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How major signaling pathways are wired to our genome gives new insight into disease processes
Date:10/27/2011

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The discovery sheds new light on the relationship between signaling pathways, gene expression, cell function, and diseaseat the same time revealing potential targets for therapeutic intervention and novel approaches for reprogramming neurons or insulin-producing beta cells to treat nerve damage or diabetes.

"This is a broad, simplifying concept that is key to understanding how the whole human system works and how the genome responds to the world around itthat each signaling pathway has its own signaling molecule that finds its way to that cell's type-specific master transcription factor," says Young, who is also a professor of biology at MIT. "This idea allows us to think clearly about what is going awry in disease and how we potentially can treat people by modifying these signaling pathways."

To tease apart how signaling pathways modulate gene expression, Alan Mullen, who is the Cell paper's first author and a visiting scientist in the Young lab, analyzed the transforming growth factor-beta (TGF-beta) signaling pathway in several types of mouse and human cells. In both developing and mature cells, the TGF-beta pathway is involved in numerous cell activities, including specialization, homeostasis, and programmed death. Yet, corrupted versions of the TGF-beta signaling pathway are frequently found in cancer cells, allowing the cancer cells to proliferate and escape normal programmed cell death.

Mullen knew that when the TGF-beta signaling pathway's receptor is triggered by an environmental change, it activates the SMAD3 protein, which somehow couriers the receptor's message to the cell's DNA. Previous research had also suggested that SMAD3 might interact with hundreds of different transcription factors to achieve the desired response to environmental input.

Looking at embryonic stem, muscle, and certain immune system cells, Mullen found that once inside the nucleus, the activated SMAD3 settles ont
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Contact: Nicole Giese
giese@wi.mit.edu
617-258-6851
Whitehead Institute for Biomedical Research
Source:Eurekalert

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