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 Making fuel out of thick air
08.12.2017 | DOE/Argonne National Laboratory

nachricht ‘Spying’ on the hidden geometry of complex networks through machine intelligence
08.12.2017 | Technische Universität Dresden

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Towards data storage at the single molecule level

The miniaturization of the current technology of storage media is hindered by fundamental limits of quantum mechanics. A new approach consists in using so-called spin-crossover molecules as the smallest possible storage unit. Similar to normal hard drives, these special molecules can save information via their magnetic state. A research team from Kiel University has now managed to successfully place a new class of spin-crossover molecules onto a surface and to improve the molecule’s storage capacity. The storage density of conventional hard drives could therefore theoretically be increased by more than one hundred fold. The study has been published in the scientific journal Nano Letters.

Over the past few years, the building blocks of storage media have gotten ever smaller. But further miniaturization of the current technology is hindered by...

Im Focus: Successful Mechanical Testing of Nanowires

With innovative experiments, researchers at the Helmholtz-Zentrums Geesthacht and the Technical University Hamburg unravel why tiny metallic structures are extremely strong

Light-weight and simultaneously strong – porous metallic nanomaterials promise interesting applications as, for instance, for future aeroplanes with enhanced...

Im Focus: Virtual Reality for Bacteria

An interdisciplinary group of researchers interfaced individual bacteria with a computer to build a hybrid bio-digital circuit - Study published in Nature Communications

Scientists at the Institute of Science and Technology Austria (IST Austria) have managed to control the behavior of individual bacteria by connecting them to a...

Im Focus: A space-time sensor for light-matter interactions

Physicists in the Laboratory for Attosecond Physics (run jointly by LMU Munich and the Max Planck Institute for Quantum Optics) have developed an attosecond electron microscope that allows them to visualize the dispersion of light in time and space, and observe the motions of electrons in atoms.

The most basic of all physical interactions in nature is that between light and matter. This interaction takes place in attosecond times (i.e. billionths of a...

Im Focus: A transistor of graphene nanoribbons

Transistors based on carbon nanostructures: what sounds like a futuristic dream could be reality in just a few years' time. An international research team working with Empa has now succeeded in producing nanotransistors from graphene ribbons that are only a few atoms wide, as reported in the current issue of the trade journal "Nature Communications."

Graphene ribbons that are only a few atoms wide, so-called graphene nanoribbons, have special electrical properties that make them promising candidates for the...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Innovative strategies to tackle parasitic worms

08.12.2017 | Event News

AKL’18: The opportunities and challenges of digitalization in the laser industry

07.12.2017 | Event News

Blockchain is becoming more important in the energy market

05.12.2017 | Event News

 
Latest News

Making fuel out of thick air

08.12.2017 | Life Sciences

Rules for superconductivity mirrored in 'excitonic insulator'

08.12.2017 | Information Technology

Smartphone case offers blood glucose monitoring on the go

08.12.2017 | Information Technology

VideoLinks
B2B-VideoLinks
More VideoLinks >>>