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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...
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:
Notch Signaling Pathway03:14

Notch Signaling Pathway

The Notch signaling pathway is a major intracellular signaling pathway that is highly conserved over a broad spectrum of metazoan species. It stands unique from other intracellular signaling mechanisms in animals because notch protein itself acts as the receptor as well as the primary signaling molecule.
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not until 1985...
Notch Signaling Pathway03:14

Notch Signaling Pathway

The Notch signaling pathway is a major intracellular signaling pathway that is highly conserved over a broad spectrum of metazoan species. It stands unique from other intracellular signaling mechanisms in animals because notch protein itself acts as the receptor as well as the primary signaling molecule.
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not until 1985...
Cancer-Critical Genes I: Proto-oncogenes01:33

Cancer-Critical Genes I: Proto-oncogenes

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.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...

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Related Experiment Video

Updated: May 27, 2026

Defining Gene Functions in Tumorigenesis by Ex vivo Ablation of Floxed Alleles in Malignant Peripheral Nerve Sheath Tumor Cells
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Aberrant expression of RasGRP1 cooperates with gain-of-function NOTCH1 mutations in T-cell leukemogenesis.

T Oki1, J Kitaura, N Watanabe-Okochi

  • 1Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

Leukemia
|November 26, 2011
PubMed
Summary

Ras guanyl nucleotide-releasing proteins (RasGRPs) are key Ras activators. RasGRP1, not RasGRP4, predominantly drives T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) by cooperating with NOTCH1 mutations.

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05:48

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Published on: January 2, 2018

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Ras guanyl nucleotide-releasing proteins (RasGRPs) activate Ras signaling pathways.
  • Previous research suggested RasGRP1 and RasGRP4 involvement in leukemogenesis.
  • The specific roles of RasGRP1 and RasGRP4 in T-cell malignancies require further clarification.

Purpose of the Study:

  • To elucidate the predominant role of RasGRP1 in T-cell leukemogenesis.
  • To investigate the cooperative mechanisms between RasGRP1 and NOTCH1 signaling in T-ALL.
  • To compare the leukemogenic potential of RasGRP1 versus RasGRP4.

Main Methods:

  • Analysis of RasGRP1 and RasGRP4 expression in human T-cell malignancies.
  • Utilizing a murine bone marrow transplantation model to assess leukemogenic potential.
  • Investigating cell survival under specific stimulation conditions (growth factor withdrawal, phorbol ester).
  • Identifying NOTCH1 mutations in T-ALL samples.

Main Results:

  • RasGRP1, but not RasGRP4, showed significantly increased expression in human T-cell malignancies.
  • RasGRP1 induced T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) with shorter latency in a mouse model compared to RasGRP4.
  • Gain-of-function NOTCH1 mutations were frequently observed in RasGRP1-mediated T-ALL, indicating cooperation between RasGRP1 and NOTCH1 signaling.
  • Disruption of a protein kinase C phosphorylation site on RasGRP1 attenuated its leukemogenic advantage.

Conclusions:

  • Aberrant RasGRP1 expression is a critical factor in T-cell leukemogenesis.
  • Cooperation between RasGRP1 and secondary NOTCH1 gain-of-function mutations plays a significant role in T-ALL development.
  • RasGRP1 exhibits a stronger leukemogenic potential than RasGRP4, partly due to specific phosphorylation sites.