Hutch News

Programmed cell death: Myc's role

Feb. 6, 2003

While too much Myc pushes cells into growth overdrive, excess levels of the protein also can trigger a seemingly opposite effect - a process called programmed cell death, which causes cells to self-destruct when they are abnormal or no longer needed.

The path chosen, said Dr. Fionnuala Morrish, a staff scientist in Hockenbery's lab, depends on the conditions under which cells are grown.

"If cells are grown in the presence of serum, which contains nutrients and growth factors, then Myc activates cell division and growth," she said. "But when deprived of serum, Myc induces programmed cell death, or apoptosis."

Research from the Hockenbery lab and others has shown that during this process, profound changes take place in cell compartments called mitochondria, which serve as energy-production factories. Among these changes is the release from the mitochondria of a protein essential to energy production called cytochrome c.

Typically, the levels of cytochrome c and other mitochondrial proteins are coordinated by a series of regulator proteins, including one known as NRF-1 (for nuclear respiratory factor 1). NRF-1, like Myc, is of a class of proteins that control gene expression by binding to specific sequences of DNA near their target genes. Studies have shown that Myc, in conjunction with a partner protein called Max, and NRF1 bind to similar DNA sequences.

The Hockenbery lab's study demonstrates that elevated levels of Myc lead to overproduction of cytochrome c and a series of other genes involved in mitochondrial function. This suggests that under normal growth conditions, Myc may have a role coordinating mitochondrial energy metabolism.

However, in the absence of other essential factors that control gene expression, Myc can elevate only a subset of the genes necessary for mitochondrial function, and this imbalance leads to mitochondrial dysfunction and cell death.

"These findings lead us to look at Myc in a different way," Morrish said. "Now that we know that this oncogene may play an essential role in mitochondrial function, we need to determine how this impacts cancer-cell metabolism."

Hockenbery praises Morrish's approach.

"Her research provides an intuitively satisfying explanation for the dual role of some proteins in cell growth and cell death," he said. "Apparently too much of a good thing is indeed bad for you."

Morrish said that a detailed understanding of how Myc affects the function of the mitochondria could lead to anti-cancer therapies that target the programmed cell-death pathway.

"The only way to approach this is to learn a lot more about the changes in mitochondrial function induced by Myc," she said.

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