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CDK2/FOXO1 as drug target to Prevent Tumors
By Mayo Clinic, Rochester,
Oct 13, 2006 - 1:10:37 AM
Mayo Clinic researchers have found that a protein that initiates a "quality control check" during cell division also directs cell death for those cells damaged during duplication. This knowledge represents a potential "bulls eye" for targeting anti-tumor drugs. The findings appear in the current issue of Science.
The researchers examined a protein called cyclin-dependent kinase 2 (CDK2), which works as a "quality control inspector." As normal cells divide, they pause in the replication process when they find inaccurate genetic code embedded in their DNA. The health and well-being of offspring cells depends on accurate genetic code transfer from one generation of cells to the next. The Mayo researchers showed that when errors in genes are irreparable, CDK2 modifies another cellular protein -- FOXO1 -- to send a signal that results in the death of the cell. This protein-to-protein relationship invites targeted drug intervention to control unregulated growth of cancer cells.
"Quality control within dividing cells is essential because mistakes during duplication of the genetic code can lead to cancer," says Donald Tindall, Ph.D., co-leader of the Mayo Clinic Cancer Center prostate cancer research program. "CDK2 is a key protein component in the cellular mechanism that leads to repair of damaged DNA."
If cells pass this quality control checkpoint, they can resume the process of dividing into two daughter cells. If, however, major irreparable discrepancies occur in the genetic code, cells are shunted toward a molecular sequence that leads to death, or apoptosis. Cells have the genetic knowledge to sacrifice themselves for the greater good of the organism rather than to pass on errant genetic codes that can lead to disease. Genetic errors that sneak past the cell's quality control check-points can make the cell prone to develop into cancer.
The Mayo researchers documented that CDK2 infuses high energy into another cellular protein, FOXO1, switching it on as the initial link in a signal that tells the cell to set itself up for apoptosis. CDK2 adds phosphorylation to a specific serine residue on the chain of amino acids that make up FOXO1. In case of robust errors found in the genetic code, CDK2 signals FOXO1 to explicitly call for the cell to produce a set of proteins leading to apoptosis.
"If the cell has minor alterations in the DNA code that can be repaired, those repairs are made," says first author Haojie Huang, Ph.D. "If the genetic message cannot be repaired, our studies show that CDK2 can initiate the steps necessary for cells to order the production of genes involved with cell death, and the errant cell dies without propagating its damaging genetic message to progeny cells of its own."
"As patients and their physicians seek to control or cure tumors, research is providing new approaches to limiting cancer from growing and spreading," Dr. Tindall said. "With this new understanding of the biology driven by critical dual functions of CDK2, the cancer community can focus on ways to regulate a mechanism that the cell contains to prevent damaged genetic messages from being inherited and spread in proliferating tumor cells."
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