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Signal Transduction Involving the Dmp1 Transcription Factor and its Alteration in Human Cancer

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Author(s): Takayuki Sugiyama | Donna P. Frazier | Pankaj Taneja | Robert D. Kendig | Rachel L. Morgan | Lauren A. Matise | Sarah J. Lagedrost | Kazushi Inoue

Journal: Clinical Medicine : Oncology
ISSN 1177-9314

Volume: 2;
Start page: 209;
Date: 2008;
Original page

Keywords: Dmp1 | Arf | p53 | Ras | haplo-insufficiency | lung cancer

ABSTRACT
Dmp1 (cyclin D-interacting myb-like protein 1; also called Dmtf1) is a transcription factor that has been isolated in a yeast two-hybrid screen through its binding property to cyclin D2. Dmp1 directly binds to and activates the Arf promoter and induces Arf-p53-dependent cell cycle arrest in primary cells. D-type cyclins usually inhibit Dmp1-mediated transcription in a Cdk-independent fashion; however, Dmp1 shows synergistic effects with D-cyclins on the Arf promoter. Ras or Myc oncogene-induced tumor formation is accelerated in both Dmp1+/− and Dmp1−/− mice with no significant differences between Dmp1+/− and Dmp1−/−. Thus, Dmp1 is haplo-insufficient for tumor suppression. Tumors from Dmp1−/− or Dmp1+/− mice often retain wild-type Arf and p53, suggesting that Dmp1 is a physiological regulator of the Arf-p53 pathway. The Dmp1 promoter is activated by oncogenic Ras-Raf signaling, while it is repressed by physiological mitogenic stimuli, overexpression of E2F proteins, and genotoxic stimuli mediated by NF-κB. The human DMP1 gene (hDMP1) is located on chromosome 7q21 and is hemizygously deleted in approximately 40% of human lung cancers, especially those that retain normal INK4a/ARF and P53 loci. Thus, hDMP1 is clearly involved in human carcinogenesis, and tumors with hDMP1 deletion may constitute a discrete disease entity.
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