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Inhibition of an activated Ras protein with genetically selected peptide aptamers

Stephen E Kurtz1, Kim Esposito, Weimin Tang

  • 1Department of Immunology, Veterans Affairs Medical Center, Portland, Oregon 97201, USA. skurtz@qwest.net

Biotechnology and Bioengineering
|February 6, 2003
PubMed

Insights

Researchers identified peptide aptamers that suppress activated Ras signaling in yeast. These aptamers reduce growth arrest, lower cAMP levels, and mitigate heat shock sensitivity, demonstrating in vivo functionality.

Area of Science:

  • Molecular Biology
  • Yeast Genetics
  • Signal Transduction

Background:

  • Mutant Ras alleles lock signaling pathways in an "on" state, driving uncontrolled cell proliferation.
  • Ras signaling is crucial for cell growth and stress response, and its dysregulation is implicated in diseases like cancer.

Purpose of the Study:

  • To identify novel peptide aptamers capable of inhibiting constitutively active Ras signaling.
  • To characterize the functional capacity of these peptide aptamers in a living organism.

Main Methods:

  • Genetic selection in Saccharomyces cerevisiae to screen for suppressor peptides.
  • Expression of peptide aptamers as fusions to glutathione-S-transferase and thioredoxin.
  • Assay of growth arrest, cAMP levels, and heat shock sensitivity in yeast cells.

Main Results:

  • A peptide aptamer was identified that effectively suppresses the growth arrest caused by activated Ras2-Val19.
  • Aptamer expression normalized elevated cAMP levels and reversed heat shock sensitivity in Ras-activated yeast.
  • The peptide aptamer demonstrated functional activity when expressed as an unconstrained peptide in vivo.

Conclusions:

  • Peptide aptamers can be effectively developed to target and modulate aberrant signaling pathways like Ras.
  • This study validates a strategy for discovering and utilizing peptide aptamers for therapeutic intervention in diseases driven by Ras mutations.

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