Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Advanced technology for gene expression analysis can facilitate drug development

07.10.2013
Researchers from the RIKEN Center for Life Science Technologies report a new method to monitor and quantify the activity of gene promoters during the response to a drug, using the advanced gene expression analysis method CAGE followed by single-molecule sequencing.

When developing new drugs, monitoring cellular responses to candidate compounds is essential for assessing their efficacy and safety. Researchers from the RIKEN Center for Life Science Technologies report a new method to monitor and quantify the activity of gene promoters during the response to a drug, using the advanced gene expression analysis method CAGE followed by single-molecule sequencing. This research paves the way to a more precise analysis of cellular responses to drugs, at the level of individual promoters.

The study is published this week in the journal CPT: Pharmacometrics & Systems Pharmacology.

Microarray-based technologies are widely used to monitor cellular changes in response to drug administration at the level of genes. However, microarrays have several limitations due to the fact that they rely on pre-designed oligonucleotide probes and detection based on hybridization.

In order to circumvent the limitations imposed by the use of microarray-based technology for the development of new drugs, Dr Harukazu Suzuki and his team at CLST developed a new technique combining Cap Analysis of Gene Expression (CAGE) with 3rd generation, single-molecule sequencing.

CAGE is a method developed at RIKEN to comprehensively map human transcription start sites and their promoters, and quantify the set of mRNAs in a cell, also called the transcriptome.

During CAGE the 5’-end of mRNAs is sequenced in order to produce a series of 20-30 nucleotide sequences that can then be mapped onto the genome and provide information about the level of expression of genes.

Dr Suzuki and his team used CAGE, combined with a single-molecule sequencer, to monitor the effect of three drugs, U0126, wortmannin and gefitinib on human breast cancer cells.

U0126 and wortmannin are known to inhibit the Ras-ERK and phosphatidylinositol-3-kinase (PI3K)-Akt signalling pathways within cells. Gefinitib is a potent inhibitor of the epidermal growth factor receptor kinase (EGFR kinase) and mainly inhibits the Ras-ERK and PI3K-Akt pathways downstream of EGFR.

The researchers identified a distinct set of promoters that were affected by low doses of the drugs, and therefore showed sensitivity to a weak inhibition of the Ras-ERK and PI3K-Akt signal-transduction pathways. This level of precision would would have been very difficult to achieve using microarray-based profiling.

Furthermore, a quantitative analysis showed that the inhibitory profiles of both U0126 and wortmannin are constitutive components of the transcriptome profile obtained by inhibition of the EGFR kinase. Using a regression model, the researchers were able to quantitatively predict the promoter activity profile of gefitinib, based on the U0126 and wortmannin profiles.

These results demonstrate the potential utility of highly quantitative promoter activity profiling in drug research.

“Quantitative transcriptome analysis is potentially widely applicable to determine the target proteins and action mechanisms of uncharacterized compounds,” concludes Dr Suzuki. “Our study paves the wayfor quantitative analysis of drug responses at the promoter level, and moreover, is potentially applicable for the evaluation of combinatorial or serial drug treatment in a clinical setting,” he adds.

This press release is available online at: http://www.riken.jp/en/pr/press/2013/20131003_3/

Dr Suzuki is available for interviews on the phone at +81 45-503-9222 or by email at harukazu@gsc.riken.jp

Alternatively please contact:
Juliette Savin
RIKEN
Tel: +81-(0)48-462-1225
Email: pr@riken.jp
Reference:
Kazuhiro Kajiyama et al.
“Capturing drug responses by quantitative promoter activity profiling”
CPT: Pharmacometrics & Systems Pharmacology, 2013 DOI: 10.1038/psp.2013.53
The paper is available at
http://www.nature.com/psp/journal/v2/n9/full/psp201353a.html
About RIKEN
RIKEN is Japan's flagship research institute for basic and applied
research. Over 2500 papers by RIKEN researchers are published every year
in reputable scientific and technical journals, covering topics ranging
across a broad spectrum of disciplines including physics, chemistry,
biology, medical science and engineering. RIKEN's advanced research
environment and strong emphasis on interdisciplinary collaboration has
earned an unparalleled reputation for scientific excellence in Japan and
around the world.
About the Center for Life Science technologies
The RIKEN Center for Life Science Technologies aims to develop key
technologies for breakthroughs in the medical and pharmaceutical
applications of life science as well as conduct ground-breaking research
and development for the next-generation life sciences.

gro-pr | Research asia research news
Further information:
http://www.riken.jp
http://www.researchsea.com

More articles from Life Sciences:

nachricht NYSCF researchers develop novel bioengineering technique for personalized bone grafts
18.07.2018 | New York Stem Cell Foundation

nachricht Pollen taxi for bacteria
18.07.2018 | Technische Universität München

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: First evidence on the source of extragalactic particles

For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.

To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...

Im Focus: Magnetic vortices: Two independent magnetic skyrmion phases discovered in a single material

For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.

Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...

Im Focus: Breaking the bond: To take part or not?

Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.

A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...

Im Focus: New 2D Spectroscopy Methods

Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.

"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....

Im Focus: Chemical reactions in the light of ultrashort X-ray pulses from free-electron lasers

Ultra-short, high-intensity X-ray flashes open the door to the foundations of chemical reactions. Free-electron lasers generate these kinds of pulses, but there is a catch: the pulses vary in duration and energy. An international research team has now presented a solution: Using a ring of 16 detectors and a circularly polarized laser beam, they can determine both factors with attosecond accuracy.

Free-electron lasers (FELs) generate extremely short and intense X-ray flashes. Researchers can use these flashes to resolve structures with diameters on the...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Leading experts in Diabetes, Metabolism and Biomedical Engineering discuss Precision Medicine

13.07.2018 | Event News

Conference on Laser Polishing – LaP: Fine Tuning for Surfaces

12.07.2018 | Event News

11th European Wood-based Panel Symposium 2018: Meeting point for the wood-based materials industry

03.07.2018 | Event News

 
Latest News

NYSCF researchers develop novel bioengineering technique for personalized bone grafts

18.07.2018 | Life Sciences

Machine-learning predicted a superhard and high-energy-density tungsten nitride

18.07.2018 | Materials Sciences

Why might reading make myopic?

18.07.2018 | Health and Medicine

VideoLinks
Science & Research
Overview of more VideoLinks >>>