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Molecular and Cellular Biology, February 2004, p. 1560-1569, Vol. 24, No. 4
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.4.1560-1569.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Mnt Loss Triggers Myc Transcription Targets, Proliferation, Apoptosis, and Transformation

Jonas A. Nilsson, Kirsteen H. Maclean, Ulrich B. Keller, Helene Pendeville, Troy A. Baudino, and John L. Cleveland*

Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, Tennessee 38105

Received 20 August 2003/ Returned for modification 26 September 2003/ Accepted 14 November 2003

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.

* Corresponding author. Mailing address: St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105. Phone: (901) 495-2398. Fax: (901) 525-8025. E-mail: john.cleveland{at}stjude.org.

Molecular and Cellular Biology, February 2004, p. 1560-1569, Vol. 24, No. 4
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.4.1560-1569.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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