Description: A strategy for developing anti-cancer therapies is to inactivate proteins that are required for the integrity of DNA repair signaling pathways. Inactivation of such proteins may lead to greater therapeutic effectiveness of the many current cancer treatments that act by causing DNA damage, such as radiation therapy and many chemotherapeutic agents.
When cells incur damage in the form of DNA double strand breaks, normal cells will arrest at various checkpoints throughout the cycle to allow for DNA repair. Several pathways are involved in a DNA damage checkpoint at the G1/S phase cell cycle boundary. One pathway is mediated by the p53 tumor suppressor. P53 induces the kinase inhibitor p21, resulting in the arrest of cells at G1/S. This pathway is compromised due to mutation or loss of p53 in about 80% of human tumors.
The regulation of a second pathway has recently been discovered in the laboratory of Dr. Peter Stambrook at the University of Cincinnati. For cells to activate the G1/S checkpoint, CDC25A phosphatase must be degraded. Using cultured mammalian cells and mouse knockout models, Dr. Stambrook’s work has demonstrated that Polo-like kinase 3 (Plk3), a member of a conserved family of serine/threonine protein kinases, is likely the principle kinase required to facilitate the degradation of CDC25A at the G1/S checkpoint.
Therefore, Plk3 is proposed as a novel target for the discovery of inhibitory molecules that would be useful as cancer therapeutics. The rationale is that most human tumors are p53 deficient and therefore one of the pathways leading to G1 checkpoint arrest is compromised. If the alternate pathway is also compromised by inhibition of Plk3 by a small molecule inhibitor, the tumors would be selectively killed or sensitized to low levels of standard chemotherapies.
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