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 Rutgers scientists discover 'Legos of life'
23.01.2018 | Rutgers University

nachricht Researchers identify a protein that keeps metastatic breast cancer cells dormant
23.01.2018 | Institute for Research in Biomedicine (IRB Barcelona)

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Optical Nanoscope Allows Imaging of Quantum Dots

Physicists have developed a technique based on optical microscopy that can be used to create images of atoms on the nanoscale. In particular, the new method allows the imaging of quantum dots in a semiconductor chip. Together with colleagues from the University of Bochum, scientists from the University of Basel’s Department of Physics and the Swiss Nanoscience Institute reported the findings in the journal Nature Photonics.

Microscopes allow us to see structures that are otherwise invisible to the human eye. However, conventional optical microscopes cannot be used to image...

Im Focus: Artificial agent designs quantum experiments

On the way to an intelligent laboratory, physicists from Innsbruck and Vienna present an artificial agent that autonomously designs quantum experiments. In initial experiments, the system has independently (re)discovered experimental techniques that are nowadays standard in modern quantum optical laboratories. This shows how machines could play a more creative role in research in the future.

We carry smartphones in our pockets, the streets are dotted with semi-autonomous cars, but in the research laboratory experiments are still being designed by...

Im Focus: Scientists decipher key principle behind reaction of metalloenzymes

So-called pre-distorted states accelerate photochemical reactions too

What enables electrons to be transferred swiftly, for example during photosynthesis? An interdisciplinary team of researchers has worked out the details of how...

Im Focus: The first precise measurement of a single molecule's effective charge

For the first time, scientists have precisely measured the effective electrical charge of a single molecule in solution. This fundamental insight of an SNSF Professor could also pave the way for future medical diagnostics.

Electrical charge is one of the key properties that allows molecules to interact. Life itself depends on this phenomenon: many biological processes involve...

Im Focus: Paradigm shift in Paris: Encouraging an holistic view of laser machining

At the JEC World Composite Show in Paris in March 2018, the Fraunhofer Institute for Laser Technology ILT will be focusing on the latest trends and innovations in laser machining of composites. Among other things, researchers at the booth shared with the Aachen Center for Integrative Lightweight Production (AZL) will demonstrate how lasers can be used for joining, structuring, cutting and drilling composite materials.

No other industry has attracted as much public attention to composite materials as the automotive industry, which along with the aerospace industry is a driver...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

10th International Symposium: “Advanced Battery Power – Kraftwerk Batterie” Münster, 10-11 April 2018

08.01.2018 | Event News

See, understand and experience the work of the future

11.12.2017 | Event News

Innovative strategies to tackle parasitic worms

08.12.2017 | Event News

 
Latest News

Rutgers scientists discover 'Legos of life'

23.01.2018 | Life Sciences

Seabed mining could destroy ecosystems

23.01.2018 | Earth Sciences

Transportable laser

23.01.2018 | Physics and Astronomy

VideoLinks Science & Research
Overview of more VideoLinks >>>