Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Cancer related gene p53 not regulated as indicated by previous tissue culture research

28.06.2005


Results may be relevant to drug development



The cellular cascade of molecular signals that instructs cells with fatally damaged DNA to self-destruct pivots on the p53 tumor suppressor gene. If p53 is inactivated, as it is in over half of all human cancers, checks and balances on cell growth fail to operate, and body cells start to accumulate mutations, which ultimately may lead to cancer. Not surprisingly, the regulation of this vital safeguard has been studied in great detail for many years but mainly in tissue culture, or in vitro, models.

A new mouse model, created by scientists at the Salk Institute for Biological Studies, suggests that what researchers have learned about the regulation of p53 activity from in vitro studies may not be relevant to living, breathing organisms. The Salk scientists’ findings are published in this week’s online early edition of the journal Proceedings of the National Academy of Sciences.


Until now, scientists had assumed, based on studies in cultured cells, that p53 had to be modified by attaching chemical groups to specific sites on the protein to function normally in the body. The new research indicates that these modifications are not necessary to activate p53 under conditions of stress or to prevent p53 from throwing a wrench into the cell cycle machinery, when nothing is wrong.

"The chemical modifications of the p53 protein that we thought were essential for its normal function may just fine-tune the activity of the protein under physiological conditions in a living organism, but they are not essential," explains lead investigator professor Geoffrey M. Wahl. "This new study focuses our attention on the network of regulators of p53 and how they are regulated."

"This study caused a big shift in how we think about p53," explains Salk scientist and first author Kurt Krummel. "You have to look at all interacting partners because after all, modifications of p53 itself might not be so important as modifications of negative regulators and co-activators."

Many chemotherapeutical drugs used to treat cancer exert their biological effects on tumor cells through activation of the p53 pathway. Having an accurate view of how p53 is regulated will allow the development of specific drugs that unleash the killing power of p53 by interfering with its negative regulators.

Our cells are vulnerable to DNA breaks caused by UV light, ionizing radiation, toxic chemicals or other environmental damages. Unless promptly and properly repaired, these DNA breaks can let cell division spiral out of control, ultimately causing cancer.

Under normal conditions, the p53 protein is very unstable and found only at very low levels in the cell. But when the cell senses that its DNA has been damaged, it slows down the degradation of p53, so that p53 protein levels can rise and initiate protective measures. When higher than normal levels of p53 tumor suppressor exist, there is enough p53 to bind to many regulatory sites in the cell’s genome to activate the production of other proteins that will halt cell division if the DNA damage can be repaired.

Or, if the damage is too severe for the breaks to be repaired, critical backup protection, also governed by the p53 tumor suppressor protein, kicks in. It initiates the process of programmed cell death, or apoptosis, which directs the cell to commit suicide, permanently removing the damaged DNA from the organism.

Since the p53 protein is able to trigger such drastic action as cellular suicide, the cells of the body must ensure that the p53 protein is only activated when damage is sensed and that the protein is quickly degraded when it is not needed. Until now, many scientists thought that specific modifications on the easily accessible tail end, or C-terminus, of the p53 protein are crucial for both, timely degradation or activation.

To explore the effects of these modifications in vivo, Salk scientists genetically engineered mice to produce a p53 protein with an altered C-terminus instead of the normal version. Previous tissue culture studies by several labs around the world indicated that tinkering with the tail end prevented the protein from being flagged for degradation or activation. Instead of accumulating in mouse cells and halting cell division in the genetically engineered mice, the altered p53 protein performed flawlessly: it was unstable when no DNA damage was present and was stable and fully functional when needed to halt the cycle cell to repair DNA damage or to induce apoptosis.

"It came as a complete surprise. We even used a system that would have allowed us to switch on the modified p53 protein at will because we feared that the mice might not be viable and would die during early embryonic development," says Krummel.

More detailed investigations revealed that the altered p53 protein still binds to Mdm2, one of the negative regulators of p53 that facilitate its degradation.

When p53 is activated by DNA damage the same sites that are modified when the protein is slated for degradation, a different kind of chemical modification, so-called acetylation, takes place. But without acetylation, p53 functions just as well in mice, found the researchers.

Cathy Yarbrough | EurekAlert!
Further information:
http://www.salk.edu

More articles from Life Sciences:

nachricht The irresistible fragrance of dying vinegar flies
16.08.2017 | Max-Planck-Institut für chemische Ökologie

nachricht How protein islands form
15.08.2017 | Albert-Ludwigs-Universität Freiburg im Breisgau

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Exotic quantum states made from light: Physicists create optical “wells” for a super-photon

Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.

Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...

Im Focus: Circular RNA linked to brain function

For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.

While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...

Im Focus: RAVAN CubeSat measures Earth's outgoing energy

An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.

The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...

Im Focus: Scientists shine new light on the “other high temperature superconductor”

A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.

Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...

Im Focus: Scientists improve forecast of increasing hazard on Ecuadorian volcano

Researchers from the University of Miami (UM) Rosenstiel School of Marine and Atmospheric Science, the Italian Space Agency (ASI), and the Instituto Geofisico--Escuela Politecnica Nacional (IGEPN) of Ecuador, showed an increasing volcanic danger on Cotopaxi in Ecuador using a powerful technique known as Interferometric Synthetic Aperture Radar (InSAR).

The Andes region in which Cotopaxi volcano is located is known to contain some of the world's most serious volcanic hazard. A mid- to large-size eruption has...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Call for Papers – ICNFT 2018, 5th International Conference on New Forming Technology

16.08.2017 | Event News

Sustainability is the business model of tomorrow

04.08.2017 | Event News

Clash of Realities 2017: Registration now open. International Conference at TH Köln

26.07.2017 | Event News

 
Latest News

New thruster design increases efficiency for future spaceflight

16.08.2017 | Physics and Astronomy

Transporting spin: A graphene and boron nitride heterostructure creates large spin signals

16.08.2017 | Materials Sciences

A new method for the 3-D printing of living tissues

16.08.2017 | Interdisciplinary Research

VideoLinks
B2B-VideoLinks
More VideoLinks >>>