Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Scripps Research Institute Scientists Uncover New Details of Natural Anticancer Mechanism

12.06.2013
Scientists at The Scripps Research Institute (TSRI) have identified key triggers of an important cancer-blocking mechanism in cells.
Termed “oncogene-induced senescence,” this mechanism can block most cancer types, and is commonly experienced when incipient skin cancers turn instead into slow-growing moles. Tumors that achieve malignancy often do so by defeating or circumventing this growth barrier—which is why scientists have been eager to find out precisely how it works.

“We have known about some of the molecular signals that mediate this senescence response, but we’ve needed to understand the signaling pathway in much more detail,” said Peiqing Sun, associate professor in TSRI’s Department of Cell and Molecular Biology.

In the new study, published recently by the journal Molecular Cell, Sun and his colleagues describe the cascading interactions of three enzymes that are necessary to initiate a common type of oncogene-induced senescence.

Looking for Binding Partners

Oncogenes are growth-related genes that, through DNA damage, inherited mutations or some other cause, push cells to keep dividing beyond normal limits. Oncogenes in the ras gene family are the ones that have been most commonly linked to human cancers—and most studied as triggers of senescence.

Sun and other researchers showed a decade ago that an enzyme called p38 sits near the top of the ras-induced senescence response cascade. In 2007, Sun and his colleagues reported that p38 plays a role in this cascade by activating another enzyme, PRAK, through the addition of a phosphor group, a modification known as phosphorylation. For the new study, Sun and first author Research Associate Hui Zheng, along with other members of the laboratory, sought more details of PRAK’s role in this cascade.

Zheng began the investigation by searching for binding partners of PRAK. With a series of protein-interaction assays he isolated an enzyme called Tip60, which binds tightly to PRAK. Further tests indicated that Tip60 does indeed lie within the senescence-inducing signaling cascade, because senescence fails to occur when Tip60 is absent.

PRAK is a kinase enzyme that, like p38, phosphorylates other proteins. Initially Zheng and Sun suspected that PRAK interacts with Tip60 by phosphorylating it, and thereby activating it.

Instead, the reverse turned out to be true: Tip60 acts on PRAK. Tip60 is a type of enzyme called an acetyltransferase, which modifies other proteins by adding acetyl groups. “Our tests showed that Tip60 binds to PRAK and acetylates it at a certain location, which helps activate PRAK,” said Zheng.

Thus, the key enzyme PRAK requires two signals: “First the phosphorylation by p38 and then the acetylation by Tip60 are required for fully activating PRAK in this senescence–induction cascade,” Zheng said.

Potential Cancer-Drug Strategy

What controls Tip60’s own activation in this cascade? None other than the master switch, p38. “As a first step, p38 phosphorylates both Tip60 and PRAK,” said Sun. Activated Tip60 then acetylates PRAK, completing PRAK’s activation.

Previously Sun and his laboratory have shown that PRAK, when activated, goes on to activate the key tumor-suppressor protein p53, which exerts more direct control over a cell’s growth machinery.

Sun and his team have been looking for ways to force the activation of the senescence response in cancer cells, as a potential cancer-drug strategy. “Finding these details of the early part of the signaling cascade helps us understand better what we need to target,” he said.

Other contributors to the study, “A Posttranslational Modification Cascade Involving p38, Tip60 and PRAK Mediates Oncogene-Induced Senescence,” were John Tat and Rong Liao of Sun’s laboratory, and Xuemei Han, Aaron Aslanian and John R. Yates III of the Yates lab at TSRI. For more information, see http://www.cell.com/molecular-cell/abstract/S1097-2765(13)00294-3

The study was funded in part by the National Institutes of Health (grants CA106768 and CA131231).

About The Scripps Research Institute

The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs about 3,000 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists—including three Nobel laureates—work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see www.scripps.edu.
For information:
Office of Communications
Tel: 858-784-2666
Fax: 858-784-8136
press@scripps.edu

Mika Ono | EurekAlert!
Further information:
http://www.scripps.edu

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 >>>