Related Experiment Video

Updated: Jun 13, 2026

Bioluminescence Resonance Energy Transfer (BRET)-Based Assay for Measuring Interactions of CRAF with 14-3-3 Proteins in Live Cells
06:44

Bioluminescence Resonance Energy Transfer (BRET)-Based Assay for Measuring Interactions of CRAF with 14-3-3 Proteins in Live Cells

Published on: March 1, 2024

Tissue-specific p19Arf regulation dictates the response to oncogenic K-ras

Nathan P Young1, Tyler Jacks

  • 1Koch Institute for Integrative Cancer Research and Department of Biology and Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

Proceedings of the National Academy of Sciences of the United States of America
|May 19, 2010
PubMed

Insights

Oncogenic Ras triggers tumor suppressor activation, but this response varies by tissue. Lung tumors rarely activate p19-Arf, while sarcomas always do, revealing tissue-specific regulation of tumor suppression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Oncogenes can activate tumor suppressor pathways, limiting tumor cell growth.
  • Oncogenic Ras typically induces the Ink4a/Arf locus, causing cell cycle arrest or senescence.
  • The tissue-specific capacity for tumor suppressor activation following oncogenic K-ras expression in vivo is not well understood.

Purpose of the Study:

  • To investigate the tissue-specific regulation of tumor suppressor pathways in response to oncogenic K-ras.
  • To determine the role of p19-Arf induction in different tissues during K-ras-driven tumorigenesis.
  • To elucidate the molecular mechanisms underlying differential Ink4a/Arf locus regulation by oncogenic K-ras.

Main Methods:

  • Utilized compound mutant mice with Arf(GFP) reporter and K-ras(LA2) allele for in vivo studies.
  • Employed constitutive and inducible RNA interference (RNAi) systems in vivo.
  • Analyzed p19-Arf up-regulation and chromatin regulation of the Ink4a/Arf locus in different tumor types.

Main Results:

  • Demonstrated dramatic tissue specificity in K-ras(G12D)-dependent p19-Arf up-regulation.
  • Observed rare p19-Arf induction in lung tumors, which can arise with functional p19-Arf.
  • Found robust p19-Arf activation in sarcomas, correlating with the necessity of p19-Arf-p53 pathway loss for sarcomagenesis.
  • Identified Polycomb-group complexes repressing Ink4a/Arf in lung tumors and Snf5 mediating p19-Arf induction in sarcomas.

Conclusions:

  • Tissue-specific chromatin regulation of Ink4a/Arf is a critical determinant of cellular responses to oncogenic K-ras.
  • Differential tumor suppressor induction explains variations in tissue susceptibility to Ras-mediated transformation.
  • Loss of the p19-Arf-p53 pathway is essential for sarcomagenesis, unlike lung tumorigenesis.

More Related Videos

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods07:49

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods

Published on: July 17, 2019

Identification of EGFR and RAS Inhibitors using Caenorhabditis elegans08:12

Identification of EGFR and RAS Inhibitors using Caenorhabditis elegans

Published on: October 5, 2020

Related Concept Videos

The Ras Gene02:38

The Ras Gene

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.
Ras is a superfamily...
Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the daughter...
MAPK Signaling Cascades01:07

MAPK Signaling Cascades

Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
Small GTPases - Ras and Rho01:24

Small GTPases - Ras and Rho

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.
Three regulatory proteins control their activity:
Negative Regulator Molecules01:23

Negative Regulator Molecules

Positive regulators allow a cell to advance through cell cycle checkpoints. Negative regulators have an equally important role as they terminate a cell’s progression through the cell cycle—or pause it—until the cell meets specific criteria.