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Signal transduction involving the dmp1 transcription factor and its alteration in human cancer

Takayuki Sugiyama1, Donna P Frazier, Pankaj Taneja

  • 1The Department of Pathology, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, N.C. 27157-0001, U.S.A.

Clinical Medicine. Oncology
|September 6, 2011
PubMed

Insights

Cyclin D-interacting myb-like protein 1 (Dmp1) regulates the Arf-p53 pathway and cell cycle arrest. Dmp1 is haplo-insufficient for tumor suppression, and its deletion is linked to human lung cancer.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Oncology

Background:

  • Dmp1 (cyclin D-interacting myb-like protein 1) is a transcription factor that binds cyclin D2.
  • Dmp1 activates the Arf promoter, inducing Arf-p53-dependent cell cycle arrest.
  • D-type cyclins can inhibit or synergize with Dmp1 on the Arf promoter.

Purpose of the Study:

  • To investigate the role of Dmp1 in tumor suppression.
  • To understand the regulation of the Dmp1 promoter.
  • To assess the involvement of human DMP1 (hDMP1) in human carcinogenesis.

Main Methods:

  • Yeast two-hybrid screen to identify Dmp1 binding partners.
  • Analysis of Arf promoter activity and cell cycle arrest in response to Dmp1.
  • Tumor formation studies in Dmp1(+/-) and Dmp1(-/-) mice.
  • Analysis of Dmp1 promoter regulation by various signaling pathways.
  • Genetic analysis of hDMP1 in human lung cancers.

Main Results:

  • Dmp1 is haplo-insufficient for tumor suppression in mice, with accelerated tumor formation in Dmp1(+/-) and Dmp1(-/-) models.
  • Dmp1 is a physiological regulator of the Arf-p53 pathway.
  • The Dmp1 promoter is activated by oncogenic Ras-Raf signaling and repressed by mitogenic, E2F, and NF-κB stimuli.
  • hDMP1 is hemizygously deleted in ~40% of human lung cancers, particularly those with intact INK4a/ARF and P53 loci.

Conclusions:

  • Dmp1 functions as a tumor suppressor by regulating the Arf-p53 pathway.
  • Dmp1's role in tumor suppression is haplo-insufficient.
  • hDMP1 deletion is implicated in human lung carcinogenesis, suggesting hDMP1-deleted tumors may represent a distinct entity.
Keywords:
ArfDmp1Rashaplo-insufficiencylung cancerp53

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