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New and unexpected: forkhead meets ARF

Robert H Costa1, Vladimir V Kalinichenko, Michael L Major

  • 1Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, College of Medicine, Chicago, Illinois 60607, USA. robcosta@uic.edu

Current Opinion in Genetics & Development
|January 22, 2005
PubMed

Insights

Mice lacking the Foxm1b transcription factor resist liver cancer. A p19ARF peptide inhibits Foxm1b, offering a potential therapy for hepatocellular carcinoma.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Hepatocellular carcinoma (HCC) is a lethal cancer.
  • Foxm1b (forkhead box m1b) transcription factor promotes HCC.
  • p19ARF tumor suppressor inhibits Foxm1b early in tumorigenesis, but its expression is lost in advanced tumors.

Purpose of the Study:

  • To investigate the inhibitory mechanism of p19ARF on Foxm1b.
  • To evaluate a p19ARF-derived peptide as a potential HCC therapy.

Main Methods:

  • Structure-function analysis of p19ARF protein domains.
  • Assessment of a modified p19ARF peptide's cellular uptake and inhibitory activity.
  • Evaluation of the peptide's effect on Foxm1b-driven anchorage-independent cell growth.

Main Results:

  • Amino acids 26-46 of p19ARF bind Foxm1b and inhibit its transcriptional activity by promoting nucleolar targeting.
  • A modified p19ARF peptide (amino acids 24-46) effectively inhibits Foxm1b activity.
  • This peptide prevents Foxm1b-induced anchorage-independent growth, a hallmark of cancer cells.

Conclusions:

  • The p19ARF peptide is a potent inhibitor of Foxm1b transcriptional activity.
  • This p19ARF peptide represents a promising therapeutic strategy for hepatocellular carcinoma by targeting Foxm1b.

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