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The Ras Gene02:38

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The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
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Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
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Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
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Related Experiment Video

Updated: Nov 23, 2025

Real-time Imaging of Myeloid Cells Dynamics in ApcMin/+ Intestinal Tumors by Spinning Disk Confocal Microscopy
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A RAC-GEF network critical for early intestinal tumourigenesis.

K A Pickering1, K Gilroy1, J W Cassidy2

  • 1CRUK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK.

Nature Communications
|January 5, 2021
PubMed
Summary
This summary is machine-generated.

Targeting RAC-GEFs suppresses Apc-driven intestinal tumors by inhibiting RAC1 activity. However, this therapeutic benefit is lost in late-stage disease with KRAS mutations.

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Area of Science:

  • Oncology
  • Molecular Biology
  • Gastroenterology

Background:

  • RAC1 activity is essential for intestinal homeostasis and Apc-deficient hyperproliferation.
  • Directly targeting RAC1 may disrupt normal intestinal function.
  • Indirect targeting of RAC1 via RAC-GEFs is a potential therapeutic strategy.

Purpose of the Study:

  • To investigate the role of RAC-GEFs (Vav3, Tiam1) in Apc-driven intestinal hyperproliferation and tumor development.
  • To assess the therapeutic potential of targeting RAC-GEFs in early-stage intestinal tumorigenesis.
  • To determine if oncogenic KRAS mutations affect RAC-GEF dependency.

Main Methods:

  • Transcriptional profiling of Apc-deficient murine intestinal tissue.
  • Gene deletion studies (Tiam1-/-, Vav3-/-, Vav2-/-, Vav3-/-, Tiam1-/-).
  • Assessment of RAC1 activity, hyperproliferation, and tumor development.
  • Evaluation of KRAS mutation impact on RAC-GEF dependency.

Main Results:

  • Tiam1 deficiency suppressed Apc-driven hyperproliferation but not tumorigenesis.
  • Vav3 deficiency had no significant effect on hyperproliferation or tumorigenesis.
  • Combined deletion of Vav2, Vav3, and Tiam1 profoundly suppressed hyperproliferation, tumor development, and RAC1 activity without impacting homeostasis.
  • Oncogenic KRAS mutations negated the RAC-GEF dependency.

Conclusions:

  • Targeting RAC-GEFs shows therapeutic promise for early-stage Apc-driven intestinal tumorigenesis.
  • The therapeutic efficacy of RAC-GEF inhibition is limited in the presence of oncogenic KRAS mutations, indicating a loss of benefit in late-stage disease.
  • Vav2, Vav3, and Tiam1 are key regulators of RAC1 activity in Apc-deficient intestinal tumors.