By Dean Hancock

Special To BioWorld Today

Fortunately, the "program" that guides a cell through its life cycle is not subject to the Year 2000 problem that looms over the users of outdated computer software. There will be no extraordinary crashes on the cellular level, when the calendar flips from 1999 to 2000. The same is true of apoptosis, or programmed cell death, the defined sequence of events that guides cells toward self-destruction when they are no longer needed during development or when they become dangerously transformed.

There are, of course, other programming flaws that present constant threats to cells. One of the more serious occurs when a glitch arises in the programmed cell-death sequence. This can result in the survival of a transformed cell that should have been destroyed.

Many researchers suspect that progression of the cell cycle, growth and division, is very closely linked to the control of programmed cell death. The details of the link have not been worked out on a molecular level, but a report in today's issue of Nature provides evidence of "a new interface between cell-cycle progression and control of apoptosis." The work holds potential significance for understanding basic cell biology and cancer.

"The paper is interesting, because it really shows a direct connection between the cell cycle and apoptosis," said John Reed, scientific director at the Burnham Institute, in La Jolla, Calif. "There have been a lot of studies over the last few years [showing] that, as cells go through the cell cycle, they meet certain checkpoints. If things go wrong, they commit suicide. In most cases, it hasn't been entirely clear why they commit suicide. The connections have not been as direct as one would like to see."

One important interface between the normal cell cycle and apoptosis appears to be a protein named survivin, one of the family of Inhibitor of Apoptosis (IAP) proteins that have been discovered in the last three or four years. IAP proteins are highly conserved from viruses all the way up to mammalian cells. Last year in Nature Medicine, Dario Altieri, associate professor of pathology at the Boyer Center for Molecular Medicine, at the Yale University School of Medicine, in New Haven, Conn., and his colleagues reported the identification and cloning of the survivin gene. Survivin differs from other described proteins in an important way.

"In mammalian cells," Altieri said, "all of the other members of the IAP family are abundantly expressed and widely distributed in adults and in embryonic and fetal tissues. We found that for survivin, the critical feature was its selective distribution. It was abundantly expressed during fetal development, and down-regulated and undetectable in adult tissue."

Survivin Expressed In Many Cancers

Significantly, Altieri's group found that survivin is re-expressed in a variety of cancers.

The most recent research concerning survival appears in a letter, "Control of apoptosis and mitotic spindle checkpoints by survivin," co-authored by Altieri, that appears in the Dec. 8 issue of Nature. Experiments using HeLa cells indicate that survivin normally may serve as a "brake" on a default pathway that leads to cell death.

"It is an important piece of work because it shows what appears to be a fairly direct connection between a step in cell division and the apoptosis pathway," Reed said. "As long as this process of mitosis is proceeding normally, the survivin protein will be active and able to suppress apoptosis. But if something goes wrong the cell defaults to apoptosis."

In cancer cells, survivin's activities are closely coordinated with the progression of the cell cycle, which includes resting phases and phases of chromosomal duplication and cell division. As a cell's nucleus begins to replicate and divide prior to division of the cell body, survivin binds to microtubules. These cytostructural elements form spindles that connect to and organize the replicating chromosomes. If, at this crucial time, the association between survivin and the microtubules is broken, the IAP protein loses its ability to stop apoptosis. Interference of the survivin-microtubule association leads to increased activity of the enzyme caspase-3, which plays a key role in initiating programmed cell death during mitosis.

"Caspases are really the effector molecules of apoptosis," Altieri told BioWorld Today. "Work in the literature over the past year and a half suggests that IAP proteins are in fact direct inhibitors of caspases. Survivin apparently is no exception to that."

The main implication of this work, according to Altieri, is to identify survivin as a target for cancer therapy. Overexpression of survivin might be expected to inhibit apoptosis and aid the survival of cancer cells.

"The tumor cell exploits the mechanism that is probably operative during development and differentiation," Altieri said. "Remember, survivin is very abundant in vivo in embryonic tissue. It exploits it to acquire an additional advantage factor for cell proliferation."

The survivin gene, he noted, is not an oncogene in itself, but it helps that cell going through mitosis at a point where a checkpoint would normally eliminate a transformed cell, by preventing the cell from going through the cell cycle progression.

Now Comes In Vivo Work

Now, the first objective in Altieri's lab is to extend the cell culture findings to an in vivo system. The researchers also want to generate reagents that target survivin using retroviral constructs and antisense technology and to dissect the signal transduction pathway that leads to the up-regulation of the survivin gene.

"The overall objective would be to identify potential antagonists that either disrupt the expression of the survivin gene or interfere with the function of the survivin protein," Altieri said.

Survivin also has potential uses for preventing cell death following tissue injury from stroke and heart attacks.

"We are working on the possibility of generating adenoviral delivery of survivin to see if local increases in survivin concentrations in the myocardium, for instance, or in damaged neurons after hypoxia and ischemia, would in fact increase survival of cells," Altieri said. His research is supported by the National Cancer Institute. His group also is working closely with Abbott Laboratories, of Abbott Park, Ill. n

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