Cancer researchers find key protein link

A new understanding of proteins at the nexus of a cell’s decision to survive or die has implications for researchers who study cancer and age-related diseases, according to biophysicists at the Rice University-based Center for Theoretical Biological Physics (CTBP).Experiments and computer analysis of two key proteins revealed a previously unknown binding interface that could be addressed by medication. Results of the research appear this week in an open-source paper in the Proceedings of the National Academy of Sciences.The proteins are Bcl-2, well-known for its role in programmed cell death, and NAF-1, a member of the NEET family that binds toxic clusters of iron and sulfur. How the two interact is now known as a major determinant in the cell processes of autophagy and apoptosis — literally, life and death. An ability to uncover binding sites on the proteins that send the cell one way or the other opens a path toward the regulation of those processes, according to Jos Onuchic, Rice’s the Harry C. and Olga K. Wiess Chair of Physics and professor of physics and astronomy.Pockets and folds in proteins exist to bind to other molecules and catalyze actions in a cell in signaling pathways. The ability to block a specific binding site or to enhance a desired interaction is critical to drug design, Onuchic said.”In our early work we have shown the link between NEET proteins and cancer. Now we can understand the molecular details of how these interactions are governed,” Onuchic said. “Others have shown that NAF-1 is up-regulated in cancer cells, which leads us to believe that cancer may hijack control over the expression of this protein. This affects the cell’s system of checks and balances. …

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NEETs are prime suspects in breast cancer proliferation

Aug. 20, 2013 — Two proteins have been identified as prime suspects in the proliferation of breast cancer in a study by an international consortium of researchers from Rice University, the University of North Texas, Denton (UNT); the University of California, San Diego (UCSD); and the Hebrew University of Jerusalem.The research, which appears this week in the Proceedings of the National Academy of Sciences’ Online Early Edition, may offer a path to therapies that could slow or stop tumors from developing.Rice’s Center for Theoretical Biological Physics (CTBP) coordinated the research, which found that reducing the expression of a pair of proteins known as NEETs — NAF-1 and mitoNEET — significantly reduced cancer cell proliferation and breast cancer tumor size.The research stemmed from a recent CTBP study of the shape and functions of one of the proteins, mitoNEET. The other protein, NAF-1, is closely related to mitoNEET.CTBP co-director José Onuchic, a biological physicist at Rice, said the new study was triggered by the team’s recognition of a connection between NEETs and reduced rates of breast cancer among women who take a diabetes drug that targets mitoNEET.”NEET proteins play a key role in the overall stress response of cells,” Onuchic said. “Anytime you stress a system, these proteins are there to help, but in cases where cells are overcome by stress, NEETs can become highly overexpressed. That’s what drew our interest in a potential connection to cancer.”Onuchic, Rice’s Harry C. and Olga K. Wiess Professor of Physics and Astronomy, co-authored the study with longtime research partner Patricia Jennings, professor of chemistry and biochemistry at UCSD; Rachel Nechushtai, a professor at the Alexander Siberman Life Science Institute of the Hebrew University of Jerusalem; and Ron Mittler, professor of biological sciences at UNT.NEET proteins transport iron molecules or iron sulfur clusters inside cells. The proteins naturally adhere to the outer surface of the mitochondria, the “power plant” that supplies cells with chemical energy. Mitochondria also play a role in a cell’s life cycle, including its death.”Maintaining mitochondrial health is a key factor in the health of a cell,” said Nechushtai. She and Mittler are experts in iron and reactive oxygen metabolism and collaborated on a prior study that identified a key role for NEET proteins in maintaining mitochondrial function in cells under conditions that resembled cancer cell metabolism.”We found that novel motions in NEET proteins control cluster properties and suggest the NEET proteins can be your best friend or worst enemy,” Jennings said.”Based on our own prior results and the recent CTBP findings, we decided to examine the role that NEET proteins and iron metabolism might play in conferring drug resistance to breast cancer cells and tumors,” Nechushtai said.Experiments in Mittler’s and Nechushtai’s labs found an overabundance of both mitoNEET and NAF-1 in breast cancer cells. …

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