Healing Power In A Gene

University of Illinois at Chicago researcher Robert Costa believes he knows why: our FoxM1B gene retires.

In a paper to be published in the Dec. 24 issue of the Proceedings of the National Academy of Sciences, Costa's research group has shown that the FoxM1B gene, found on human chromosome number 12, is critical for tissues to heal and replenish themselves.

If the gene is defective or just tired out (as in old age and rare genetic disorders causing premature aging), DNA can't duplicate itself, and cells can't divide and multiply the way they normally do. The result: a flood of activity in genes associated with aging.

Costa has been working on the FoxM1B gene since he discovered the whole family of Fox genes in 1993. Research has since shown that Fox family genes, found in animals from insects on up through mammals, are involved in the entire life cycle of a cell -- its proliferation, maturation and death.

Fox is short for Forkhead Box, a name referring to a mutation in the gene in the fruit fly that causes a duplication in the head structure.

One key finding came last year: Costa's research group was studying the FoxM1B gene in mice; in particular how it affects growth of the liver after a portion of the organ is removed. One of the few adult organs capable in mammals of completely regenerating itself, the liver is also the only organ that regenerates from fully mature cells. Others, like blood, form new tissue from immature cells.

The experiment showed that the liver grew back at a rate typical of young mice -- a discovery that led Costa to dub FoxM1B the "fountain-of-youth gene."

In the new study, Costa's team set out to understand how FoxM1B directs the busy molecular traffic inside a cell to make it proliferate. In a feat of genetic engineering, the team created mice with liver cells lacking the FoxM1B gene. Rates of regeneration were measured in these mice and in mice whose FoxM1B gene was intact. Without FoxM1B, regeneration was slow.

Cell division requires two basic steps: first a doubling of DNA, the genetic instructions inside a cell, and then a process called mitosis, in which the duplicated DNA is separated into two new daughter cells.

Like a traffic cop, FoxM1B controls both steps, Costa says. "If the cells had no FoxM1B gene," he said, "their DNA often failed to make a copy of itself, and they had trouble dividing."

The DNA failed to duplicate due to a pileup of a protein called p21Cip1.

According to Costa, FoxM1B probably unleashes the enzyme that normally digests this protein to prevent it from building up in the cell.

When the p21Cip1 protein accumulates, Costa says, it sets in motion a series of molecular events, like falling dominoes, that prevents DNA from doubling and gives a green light to genes linked with the diseases of old age.

"We know from earlier research by others that abnormal accumulation of p21Cip1 protein occurs during aging, turning on a host of genes associated with diseases found in the elderly, like Alzheimer's and cancer," Costa said.

Costa's team also found that FoxM1B controls a key enzyme needed to help cells pull apart at the end of mitosis, the final step in cell division.

"These results clearly link FoxM1B with the failure of tissues to mend," Costa said. "And in old age, when the FoxM1B gene is essentially out of action, we see the results."

###

The study was supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases, one of the National Institutes of Health.

Other UIC researchers involved in the study were Margaret Dennewitz, Kiroaki Kiyokawa and Zinhe Wang.