The study, published in the Sept. 21 issue of Cell, describes how organs can grow uncontrollably huge and become cancerous when this chain reaction is perturbed.

This chain reaction, a domino-like chain of events we call the Hippo pathway, adds a single chemical group on a protein nicknamed Yap, says lead author Duojia Pan, Ph.D., associate professor of molecular biology and genetics. The good news is that maybe all organ growth can be reduced to this one chemical event on the Yap protein ” but the better news is that we potentially have a new target for cancer therapy.

Pan and colleagues previously had discovered in fruit flies that too much Yap supercharges growth-inducing genes and causes organs to overgrow.

In the new study designed to see if the same effect occurred in mammals, the research team genetically altered mice to make high levels of Yap protein, but only in liver cells. These animals' livers grew to be five times the size of a normal mouse liver and often were dotted with large tumors.

We were totally amazed, says Pan. Five times is just a huge effect. When the researchers next looked at a variety of human cancer cells, they found that 20 percent to 30 percent contained increased levels of Yap. We think it might be the extra Yap in these cells contributing to their cancerous growth, says Pan.

Yap, like most proteins, exists in more than one form, in this case two, one with and one without a chemical phosphate tag attached. Such tags can dramatically alter what proteins do in the body.

When the Hopkins team engineered the cells to stop or slow growth, Yap in those cells has its phosphate attached and moves from the nucleus ”the brain center of the cell ”into the main body of cells, or cytoplasm.

A drug that somehow turns off Yap might also stop cancer cells from growing, says Pan, and manipulating the Hippo pathway could provide a way to grow organs to a pre-determined size for transplantation.

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"We're not sure yet what particular mechanism is activated by these increased levels of NAD, and as a result SIRT3 and SIRT4," says Sinclair, "but we do see that normal cell-suicide programs are noticeably attenuated. This is the first time ever that SIRT3 and SIRT4 have been linked to cell survival."

In fact, the mitochondria appear to be so essential to the cell's life that when all other energy sources inside the cell--including the nucleus--are wiped out, yet the mitochondria are kept intact and functional, the cell remains alive.

"Mitochondria are the guardians of cell survival," says Sinclair. "If we can keep boosting levels of NAD in the mitochondria, which in turn stimulates buckets more of SIRT3 and SIRT4, then for a period of time the cell really needs nothing else."

Sinclair and his colleagues have coined a phrase for this observation: the Mitochondrial Oasis Hypothesis.

SIRT3 and SIRT4 may now also be potential drug targets for diseases associated with aging. For example, in recent years scientists have become increasingly aware of the importance of mitochondrial function in treating diseases such as cancer, diabetes, and neurodegeneration.

"Theoretically, we can envision a small molecule that can increase levels of NAD, or SIRT3 and SIRT4 directly, in the mitochondria," says Sinclair. "Such a molecule could be used for many age-related diseases."

According to Suave of Cornell, "This study also highlights how advanced technological methods can help resolve fundamental biological questions in ways that were hard to achieve as recently as a few years ago."

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