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  • The EMBO Journal (2003) 22, 4584 - 4596
  • doi:10.1093/emboj/cdg442

Deletion of Mnt leads to disrupted cell cycle control and tumorigenesis

Peter J. Hurlin1,2, Zi-Qiang Zhou1, Kazuhito Toyo-oka3,4, Sara Ota1, William L. Walker1, Shinji Hirotsune3,4 and Anthony Wynshaw-Boris3

  1. Shriners Hospitals for Children, Oregon Health Sciences University, Portland, OR, USA
  2. Department of Cell and Developmental Biology, Oregon Health Sciences University, Portland, OR, USA
  3. Departments of Pediatrics and Medicine, UCSD Comprehensive Cancer Center, University of California, San Diego, School of Medicine, San Diego, CA, USA
  4. Center for Genome Medical Science, Saitama Medical School PRESTO, Japan Science and Technology Corporation Inariyama, 1397-1 Yamane, Hidaka City, Saitama 350-1241, Japan

Correspondence to:

Peter J. Hurlin, E-mail: pjh@shcc.org

Received 13 June 2003; Accepted 17 July 2003; Revised 16 July 2003

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.

  • Keywords:

    • breast cancer,
    • Cdk4,
    • cyclin E,
    • Mnt,
    • Myc