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D015500:Chloramphenicol O-Acetyltransferase / Q000378:metabolism; D004396:Coloring Agents / Q000494:pharmacology; D019941:Cyclin-Dependent Kinase Inhibitor p16; D000939:Epitopes; D005347:Fibroblasts / Q000378:metabolism; D016193:G1 Phase; D017930:Genes, Reporter; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D016364:Reading Frames; D016196:S Phase; D013752:Tetracycline / Q000494:pharmacology; D014158:Transcription, Genetic; D014162:Transfection; D019076:Transgenes; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
C417743:Cdkn2a protein, mouse; D004396:Coloring Agents; D019941:Cyclin-Dependent Kinase Inhibitor p16; D000939:Epitopes; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D015500:Chloramphenicol O-Acetyltransferase; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D013752:Tetracycline; D001973:Bromodeoxyuridine