Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Scripps Research study reveals new function of protein kinase pathway in tumor suppression

Discovery could lead to drug development for cancer treatment

The study, led by Associate Professor Peiqing Sun and Professor Jiahuai Han of The Scripps Research Institute, is being published on January 26, 2007 in the journal Cell.

The research focused on signaling pathways that mediate an anti-tumor defense response called senescence, or cellular aging. The research, which was conducted in both human cell culture and rodent models with skin cancer or lymphoma, identified one essential element of this anti-tumor response, namely, p38-regulated/activated protein kinase (PRAK). Previous to this research, PRAK's physiological functions had been poorly understood.

"In uncovering this basic mechanism, we've advanced our knowledge in terms of how cancers develop," Sun said. "More importantly, we have identified a pathway in normal cells that, when activated, can inhibit tumor development. This lays the groundwork for new cancer therapy--for future drug development to artificially activate this pathway in cancer cells."

The human body has several built-in mechanisms that prevent cancer development. One is cell death, or apoptosis. Another is premature senescence, a recently identified tumor-restricting response that permanently stops cell proliferation.

"A normal cell stops dividing when it gets old," Sun explained. "This is referred to as senescence of a cell. A young cell will become senescent prematurely when it acquires a mutation that activates an oncogene. This is one of the ways our body tries to eliminate cells that might become cancerous."

In previous research that set the stage for this current project, Sun's lab worked to identify the signaling cascade that mediates ras-induced premature senescence (ras is an oncogene, a gene that, when activated by mutations, causes cancer by transducing unrestricted growth signals). Using human cells in culture, Sun's team showed that the p38 mitogen-activated protein (MAP) kinase is required for ras to induce senescence in cell culture.

"After these findings, we wanted to look downstream of p38 to see exactly how this MAP kinase mediates senescence," Sun explained. "We knew the effect of p38 is achieved through its ability to regulate its downstream substrates, so we started to investigate various substrate candidates to see which ones were involved."

Fortunately, Sun added, his research team could easily link up with a leading expert in the p38 field, Professor Jiahuai Han. The p38 gene was cloned by Han in 1994. Since then, the Han lab has identified some p38 downstream protein kinases, including PRAK, and has shown that PRAK can be activated by various stresses. The Han research group also engineered PRAK knockout mice, animals that lack the PRAK gene, expecting that these mice would be defective in stress response. To the researchers' surprise, the mice responded normally to stresses, an indication that this gene may not be required for the stress pathway.

Joining forces, Sun and Han collaborated to investigate the role of PRAK in senescence response and tumor suppression. They also enlisted the expertise of Scripps Research investigators John Yates and Peter Wright and their laboratory groups.

What the researchers found was that PRAK is required for ras to induce senescence in vitro in normal cells derived from a mouse. They also did an experiment to see if the lack of PRAK would make a difference in senescence induction in human cells. The team introduced double-strand RNA into normal human fibroblast cells to inhibit the expression of PRAK and then activated the ras oncogene in these cells. The results were identical to those in mouse cells. When PRAK was inactivated in normal human cells, these cells did not undergo premature senescence.

"These experiments tell us that PRAK in both human cells and in mouse cells is an essential component that mediates ras-induced senescence," said Sun.

The researchers wanted, next, to find out whether PRAK was essential for ras-induced senescence in vivo, and whether deletion of the PRAK gene would make a difference in the ras-induced tumor-development process in PRAK knockout mice. A group of these mice and a group of normal mice were treated with DMBA, an environmental pollutant found in cigarette smoke and gas emissions, which can induce ras mutations and cause skin tumor formation. The researchers monitored the incidence of skin tumor formation in these mice, and after tumors formed, the degree of cell senescence in the tumors. The results, Sun said, were exciting.

"The mice lacking the PRAK gene were more susceptible to skin tumor induction by DMBA, as compared to wild-type mice," Sun said. "This indicates that the presence of the normal PRAK gene suppresses tumor formation. In the wild-type, normal mice, DMBA induced premature senescence, but in the knockout tumors there were no senescent cells. The PRAK knockout animals were resistant to ras-induced senescence but prone to tumor induction, which led us to the happy conclusion that PRAK and the senescence response mediated by PRAK has a tumor-suppressing function in vivo. The knockout mice were more vulnerable to tumor induction because the senescence pathway, which is responsible for the anti-tumor self-defense mechanism, had been compromised. In addition to the skin cancer model, loss of the PRAK gene in mice also accelerates lymphoma development, which indicates that PRAK may be involved in suppressing tumor formation in multiple tissues."

Keith McKeown | EurekAlert!
Further information:

Further reports about: Han Kinase PRAK Ras mediate p38 premature ras-induced senescence tumor formation

More articles from Life Sciences:

nachricht First time-lapse footage of cell activity during limb regeneration
25.10.2016 | eLife

nachricht Phenotype at the push of a button
25.10.2016 | Institut für Pflanzenbiochemie

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Etching Microstructures with Lasers

Ultrafast lasers have introduced new possibilities in engraving ultrafine structures, and scientists are now also investigating how to use them to etch microstructures into thin glass. There are possible applications in analytics (lab on a chip) and especially in electronics and the consumer sector, where great interest has been shown.

This new method was born of a surprising phenomenon: irradiating glass in a particular way with an ultrafast laser has the effect of making the glass up to a...

Im Focus: Light-driven atomic rotations excite magnetic waves

Terahertz excitation of selected crystal vibrations leads to an effective magnetic field that drives coherent spin motion

Controlling functional properties by light is one of the grand goals in modern condensed matter physics and materials science. A new study now demonstrates how...

Im Focus: New 3-D wiring technique brings scalable quantum computers closer to reality

Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.

"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...

Im Focus: Scientists develop a semiconductor nanocomposite material that moves in response to light

In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.

A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...

Im Focus: Diamonds aren't forever: Sandia, Harvard team create first quantum computer bridge

By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.

"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...

All Focus news of the innovation-report >>>



Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

Agricultural Trade Developments and Potentials in Central Asia and the South Caucasus

14.10.2016 | Event News

World Health Summit – Day Three: A Call to Action

12.10.2016 | Event News

Latest News

Greater Range and Longer Lifetime

26.10.2016 | Power and Electrical Engineering

VDI presents International Bionic Award of the Schauenburg Foundation

26.10.2016 | Awards Funding

3-D-printed magnets

26.10.2016 | Power and Electrical Engineering

More VideoLinks >>>