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Understanding STAT

How a key cancer protein also plays a role in normal tissue development

BY JASON GORSS

Learning to read signals, whether they come from a boss or a spouse, can make all the difference in a relationship. The same goes for cells: understanding how they take their molecular cues could lead to new therapies for diseases that stem from miscommunication at the cellular level.

“When cells communicate with each other, there are some signals outside the cell, and somehow those signals need to be transduced into the cell to direct gene expression,” says Yuhong Shen, a postdoc in James Darnell’s lab.

Proteins call STATs — signal transducers and activators of transcription — which Darnell’s lab discovered in 1992, play a critical role in this process. They help cells interpret and respond to a glut of incoming messages, and they travel to the nucleus to activate the proper genes. To better understand how STATs work, Darnell, the university’s Vincent Astor Professor, Shen and colleagues engineered a mouse that produced less STAT3, one of the STAT proteins believed to play a key role in cancer.

In previous experiments, Darnell’s Laboratory of Molecular Cell Biology showed that repeated activation of STAT3 can cause normal cells to behave like cancer cells, leading to tumors in mice. STAT3 has also been found to be active in leukemia, breast cancer and many head and neck cancers. Eliminate STAT3 completely, on the other hand, and cells die altogether — mice embryos without the protein can’t survive past seven days.

This time, the researchers tested two types of mice: one that produced about 50 percent of the normal level of STAT3 and one that produced 25 percent. The mice with 50 percent STAT3 turned out normal; those with 25 percent did not. “With 25 percent STAT3, the mice survived through embryogenesis, but 70 percent died shortly after birth,” Shen says. “Those that did not die were born smaller and grew at a reduced rate.”

After exploring several potential connections, the researchers pinpointed one: a compound called insulin-like growth factor 1, or IGF-1, the main regulator of late-stage embryo development and early postnatal growth in mice. “We found that our STAT3 mutant animals had less IGF-1, probably about 50 percent when compared to control animals,” Shen explains.

While the implications aren’t yet clear, the bigger, more complicated picture of the STAT3 universe suggests that in addition to its role in tumor formation, STAT3 may be more important to normal, non-cancerous developmental processes than was previously believed.

February 27, 2004

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