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Specific contributions of the small GTPases Rho, Rac, and Cdc42 to Dbl transformation

R Lin1, R A Cerione, D Manor

  • 1Department of Molecular Medicine, Veterinary Medical Center, Cornell University, Ithaca, New York 14853, USA.

The Journal of Biological Chemistry
|August 7, 1999
PubMed

Insights

Oncogene Dbl activates Rho GTPases, crucial for cell transformation. Researchers created "fast-cycling" mutants of Cdc42, Rac1, and RhoA, which mimic Dbl

Area of Science:

  • Oncogenes and signal transduction pathways.
  • Cellular transformation and tumorigenesis.
  • Small GTPase regulation and function.

Background:

  • Dbl oncoproteins activate Rho-like GTPases, implicated in neoplastic pathologies.
  • GTPase-defective Rho proteins show weak or inhibitory transformation capacity.
  • Mimicking Dbl activation is key to understanding oncogenesis.

Purpose of the Study:

  • To generate spontaneously activated Rho GTPase mutants (Cdc42, Rac1, RhoA).
  • To investigate if these mutants can reconstitute Dbl-induced NIH3T3 fibroblast transformation.
  • To determine the distinct contributions of each activated GTPase to transformation.

Main Methods:

  • Generation of
  • fast-cycling
  • mutants of Cdc42, Rac1, and RhoA.
  • Stable expression of these mutants in NIH3T3 fibroblasts.
  • Assessment of cellular transformation phenotypes (serum dependence, saturation density) and tumorigenicity in nude mice.

Main Results:

  • All three spontaneously activated mutants induced loss of serum dependence and increased saturation density in NIH3T3 cells.
  • Stable cell lines expressing these mutants were tumorigenic upon injection into nude mice.
  • Activation of each Dbl target GTPase contributes distinct facets to cellular transformation.

Conclusions:

  • Spontaneously activated Cdc42, Rac1, and RhoA mutants effectively mimic Dbl oncoprotein effects.
  • Full Dbl-induced transformation requires activation of all three targets.
  • Each activated GTP-binding protein plays a unique role in driving cellular transformation and tumorigenesis.

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