Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Scientists unlock solid tumor treatment genetic secrets

05.12.2005


Study suggests that histone deacetylase enzymes cooperating with CBP/p300 histone acetylases trigger expression of many genes that respond to hypoxia, according to St. Jude



A biochemical mechanism that cells use to cope with hypoxia (lack of oxygen) actually cooperates with a less well-known mechanism that helps increase the expression of those hypoxia-sensitive genes, according to investigators at St. Jude Children’s Research Hospital.

The two mechanisms each enable a transcription factor called hypoxia-inducible factor (HIF) to increase expression of genes that the cell uses to respond to the stress of hypoxia. Transcription factors bind to a site on the gene called the promoter and trigger the process that decodes the gene and makes the protein for which that gene codes. HIF binds to and activates many genes that contribute to the survival response of tumors; for example, genes that control biochemical reactions that don’t require oxygen to extract energy from glucose or genes needed to build new blood vessels that bring additional oxygen to hypoxic cells.


The St. Jude finding is important because it suggests that developing new therapies that interfere with both mechanisms instead of just one might enhance the efficacy of treatments designed for solid tumors that become hypoxic as they outgrow their oxygen supply, according to Paul Brindle, Ph.D., an associate member of the Department of Biochemistry. Brindle is senior author of a report on this work that appeared in November 16 issue of The EMBO Journal.

The St. Jude researchers showed that, in addition to a mechanism controlled by two proteins called CBP and p300 (CBP/p300 collectively), a second mechanism that appears to use an enzyme called a histone deacetylase (HDAC) contributes significantly to increasing the expression of hypoxia-sensitive genes. The investigators also found evidence that suggests HIF might activate genes by a third type of biochemical pathway. If true, this would further expand the range of potential strategies for treating solid tumors.

HIF is unstable and cannot work well when the cell contains a normal amount of oxygen. But when oxygen levels are so low they stress the cell, HIF becomes stable and binds to specific genes. Once on a target gene, HIF recruits CBP and p300, each of which contains a section called the CH1 domain. The CH1 domain of each protein binds to a section of HIF called the C-TAD. This binding of the CH1 domain to the C-TAD prompts HIF to turn on the gene. Because CBP and p300 each help HIF activate genes, they are called co-activators.

CBP and p300 belong to a group of coactivators called acetylases, and have long been thought to bind to HIF during the cell’s response to hypoxia, but definitive evidence for this occurring in cells was previously lacking. In contrast, HDACs were thought to be proteins that interfere with the expression of genes. Unexpectedly, the St. Jude team discovered that a drug-like inhibitor of HDACs called TSA interferes with the ability of HIF to turn on a large number of genes during times of hypoxia. The study further suggests that HDACs appear to cooperate with CBP/p300 to help HIF trigger the expression of most of the approximately 40 HIF responsive genes tested. The study also showed that different HIF-targeted genes rely to various degrees on the CH1 domain and the mechanism sensitive to TSA.

"This finding was surprising because until now it was generally accepted that acetylases are involved in activating genes, while deacetylases were mostly thought to have the opposite effect," Brindle said. "That increases our appreciation for the complexity of the control of HIF-responsive genes. That is important for future studies on how to manipulate these mechanisms to treat diseases linked to hypoxia."

Brindle’s team studied HIF activation in laboratory models that had mutations that eliminated the CH1 domain in either or both of the genes for CBP and p300. The investigators found that certain genes whose activity could be induced by hypoxia were moderately to strongly dependent on the CH1 domain. One of these genes, Vegf, is important for the growth of new blood vessels, while another gene, Slc2a1, is important in bringing glucose into the cell for energy.

In addition, the St. Jude team discovered that some genes continue to be expressed fairly well even when both the CH1 and HDAC mechanisms are disrupted. This suggests that there are other coactivators, or that other domains on CBP and p300 in addition to CH1 work with HIF to activate gene expression. Alternatively, transcription factors other than HIF may mediate part of the response to hypoxia.

"Our study clearly showed that there is more to activating HIF-responsive gene expression than just the previously recognized CBP/p300 mechanism," said Lawryn H. Kasper, Ph.D., a research laboratory specialist in Brindle’s laboratory. "In fact, not only does a mechanism involving HDAC appear to play a major role; but there is also evidence for a completely different pathway." Kasper is the first author of the article and together with her co-worker Fayçal Boussouar, Ph.D., did most of the work on this study.

Carrie Strehlau | EurekAlert!
Further information:
http://www.stjude.org

More articles from Life Sciences:

nachricht What happens in the cell nucleus after fertilization
06.12.2016 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt

nachricht Researchers uncover protein-based “cancer signature”
05.12.2016 | Universität Basel

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Significantly more productivity in USP lasers

In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.

Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...

Im Focus: Shape matters when light meets atom

Mapping the interaction of a single atom with a single photon may inform design of quantum devices

Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...

Im Focus: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

Im Focus: MADMAX: Max Planck Institute for Physics takes up axion research

The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.

The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

 
Latest News

Robot on demand: Mobile machining of aircraft components with high precision

06.12.2016 | Power and Electrical Engineering

A new dead zone in the Indian Ocean could impact future marine nutrient balance

06.12.2016 | Earth Sciences

Significantly more productivity in USP lasers

06.12.2016 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>