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PTEN Extends Mouse Life Span, Partly via Affecting Metabolism

By Anette Breindl
Science Editor

A team of researchers has shown that transgenic mice with increased levels of the tumor suppressor PTEN have a longer life span than their wild-type brethren.

That higher-than-normal levels of a tumor suppressor increase life span may itself be unsurprising. But the protein appears to work partially via an unexpected mechanism. PTEN's inhibition of PI3 kinase has beneficial effects on metabolism, by activating the energy-burning brown fat tissue.

The findings, Manuel Serrano told BioWorld Today, open up "a new avenue to manipulate the brown adipose tissue" – an approach that "is considered nowadays the most promising way to combat obesity and metabolic syndrome." Serrano is a group leader at the Spanish National Cancer Research Center (NCIO).

Because the team was able to achieve the same effects by inhibiting PI3 kinase, which is PTEN's main job in the cell, as by overexpressing PTEN, from a practical perspective, the findings suggested "the exciting prospect that PI3K inhibitors could have an additional, unsuspected activity."

And with companies like Exelixis Inc., Intellikine Inc. (now part of Takeda Pharmaceuticals Co.) and Calistoga Pharmaceuticals Inc. (now part of Gilead Sciences Inc.) all developing PI3 kinase inhibitors for cancer, therapeutics based on the new insights conceivably could make it to market "much faster than usual."

More generally, the work, which was published in the March 7, 2012, issue of Cell Metabolism, adds to a growing recognition that most of the major tumor suppressors have beneficial effects that go beyond tumor suppression.

Senior author Serrano emphasized that such beneficial effects "are only visible when the tumor suppressors are enhanced moderately and preserving their normal regulation. . . . Abnormal or too high expression of these genes is detrimental because it prevents the normal process of cell renewal, which is obviously detrimental."

Nevertheless, Serrano and his team, as well as other labs, have demonstrated that mice with increased gene copies of the tumor suppressors live longer than their wild-type cousins. The same also has been shown for mice with increased levels of p53, though in the case of p53 the effects seem to be due mainly to tumor suppression.

In their current studies, Serrano, first author Ana Ortega and their colleagues at the CNIO gave mice an extra copy of the PTEN gene via a bacterial artificial chromosome. Serrano said inserting a transgene in that way has several advantages for looking at the effects of increasing PTEN levels.

Bacterial artificial chromosomes, he said, "contain large unmodified pieces of DNA that include the entire gene (which is easy to recognize) but also surrounding sequences (that contain regulatory elements that are not obviously recognized)." Inserting those regulatory sequences along with the gene means that the transgene is regulated in pretty much the same way, and in response to the same stimuli, as the animals' own two copies of the transgene.

Overall, that also means that compared to the most popular transgenic technologies – which, he estimated, typically increase gene dosage by 10-fold or more – the increase in gene expression due to a transgene on an artificial chromosome is a more modest 50 percent to 100 percent.

Finally, the gene is expressed throughout the body, whereas normally, transgenic mice express the transgene in specific tissues.

The method, Serrano said, "is a proof of principle of a pharmacological intervention because drugs usually have systemic effects, usually have moderate effects on the biochemical pathways and usually do not alter the normal regulation of a biochemical pathway (drugs usually increase or decrease the activity levels)."

Using their method, Ortega, Serrano and their team saw that the increased dosage of PTEN increased the life span of mice. Part of the reason was that the animals developed fewer cancers. But even cancer-free wild-type mice, on the average, did not live as long as cancer-free PTEN transgenics. The team found that, aside from preventing the animals from developing cancer, the higher levels of PTEN also activated brown fat cells. Such brown fat activation has a variety of beneficial metabolic effects, and companies like Ember Therapeutics Inc. are working on ways to convert white fat to brown fat. (See BioWorld Today, June 27, 2011, and Dec. 15, 2011.)

Serrano said the CNIO has developed a small compound synthetic inhibitor of PI3K, CNIO-PI3Ki, which also boosts the activity of brown fat cells. He and his team are "treating obese mice . . . fed with a high-fat diet with CNIO-PI3Ki administered in the drinking water to see if it reduces their [weight] while eating high-fat food."

Serrano said one advantage of his team's approach is that it works directly on the brown fat cells. "As far as I know," he said, "this is the first intervention that boosts the brown fat without altering the main switch triggered by the brain (through the sympathetic nervous system, which directly innervates brown adipocytes). Previous interventions enhanced this switch . . . and this turned out to have too many side effects. Moderate inhibition of PI3K signaling only amplifies the response to the main switch, but without altering this main switch.

"That is, the brain remains in control and its signals are not modified, which is definitely a good thing."