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Induction of ARF tumor suppressor gene expression and cell cycle arrest by transcription factor DMP1

K Inoue1, M F Roussel, C J Sherr

  • 1Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.

Proceedings of the National Academy of Sciences of the United States of America
|March 31, 1999
PubMed

Insights

The transcription factor DMP1 halts cell growth by activating the ARF gene, which then triggers a p53-dependent cell cycle arrest. This process does not induce apoptosis, highlighting ARF’s role in non-lethal cell cycle regulation.

Area of Science:

  • Molecular Biology
  • Cell Cycle Regulation
  • Cancer Biology

Background:

  • The transcription factor DMP1, a cyclin D-binding Myb-like protein, exhibits antiproliferative effects.
  • The tumor suppressor gene ARF (Alternative Reading Frame) plays a crucial role in cell cycle control and tumor suppression.
  • The interplay between DMP1, ARF, and the p53 pathway in cell cycle arrest is not fully understood.

Purpose of the Study:

  • To investigate the mechanism by which DMP1 induces growth arrest.
  • To determine the role of the ARF tumor suppressor gene in DMP1-mediated antiproliferative activity.
  • To elucidate the relationship between DMP1, ARF, p53, and apoptosis.

Main Methods:

  • Expression of DMP1 in mouse embryo fibroblast strains and primary diploid fibroblasts.
  • Analysis of ARF promoter activity and gene expression.
  • Assessment of p53-dependent cell cycle arrest.
  • Comparison of DMP1's effects with other oncogenic pathway activators (Myc, E1A, E2F-1).

Main Results:

  • DMP1 induces growth arrest in fibroblasts lacking the ARF gene.
  • DMP1 directly binds to the ARF promoter, activating its expression.
  • ARF synthesis leads to p53-dependent cell cycle arrest.
  • DMP1 does not induce apoptosis, distinguishing it from Myc, E1A, and E2F-1.

Conclusions:

  • DMP1-mediated cell cycle arrest is dependent on the ARF tumor suppressor gene.
  • ARF can be induced by antiproliferative stimuli without necessarily triggering apoptosis.
  • This study clarifies ARF's role in responding to non-oncogenic stress signals.

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