Related Experiment Video

Updated: Aug 17, 2026

Studying Proteolysis of Cyclin B at the Single Cell Level in Whole Cell Populations
10:54

Studying Proteolysis of Cyclin B at the Single Cell Level in Whole Cell Populations

Published on: September 17, 2012

Ras activity regulates cyclin E degradation by the Fbw7 pathway

Alex C Minella1, Markus Welcker, Bruce E Clurman

  • 1Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.

Proceedings of the National Academy of Sciences of the United States of America
|June 28, 2005
PubMed

Insights

Oncogenic Ras activity disrupts the Fbw7 pathway, impairing cyclin E degradation. This links Ras mutations to cancer by promoting genetic instability through reduced cyclin E proteolysis.

Area of Science:

  • Cellular Biology
  • Molecular Oncology
  • Biochemistry

Background:

  • The Fbw7 ubiquitin ligase targets cyclin E for degradation, a process crucial for preventing genetic instability and tumorigenesis.
  • Fbw7 is a tumor suppressor frequently mutated in cancers, but other mechanisms may also impair its function.
  • Dysregulation of cyclin E proteolysis is implicated in cancer development.

Purpose of the Study:

  • To investigate the role of oncogenic Ha-Ras activity in regulating cyclin E degradation via the Fbw7 pathway.
  • To elucidate the specific Ras-activated signaling pathways involved in modulating cyclin E turnover.
  • To determine how Ras-mediated inhibition of cyclin E proteolysis contributes to genetic instability and tumorigenesis.

Main Methods:

  • Utilized cell-based assays to examine the impact of activated and inhibited Ras signaling on cyclin E protein levels and degradation.
  • Investigated the interaction between cyclin E and Fbw7 under conditions of altered Ras activity.
  • Assessed the role of the mitogen-activated protein kinase (MAPK) pathway in Ras-mediated regulation of cyclin E.
  • Evaluated the effect of oncogenic Ras on cyclin E-induced genetic instability.

Main Results:

  • Oncogenic Ha-Ras activity was found to inhibit Fbw7-mediated cyclin E degradation, leading to increased cyclin E abundance.
  • Inhibition of normal Ras activity resulted in decreased cyclin E levels.
  • Activation of the MAPK pathway was identified as the key Ras-dependent mechanism suppressing cyclin E turnover.
  • Activated Ha-Ras impaired the binding of cyclin E to Fbw7 and reduced cyclin E ubiquitination.
  • Oncogenic Ras potentiated cyclin E-driven genetic instability, particularly when cyclin E degradation was compromised by Fbw7.

Conclusions:

  • Ras activity directly regulates Fbw7-mediated proteolysis of cyclin E.
  • Impaired cyclin E proteolysis, driven by Ras activity, represents a novel mechanism contributing to Ras-driven tumorigenesis.
  • Targeting the Ras-Fbw7-cyclin E axis may offer therapeutic strategies for cancers with Ras mutations.

More Related Videos

Identification of Cyclin-dependent Kinase 1 Specific Phosphorylation Sites by an In Vitro Kinase Assay12:26

Identification of Cyclin-dependent Kinase 1 Specific Phosphorylation Sites by an In Vitro Kinase Assay

Published on: May 3, 2018

Analysis of Cell Cycle Position in Mammalian Cells12:19

Analysis of Cell Cycle Position in Mammalian Cells

Published on: January 21, 2012

Related Concept Videos

Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
Anaphase Promoting Complex00:50

Anaphase Promoting Complex

The stepwise destruction of specific proteins is necessary for the progression and completion of the cell cycle. Such proteins are ubiquitinated by ubiquitin ligases and then subsequently destroyed by the proteasome. The SCF (Skp1/Cullin/F-box) and the anaphase-promoting complex (APC) are two important ubiquitin ligases involved in cell cycle progression. While SCF is active throughout the cell cycle, APC gets activated during metaphase to anaphase transition. Cdc20 or Cdh1 binds to APC and...
Positive Regulator Molecules02:39

Positive Regulator Molecules

Mitotic cell division results in daughter cells that exactly resemble the parent cell. However, errors in the DNA replication or distribution of genetic material may lead to genetic mutations that may be passed down to every new cell formed from the resulting abnormal cell. Propagation of such mutant cells is restricted through checkpoint mechanisms present at different stages of the cell cycle. These checkpoints involve regulator molecules that either promote or demote cell cycle events.
Positive Regulator Molecules01:45

Positive Regulator Molecules

To consistently produce healthy cells, the cell cycle—the process that generates daughter cells—must be precisely regulated.
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.
Molecular Factors Affecting Cell Division01:27

Molecular Factors Affecting Cell Division

Several external and internal factors influence the initiation and inhibition of cell division. For instance, the death of nearby cells or the release of human growth hormone (hGH) promotes cell division. In contrast, lack of hGH or crowding of cells can inhibit cell division.
Several proteins function as internal regulators to ensure each cell cycle stage is completed faithfully before proceeding to the next. Regulator molecules may act directly or influence the activity or production of other...