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Ras-Raf-Arf signaling critically depends on the Dmp1 transcription factor

Ramesh Sreeramaneni1, Asif Chaudhry, Martin McMahon

  • 1Department of Pathology, Wake Forest University Health Sciences, 2102 Gray Building, Medical Center Blvd., Winston-Salem, NC 27157, USA.

Molecular and Cellular Biology
|December 17, 2004
PubMed

Insights

Dmp1 acts as a tumor suppressor by activating the Arf-p53 pathway. A novel Jun-Dmp1 pathway links Ras-Raf signaling to Arf, independent of the Rb-E2F pathway, explaining Dmp1

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Dmp1 is a tumor suppressor that activates the Arf-p53 pathway.
  • Oncogenic signaling pathways, such as Ras-Raf, play critical roles in cell transformation and tumor development.
  • Understanding the regulatory mechanisms linking oncogenic signaling to tumor suppressor activation is crucial for cancer research.

Purpose of the Study:

  • To elucidate the role of Dmp1 in preventing tumor formation.
  • To investigate the signaling pathways that regulate Dmp1 expression and activation.
  • To identify the molecular mechanisms by which Dmp1 links oncogenic Ras-Raf signaling to the Arf-p53 pathway.

Main Methods:

  • Analysis of Dmp1 promoter activity in cultured primary cells stimulated with oncogenic Ha-Ras(V12), c-Myc, or E2F-1.
  • Investigation of the role of Raf-MEK-ERK signaling in Dmp1 promoter activation.
  • Assessment of premature senescence and transformation in Dmp1-null cells.
  • Mapping of Ras(V12)-responsive elements in the Dmp1 and Arf promoters.
  • Analysis of transcription factor binding (Fos, Jun, Dmp1) to promoter elements.
  • Knock-down studies targeting c-Jun and JunB to assess their role in Dmp1 promoter activation.

Main Results:

  • Oncogenic Ha-Ras(V12) efficiently activated the Dmp1 promoter via Raf-MEK-ERK signaling.
  • Dmp1-null cells were resistant to Raf-mediated premature senescence and susceptible to Ras-induced transformation.
  • Jun family proteins (c-Jun, JunB) are critical for Ras(V12)-induced Dmp1 promoter activation.
  • Dmp1 binds to the Arf promoter upon oncogenic Raf activation, mediating Arf induction.

Conclusions:

  • Dmp1 acts as a crucial intermediary, linking oncogenic Ras-Raf signaling to the induction of p19(Arf).
  • A novel Jun-Dmp1 pathway directly connects Ras-Raf signaling to p19(Arf), independent of the classical cyclin D1/Cdk4-Rb-E2F pathway.
  • This pathway explains the susceptibility of Dmp1-null cells to Ras-induced transformation and highlights Dmp1's role as a tumor suppressor.

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