Protein identified as enemy of vital tumor suppressor PTEN

ScienceDaily (May 3, 2011) — A protein known as WWP2 appears to play a key role in tumor survival, a research team headed by a scientist at The University of Texas MD Anderson Cancer Center reports in an advance online publication of Nature Cell Biology.

Their research suggests that the little-studied protein binds to the tumor-suppressing protein PTEN (phosphatase and tensin homologue deleted on chromosome 10), marking it for destruction by proteasomes, which degrade proteins and recycle their components.

PTEN plays a role regulating the cellular reproduction cycle and prevents rapid cell growth, a hallmark of malignant cells. Its gene is mutated or deleted in many types of cancer, the researchers noted.

The WWP2 (atrophin-1 interacting protein 2) protein was discovered in the laboratory of Junjie Chen, Ph.D., professor and chair in MD Anderson's Department of Experimental Radiation Oncology and senior author of the paper.

"We were trying to find regulators of PTEN when we isolated the protein WWP2 as a putative PTEN-associated protein," Chen said. He noted that WWP2 caught the researchers' attention because it is similar to the NEDD4-1 protein, which has been proposed as a regulator of PTEN function.

First suspect doesn't affect PTEN

WWP2 is an E3 ubiquitin ligase in the NEDD4-like protein family. Ubiquitins attach to other proteins, labeling them for degradation by proteasomes. NEDD4-like proteins play important roles regulating gene transcription, embryonic stem cells, cellular transport and activation of T cells.

"But when NEDD4-1 is deleted in mice, researchers have not seen a clear change in PTEN protein level," Chen noted. "These findings suggest that there may be other PTEN regulators.

"Because WWP2 is part of the NEDD4-like family, we decided to take a look at it to see if it's the real regulator of PTEN," Chen continued. "When you knock down WWP2, you see an increase in PTEN level, whereas with WWP2 overexpression you can see a decrease in PTEN. This finding indicates that WWP2 may be involved in PTEN's regulation."

Overall, the study results suggest that WWP2 can regulate PTEN stability, Chen said.

Possibly a cancer-driving gene

The team uncovered evidence that WWP2 is a potential oncogene -- a driver in tumor formation and growth. In one experiment, mice with normal WWP2 developed prostate cancer tumors after nine weeks that were more than three times the size of tumors in mice with WWP2 silenced.

Chen noted that more research is needed to determine whether WWP2 is functionally important in tumors or in tumor formation. "We need to look at real tumor samples to determine whether tumors with reduced PTEN expression could result from the overexpression of WWP2."

He added that some early studies suggest that WWP2 may operate in tumors, but a correlation between WWP2 overexpression and PTEN downregulation in tumors has not been established.

This work was supported in part by a grant from the Department of Biotechnology, Ministry of Science and Technology, India, a U.S. Department of Defense Era of Hope Research Scholar Award, an NIH Specialized Program of Research Excellence award to Mayo Clinic, and a National Cancer Institute grant to MD Anderson. Also, fellowship support came from the Department of Biotechnology, Council of Scientific and Industrial Research and University Grants Commission, India, and support from the Institute of Life Sciences, Hyderabad, India.

Co-authors with Chen are first author Subbareddy Maddika, Ph.D, Sridhar Kavela, Neelam Rani, and Vivek Reddy Palicharla, all of the Laboratory of Cell Death and Cell Survival, Centre for DNA Fingerprinting and Diagnostics in Nampally, Hyderabad, India; Jenny Pokorny and Jann Sarkaria, M.D., of the Mayo Clinic, Rochester, Minn.

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by University of Texas M. D. Anderson Cancer Center.

Journal Reference:

Subbareddy Maddika, Sridhar Kavela, Neelam Rani, Vivek Reddy Palicharla, Jenny L. Pokorny, Jann N. Sarkaria, Junjie Chen. WWP2 is an E3 ubiquitin ligase for PTEN. Nature Cell Biology, 2011; DOI: 10.1038/ncb2240

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Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

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Understanding how crops deal with stress -- yield's biggest enemy

ScienceDaily (Apr. 25, 2011) — Like people, plants experience stress. And also, like people, the response to that stress can determine success.

People can exercise, or rest, or talk about the problem.

For plants, ways to deal with stress are internal. And ISU researchers are trying to understand how they do it.

Stephen Howell is a professor of genetics, development and cell biology and former director of the Plant Sciences Institute at ISU. His research is featured in the current issue of the Proceedings of the National Academy of Sciences.

"We've discovered a new arm of the pathway by which plants activate a response to environmental stress," he said.

Adverse environmental conditions, such as drought, flood, heat and other stresses, affect yield more than crop pests and diseases. Finding a way to maintain high yields for plants under stress is a goal of plant breeders and other agriculture stakeholders, said Howell.

"These are environmental stresses that the farmers can't control," Howell said. "They are acts of nature. And now seed companies are interested in trying to equip plants with the ability to tolerate stress."

Plant cells produce proteins and ship them to different parts of the cell. During production and shipment, these proteins move through an area of the cell called the endoplasmic reticulum (ER).

Under normal conditions, these proteins are folded into their normal, healthy three-dimensional structures as they are produced.

When a plant is under stress, its cells produce poorly folded or unfolded proteins. Inside the ER, a built-in, quality-control system senses this and "sets off an alarm in the cell," said Howell.

In response to the alarm, another protein (IRE1) cuts apart an important RNA molecule, but then splices it back together to create a different sequence.

This cut-and-splice event activates a cascade of stress response genes whose products bring about internal defensive measures that help the plant survive.

"As it turns out, responses that are activated under stress conditions actually inhibit the growth of plants," said Howell. "This allows them to conserve their energy to survive the stress conditions."

For plants in the wild, this response is a survival tactic, he said.

In production agriculture crops, however, these responses reduce yields.

"You don't want crop plants to [stop growing]," Howell said. "You want them to continue to grow and produce even though they are under stress."

With the new understanding of this stress response pathway, Howell says, the next step may be to silence the alarm system.

"What may be important is to disable some of these stress responses," said Howell. "That may make the plant be more productive under stress conditions."

Howell's research team included Yan Deng and Renu Srivastava, both of the Plant Sciences Institute, Ames; Sabrina Humbert and Steven Rothstein, both of University of Guelph, Canada; and Jian-Xiang Liu formerly of the Plant Sciences Institute and now a faculty member at Fudan University, China.

Howell is currently on leave from ISU and is director of the Division of Molecular and Cellular Biosciences for the National Science Foundation in Washington, D.C.

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Iowa State University.

Journal Reference:

Yan Deng, Sabrina Humbert, Jian-Xiang Liu, Renu Srivastava, Steven J. Rothstein, and Stephen H. Howell. Heat induces the splicing by IRE1 of a mRNA encoding a transcription factor involved in the unfolded protein response in Arabidopsis. Proceedings of the National Academy of Sciences, 2011; DOI: 10.1073/pnas.1102117108

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Disclaimer: Views expressed in this article do not necessarily reflect those of ScienceDaily or its staff.

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