Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Gene variation promotes uncontrolled cell division

18.12.2015

Mom’s eyes and dad’s tumor? Cancer is due to genetic defects, some of which can be hereditary. The gene variant rs351855, for example, occurs in one in two cancer patients. A team headed by Axel Ullrich from the Max Planck Institute of Biochemistry in Martinsried identified the gene variant a decade ago. Now, they succeeded for the first time in showing that the variation exposes an otherwise hidden binding site on the FGFR4 receptor. There, growth factor STAT3, which promotes cancer, binds to the exposed site. The STAT3 signaling cascade can be efficiently blocked. This could provide a promising therapeutic approach for many cancer patients. The paper was published in Nature.

A human is a human: we are all 99.9% genetically identical. However, the remaining 0.1% accounts for the unique characteristics of each individual, whether he or she is tall or short, allergic or susceptible to autoimmune diseases. Those three million or so of the 3.2 billion genetic building blocks in our genome may contain the answer to the question of whether we will develop cancer in the course of our lives.


About 30% of the world population harbors the gene variation rs351855-A in their genomes. In the event of cancer, the encoded receptor FGFR4 p.G388R contributes to a faster disease progression.

Vijay K. Ulaganathan, Monika Krause © MPI of Biochemistry

Cancer is a genetic disease, i.e. it is due to defects in the genetic material DNA. Such harmful mutations can be acquired in the course of life, as a result of exposure of skin cells to intense sunlight, for example, or toxins from cigarette smoke in the lungs. However, some defects are passed on as inheritable genetic variants to offspring, who then carry those defects in every cell of their body.

One such cancer-associated germline mutation is called rs351855. It was discovered in patients with breast cancer by a team headed by Axel Ullrich, Leader of the Molecular Biology Research Group, a decade ago. This particular genetic variant can support the growth of malignant tumors in bones, the colon, the prostate, the skin, the lungs and the head and neck, as well as to the growth of soft-tissue sarcomas and non-Hodgkin’s lymphoma.

About half of all cancer patients carry this gene variation. It is associated with a poor prognosis. The germline mutation rs351855 accounts for aggressive and rapidly growing tumors that are resistant to treatment. An effective treatment needs to be tailored to match the mutation and its biological effects.

Subsequent studies have shown that rs351855 results in the replacement of a single protein building unit in a receptor for growth factors. Fibroblast growth factor receptor 4 (FGFR4) is then expressed in the form of the FGFR4 p.Arg388 variant. Scientists around the world are trying to find out why only this particular genetic variant, out of more than 400 known ones of FGFR4, has such a high impact. Moreover, the genetic mutation occurs very frequently, around one-third of the population carry it in the genome. It is not known, whether this variation itself increases the general risk of cancer.

Ullrich and his associates have now demonstrated for the first time that the defect results in a previously unknown biological function in living cells. They showed in an animal model that the defect exposes a normally hidden binding site on the receptor molecule near the inner cell membrane. Growth factor STAT3, which promotes cell division and tumor growth, is then able to dock to the receptor.

Cells do not usually proliferate out of control, because they only divide in response to a signal that they receive from the outside. This molecular message is picked up by receptors such as FGFR4 and is then relayed through the cell membrane into the interior of the cell, thus setting in motion a cascade of molecular interactions with molecules such as STAT3 that culminates in the cell nucleus, where genes are activated that direct the actual process of cell division.

This hierarchical process is often undermined in cancer. The cells divide without an external command. That is the case, for example, when STAT3 is activated by abnormal binding to the defective receptor. Such interaction of STAT3 close to the inner cell membrane was previously unknown and unexpected. “I wasn’t really convinced until various experimental approaches produced matching results,” says Vijay K. Ulaganathan, lead author of the study.

The scientists have also shown that the growth of cells carrying this gene variant can be inhibited by blocking STAT3. “For the first time, there may be very good prospects of an effective treatment option for cancer patients with this respective germline mutation,” says Ullrich. Others may also be affected: Other germline mutations also exist that recruit STAT3 to the inner cell membrane and may also lead to cancer.

The work is an important step towards personalized medicine, which takes into account the individual genetic makeup of cancer patients. “As we have shown here, we need to focus on germline mutations as well,” says Ullrich. “Research should not be limited to environmentally-related genetic defects.” Ullrich is a pioneer in personalized medicine. Among other things, he developed together with colleagues Herceptin, a drug that is tailor-made for treating breast cancer associated with specific mutations.

Original publication:
V. K. Ulaganathan, B. Sperl, U. R. Rapp, Axel Ullrich: Germline variant FGFR4 p.G388R exposes membrane-proximal STAT3 binding site, Nature, December 2015
DOI: 10.1038/nature16449

Contact:
Prof. Dr. Axel Ullrich
Department of Molecular Biology
Max-Planck-Institut für Biochemie
Am Klopferspitz 18
82152 Martinsried
Germany
E-Mail: ullrich@biochem.mpg.de
www.biochem.mpg.de/ullrich

Dr. Vijay K. Ulaganathan
Department of Molecular Biology
Max-Planck-Institut für Biochemie
Am Klopferspitz 18
82152 Martinsried
Germany
E-Mail: ulaganat@biochem.mpg.de

Dr. Christiane Menzfeld
Public Relations
Max-Planck-Institut für Biochemie
Am Klopferspitz 18
82152 Martinsried
Germany
Tel. +49 89 8578-2824
E-Mail: pr@biochem.mpg.de
www.biochem.mpg.de

Weitere Informationen:

http://www.biochem.mpg.de - homepage max planck institute of biochemistry
http://www.biochem.mpg.de/ullrich - homepage Axel Ullrich

Dr. Christiane Menzfeld | Max-Planck-Institut für Biochemie

More articles from Life Sciences:

nachricht Cryo-electron microscopy achieves unprecedented resolution using new computational methods
24.03.2017 | DOE/Lawrence Berkeley National Laboratory

nachricht How cheetahs stay fit and healthy
24.03.2017 | Forschungsverbund Berlin e.V.

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Giant Magnetic Fields in the Universe

Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.

The results will be published on March 22 in the journal „Astronomy & Astrophysics“.

Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...

Im Focus: Tracing down linear ubiquitination

Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.

Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...

Im Focus: Perovskite edges can be tuned for optoelectronic performance

Layered 2D material improves efficiency for solar cells and LEDs

In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...

Im Focus: Polymer-coated silicon nanosheets as alternative to graphene: A perfect team for nanoelectronics

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...

Im Focus: Researchers Imitate Molecular Crowding in Cells

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International Land Use Symposium ILUS 2017: Call for Abstracts and Registration open

20.03.2017 | Event News

CONNECT 2017: International congress on connective tissue

14.03.2017 | Event News

ICTM Conference: Turbine Construction between Big Data and Additive Manufacturing

07.03.2017 | Event News

 
Latest News

Argon is not the 'dope' for metallic hydrogen

24.03.2017 | Materials Sciences

Astronomers find unexpected, dust-obscured star formation in distant galaxy

24.03.2017 | Physics and Astronomy

Gravitational wave kicks monster black hole out of galactic core

24.03.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>