Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

New model of p53 regulation proposed that suggests novel anticancer strategy

12.04.2006
Genetically engineered mice convinced scientists at the Salk Institute for Biological Studies that it was time to overhaul widely held beliefs about how a powerful tumor suppressor called p53 is controlled in cells. Their new model of p53 regulation has important implications for the development of anticancer drugs.

This new model, published in the April issue of the journal Cancer Cell, emphasizes the independent role of two proteins, called Mdm2 and Mdm4. Both proteins are part of the tightly controlled system of checks and balances ensuring that p53 keeps a tight lid on unchecked cell growth but doesn’t wreak havoc in healthy cells.

Up to this point, researchers thought Mdm2 and Mdm4 collaborated to halt the activities of p53. As a powerful tumor suppressor, p53 turns on genes that either halt cell division, to allow time for repair of damaged DNA, or, when all rescue attempts prove futile, order the cell to commit suicide. The mouse experiments revealed that, in fact, it is Mdm4 that renders p53 inactive, while Mdm2 mainly controls the stability of p53’s structure.

The distinction is important, says the study’s lead investigator, Professor Geoffrey M. Wahl, Ph.D., a professor in the Gene Expression Laboratory. "p53 is disarmed in more than half of all cancers, and Mdm2 and Mdm4 are over-expressed to act like cancer-causing oncogenes in much of the rest. We need to know how each of these p53 inhibitors work in normal cells before we can figure out the most effective therapeutic strategies to manipulate them in cancer cells," he says.

The new findings suggest that cancer drugs now being tested that inhibit Mdm2 may not work as hoped. Researchers thought that, since the functions of Mdm2 and Mdm4 were linked, it would suffice to inhibit Mdm2 to restore p53’s tumor-suppressing activity in cancer cells.

"In fact, we observed that a partial decrease in Mdm2 or Mdm4 activity only marginally affects p53 function, but that a combined decrease of Mdm2 and Mdm4 dramatically increases p53 function to improve tumor suppression," says lead author Franck Toledo, Ph.D., a former Salk scientist now at the Pasteur Institute in Paris, France. "We also found that the complete ablation of Mdm4 activity leads to very efficient tumor suppression. The clinical implications of these findings are obvious: drugs that inhibit Mdm4 need to be actively searched for, as they should be powerful tools against cancer," Toledo adds.

Researchers already knew that Mdm2 and Mdm4 were important for controlling p53, but how these enzymes interacted with p53 has been the subject of controversy. The Salk researchers discovered that the primary role of Mdm2 is to flag p53 for destruction to keep p53 protein levels low, while Mdm4 prevents p53 from turning on genes when the tumor suppressor is not needed. For p53 to be activated, Mdm4 first needs to be eliminated.

Wahl and his team now believe that DNA damage triggers the release of specific enzymes that modify Mdm2 and Mdm4. This action flips a "switch," prompting Mdm2 to target both Mdm4 and itself for degradation. Then, as p53 activates genes to shut down the cell cycle, it also turns on the gene for Mdm2. Increased p53 activity leads to heightened expression of Mdm2, which increases degradation of Mdm4 - freeing p53 to function unhindered - at the same time keeping p53 from going overboard.

"This is a very elegant system, because it acts to titrate p53, giving the cell time to repair its DNA and to gauge how much damage there really is," Wahl says.

Authors who also contributed to this work include Kurt Krummel, Crystal Lee, Chung-Wen Liu, Luo-Wei Rodewald, and Mengjia Tang, all at the Salk Institute.

Gina Kirchweger | EurekAlert!
Further information:
http://www.salk.edu

More articles from Life Sciences:

nachricht Climate Impact Research in Hannover: Small Plants against Large Waves
17.08.2018 | Leibniz Universität Hannover

nachricht First transcription atlas of all wheat genes expands prospects for research and cultivation
17.08.2018 | Leibniz-Institut für Pflanzengenetik und Kulturpflanzenforschung

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Color effects from transparent 3D-printed nanostructures

New design tool automatically creates nanostructure 3D-print templates for user-given colors
Scientists present work at prestigious SIGGRAPH conference

Most of the objects we see are colored by pigments, but using pigments has disadvantages: such colors can fade, industrial pigments are often toxic, and...

Im Focus: Unraveling the nature of 'whistlers' from space in the lab

A new study sheds light on how ultralow frequency radio waves and plasmas interact

Scientists at the University of California, Los Angeles present new research on a curious cosmic phenomenon known as "whistlers" -- very low frequency packets...

Im Focus: New interactive machine learning tool makes car designs more aerodynamic

Scientists develop first tool to use machine learning methods to compute flow around interactively designable 3D objects. Tool will be presented at this year’s prestigious SIGGRAPH conference.

When engineers or designers want to test the aerodynamic properties of the newly designed shape of a car, airplane, or other object, they would normally model...

Im Focus: Robots as 'pump attendants': TU Graz develops robot-controlled rapid charging system for e-vehicles

Researchers from TU Graz and their industry partners have unveiled a world first: the prototype of a robot-controlled, high-speed combined charging system (CCS) for electric vehicles that enables series charging of cars in various parking positions.

Global demand for electric vehicles is forecast to rise sharply: by 2025, the number of new vehicle registrations is expected to reach 25 million per year....

Im Focus: The “TRiC” to folding actin

Proteins must be folded correctly to fulfill their molecular functions in cells. Molecular assistants called chaperones help proteins exploit their inbuilt folding potential and reach the correct three-dimensional structure. Researchers at the Max Planck Institute of Biochemistry (MPIB) have demonstrated that actin, the most abundant protein in higher developed cells, does not have the inbuilt potential to fold and instead requires special assistance to fold into its active state. The chaperone TRiC uses a previously undescribed mechanism to perform actin folding. The study was recently published in the journal Cell.

Actin is the most abundant protein in highly developed cells and has diverse functions in processes like cell stabilization, cell division and muscle...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

LaserForum 2018 deals with 3D production of components

17.08.2018 | Event News

Within reach of the Universe

08.08.2018 | Event News

A journey through the history of microscopy – new exhibition opens at the MDC

27.07.2018 | Event News

 
Latest News

Smallest transistor worldwide switches current with a single atom in solid electrolyte

17.08.2018 | Physics and Astronomy

Robots as Tools and Partners in Rehabilitation

17.08.2018 | Information Technology

Climate Impact Research in Hannover: Small Plants against Large Waves

17.08.2018 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>