Deletion of Mnt leads to disrupted cell cycle control and tumorigenesis.
Mnt is a Max-interacting transcriptional repressor that has been hypothesized to function as a Myc antagonist. To investigate Mnt function we deleted the Mnt gene in mice. Since mice lacking Mnt were born severely runted and typically died within several days of birth, mouse embryo fibroblasts (MEFs) derived from these mice and conditional Mnt knockout mice were used in this study. In the absence of Mnt, MEFs prematurely entered the S phase of the cell cycle and proliferated more rapidly than Mnt(+/+) MEFs. Defective cell cycle control in the absence of Mnt is linked to upregulation of Cdk4 and cyclin E and the Cdk4 gene appears to be a direct target of Mnt-Myc antagonism. Like MEFs that overexpress Myc, Mnt(-/-) MEFs were prone to apoptosis, efficiently escaped senescence and could be transformed with oncogenic Ras alone. Consistent with Mnt functioning as a tumor suppressor, conditional inactivation of Mnt in breast epithelium led to adenocarinomas. These results demonstrate a unique negative regulatory role for Mnt in governing key Myc functions associated with cell proliferation and tumorigenesis.
Hurlin
Peter J
PJ
Shriners Hospitals for Children, Department of Cell and Developmental Biology, Oregon Health Sciences University, Portland, OR, USA. pjh@shcc.org
Zhou
Zi-Qiang
ZQ
Toyo-oka
Kazuhito
K
Ota
Sara
S
Walker
William L
WL
Hirotsune
Shinji
S
Wynshaw-Boris
Anthony
A
D000230:Adenocarcinoma / Q000235:genetics; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology*; D019927:Cyclin E / Q000235:genetics; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000235:genetics; D004622:Embryo, Mammalian; D005260:Female; D005347:Fibroblasts / Q000502:physiology; D017353:Gene Deletion; D005786:Gene Expression Regulation; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D016153:Genes, Suppressor; D016259:Genes, myc; D015674:Mammary Neoplasms, Animal / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D019927:Cyclin E; C484561:Mnt protein, mouse; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases