Scientists Unlock Molecular Mechanism That Controls Cell Growth

In order for living organisms to thrive, cells need to know when to grow. Environmental and physiological stress, such as that produced by toxins, a virus infection or poor nutrition, create an unhealthy environment at the molecular level. Cell growth under such conditions can result in serious problems, such as mistakes in chromosome replication or the beginnings of cancer.

"How does a cell know when its environment is bad?" said Morimoto. "It’s been known for centuries that stress has a negative effect on the development and growth of organisms, but until now, we didn’t know the mechanism that ties stress together with when and how cells grow."

It turns out that the signal transduction pathway, or the cascade of signals that leads to gene transcription and cell growth, is negatively regulated by a heat-shock protein called Hsp70, which acts as a stress sensor.

The protein — an ancient protein found in nearly every organism on Earth — patrols the cell’s immediate environment, in its role as constant protector. When biochemical stress builds to an unhealthy level, Hsp70 expression is rapidly activated and accumulates to high levels. The researchers showed that Hsp70 halts cell growth by binding to the protein Bag1.

In a healthy environment, Hsp70 keeps out of the way, allowing Bag1 to bind to a different protein, Raf-1, which sets the cell growth signalling process in motion. But when Bag1 is bound to Hsp70 during stressful times, it cannot bind to Raf-1 as well. When the stress ends and the numbers of Hsp70 return to normal, cell growth can continue.

"We wanted to determine if Bag1 and Hsp70 could be the source of the ongoing talk that monitors a cell’s environment and controls the growth state of a cell," said Morimoto, who cloned Hsp70 in 1985 and has been studying Bag1 for four years.

To assess the relationship between Hsp70 and Bag1, Morimoto’s team used mutants of the two proteins. Their results showed that Bag1 mutants defective in binding to Hsp70 stimulated Raf-1 and the signalling pathway, despite the fact that the numbers of Hsp70 were elevated, due to stress. They also showed that overexpressed Hsp70 mutants defective in binding to Bag1 had no effect on Raf-1 activity and cell growth. In the process, they identified the binding site on Hsp70 of Bag1.

These results indicate that the inhibitory effects of Hsp70 on the signalling pathway and cell growth require Bag1. The researchers also were able to show that only Bag1 was able to activate the signalling pathway leading to DNA synthesis, evidence that the pathway is extraordinarily selective.

Essentially, with Hsp70 and Raf-1 competing for binding to Bag1 two scenarios result: Hsp70 wins in an unhealthy and stressed environment, shutting down cell growth, and Raf-1 wins under healthy conditions, allowing cell growth.

"The identification of Hsp70 as a switch regulating Bag1 and activation of the signal transduction pathway provides scientists with a molecular framework to begin to understand the negative effects of stress on cell growth," said Morimoto.

Other authors on the paper are Jaewhan Song, who was a graduate student, and Masahiro Takeda, who was a postdoctoral fellow, at the time the research was done.

The research was supported by the National Institutes of General Medical Sciences and the Carol and Martin Gollub Foundation.