Mnt loss triggers Myc transcription targets, proliferation, apoptosis, and transformation.
Myc oncoproteins are overexpressed in most cancers and are sufficient to accelerate cell proliferation and provoke transformation. However, in normal cells Myc also triggers apoptosis. All of the effects of Myc require its function as a transcription factor that dimerizes with Max. This complex induces genes containing CACGTG E-boxes, such as Ornithine decarboxylase (Odc), which harbors two of these elements. Here we report that in quiescent cells the Odc E-boxes are occupied by Max and Mnt, a putative Myc antagonist, and that this complex is displaced by Myc-Max complexes in proliferating cells. Knockdown of Mnt expression by stable retroviral RNA interference triggers many targets typical of the "Myc" response and provokes accelerated proliferation and apoptosis. Strikingly, these effects of Mnt knockdown are even manifest in cells lacking c-myc. Moreover, Mnt knockdown is sufficient to transform primary fibroblasts in conjunction with Ras. Therefore, Mnt behaves as a tumor suppressor. These findings support a model where Mnt represses Myc target genes and Myc functions as an oncogene by relieving Mnt-mediated repression.
Nilsson
Jonas A
JA
Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Maclean
Kirsteen H
KH
Keller
Ulrich B
UB
Pendeville
Helene
H
Baudino
Troy A
TA
Cleveland
John L
JL
D000818:Animals; D017209:Apoptosis; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D005347:Fibroblasts; D015972:Gene Expression Regulation, Neoplastic; D016153:Genes, Suppressor; D051379:Mice; D008807:Mice, Inbred BALB C; D009687:Nuclear Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D009955:Ornithine Decarboxylase / Q000235:genetics; D010641:Phenotype; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins; D014158:Transcription, Genetic / Q000235:genetics*
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C484561:Mnt protein, mouse; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D012097:Repressor Proteins; D009955:Ornithine Decarboxylase