Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

RNA splicing machinery offers new drug target

19.05.2015

Blocking the spliceosome delays the progression of lymphoma in mice

A widespread cancer-causing protein called MYC promotes the growth of tumor cells in part by ensuring that RNA transcripts are properly spliced, according to latest work from A*STAR researchers1. Drugs that block parts of the cell’s splicing machinery may provide a new way to halt the proliferation of MYC-driven cancers.


Blocking the spliceosome could inhibit the growth of MYC-driven tumors.

© defun/iStock/Thinkstock

“Cells overexpressing the oncogene MYC will be more sensitive to inhibition of the splicing machinery,” says Ernesto Guccione, from the A*STAR Institute of Molecular and Cell Biology, who led the research. “Targeting the core components of the splicing machinery may be a novel Achilles’ heel to therapeutically target MYC-driven tumors.”

The MYC oncoprotein is a central driver in the majority of human cancers. MYC binds to active regulatory elements in the genome and broadly amplifies gene expression, leading to rampant cell growth. This process, however, is not random or indiscriminate. Guccione, in collaboration with colleagues in Italy, recently showed that MYC preferentially activates distinct subsets of target genes to control cellular states2.

Following up on that observation, Guccione and his colleagues from A*STAR decided to investigate which gene sets are turned on by MYC in mouse models of lymphoma. One gene set that stood out involved components of the spliceosome, the molecular complex that helps prepare messenger RNA (mRNA) transcripts for protein production by removing noncoding segments called introns.

These genes include PRMT5, which codes for a key enzyme that ensures proper maturation of the spliceosomal complex. PRMT5 and others help assemble the proteins that form the spliceosome. Guccione’s team showed that mice with only one functional copy of PRMT5 — instead of the usual two — develop lymphoma more slowly.

PRMT5 depletion led to a range of splicing defects linked to the retarded tumor growth. And drug-like molecules called antisense oligonucleotides (which disrupt proper splicing) also reduced the viability of cancer cells taken from mice with lymphoma. Together, the results suggest that splicing-associated genes like PRMT5 are critical to MYC-driven tumor formation.

Further support for this idea came from human clinical samples. Guccione and colleagues studied samples from people with lymphoma. They found a link between MYC overexpression and the activity of spliceosome-related genes. Notably, high expression of PRMT5 correlated with worse clinical outcomes. In the laboratory, knocking out PRMT5, or another core component of the splicing machinery in human lymphoma cells lines, also reduced cell viability.

“The inhibition of PRMT5 may have potential therapeutic utility in cancer treatment,” explains Cheryl Koh, a postdoctoral fellow in Guccione’s lab and the co-first author of the new study.

The A*STAR-affiliated researchers contributing to this research are from the Institute of Molecular and Cell Biology, the Institute of High Performance Computing and the Bioinformatics Institute.


References
Koh, C. M., Bezzi, M., Low, D. H. P., Ang, W. X., Teo, S. X. et al. MYC regulates the core Pre-mRNA splicing machinery as an essential step in lymphomagenesis. Nature advance online publication, 11 May 2015 (doi: 10.1038/nature14351). | article
Sabò, A., Kress, T. R., Pelizzola, M., de Pretis, S., Gorski, M. M. et al. Selective transcriptional regulation by Myc in cellular growth control and lymphomagenesis. Nature 511, 488–492 (2014). | article

A*STAR Research | ResearchSEA
Further information:
http://www.research.a-star.edu.sg/research/7236
http://www.researchsea.com

More articles from Life Sciences:

nachricht New risk factors for anxiety disorders
24.02.2017 | Julius-Maximilians-Universität Würzburg

nachricht Stingless bees have their nests protected by soldiers
24.02.2017 | Johannes Gutenberg-Universität Mainz

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Stingless bees have their nests protected by soldiers

24.02.2017 | Life Sciences

New risk factors for anxiety disorders

24.02.2017 | Life Sciences

MWC 2017: 5G Capital Berlin

24.02.2017 | Trade Fair News

VideoLinks
B2B-VideoLinks
More VideoLinks >>>