[Editors] MIT IDs role of key protein in tumor growth

[Elizabeth Thomson]

MIT News Office
Massachusetts Institute of Technology
Room 11-400
77 Massachusetts Avenue
Cambridge, MA  02139-4307
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MIT IDs role of key protein in tumor growth
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For Immediate Release
WEDNESDAY, MAR. 14, 2007
Contact: Elizabeth A. Thomson, MIT News Office
Phone: 617-258-5402
Email: thomson at mit.edu

CAMBRIDGE, Mass.--MIT researchers have identified how a missing 
protein causes tissue to become precancerous-a finding that could 
help doctors identify patients at high risk to develop tumors.

Most breast and prostate tumors are missing the protein, known as 
14-3-3 sigma, but until now it has not been clear what role it plays 
in tumor growth. The MIT researchers report in the March 15 issue of 
Nature that when the protein is knocked down, dividing cells fail to 
separate fully and become precancerous.

"The cells try to divide and try to divide, and they just give up. 
They can't finish cytokinesis (the final stages of cell division)," 
said Michael Yaffe, associate professor of biology and biological 
engineering and leader of the research team. Failing to divide 
completely, the cells recombine into a single cell with two nuclei.

Such fused, or binucleate, cells have recently been shown to be 
precursors to cancer cells. They are often found in so-called 
"dysplastic" tissue, which consists of cells that are not fully 
normal but are not cancerous, said Yaffe.

Comparing tumors to weeds, Yaffe explained that those tissues act as 
fertile "soil" for tumor development. "Tumors grow in epithelial 
tissues that are already deranged for some reason, and something 
about that soil makes it better able to grow weeds," he said.

Loss of 14-3-3 sigma in dysplastic tissue could serve as a marker to 
help doctors predict whether tumors will develop. "Our hope is that 
it will be possible to monitor 14-3-3 expression in these 'benign' 
conditions, a subset of which may not be so benign," said Yaffe, who 
is also affiliated with MIT's Center for Cancer Research, the Broad 
Institute of MIT and Harvard, and Beth Israel Deaconess Medical 
Center.

The researchers were initially intrigued by the fact that 14-3-3 
sigma is missing in normal tissue that surrounds tumors, which 
suggested that its function is lost very early in tumor development. 
Once the researchers started investigating the protein, they 
eventually unraveled a complex signaling pathway whose disruption 
leads to the failure of cell division.

They discovered that 14-3-3 sigma is most active during mitosis, when 
it helps control production of proteins necessary for division. 
Although 14-3-3 sigma interacts with many proteins, the research team 
focused on its relationship with a single protein, a translation 
factor known as eIF4B.

Translation factors are proteins that help determine the mix of 
proteins that a cell produces. Translation occurs when a messenger 
molecule known as mRNA carries information encoded by DNA to a cell 
organelle called the ribosome, which "translates" the mRNA sequence 
into a protein.

The translation factor eIF4B forms part of an enzyme that allows mRNA 
to unwind so the ribosome can read its sequence. When 14-3-3 sigma is 
knocked out, eIF4B is not produced, and mRNA for the protein p58 
cannot be translated. p58 plays a critical role in the final 
splitting of one cell into two during mitosis, so when it is missing, 
the cells cannot fully divide.

When p58 function is restored, the cells resume normal division.

The work demonstrates the importance of studying translation factors 
and the cell signaling pathways that affect them, Yaffe said. Most 
research on gene regulation focuses on transcription factors, which 
control which DNA sequences are transcribed into mRNA, but now "we're 
at the beginning of understanding another wave of regulation," which 
takes place at the translation level, he said.

The lead author of the paper is former MIT postdoctoral fellow Erik 
Wilker. Other authors are Marcel van Vugt, a postdoctoral fellow at 
the Center for Cancer Research (CCR); Steven Artim of the CCR and 
MIT's Department of Biology; Paul Huang, a professor in the 
Harvard-MIT Division of Health Sciences and Technology and Department 
of Biological Engineering; Christian Petersen, a former MIT 
postdoctoral associate; Christian Reinhardt, a postdoctoral fellow in 
the CCR and biology; Yun Feng of the CCR and biology; MIT Institute 
Professor Phillip Sharp; Nahum Sonenberg of McGill University; and 
Forest White, an assistant professor of biological engineering.

The research was funded by the Anna Fuller Fund, the National 
Institutes of Health, the European Molecular Biology Organization, 
the David H. Koch Cancer Research Fund, and a Burroughs-Wellcome 
Career Development Award.

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Written by Anne Trafton, MIT News Office