The Flip Side of p27
07/15/2007
The Flip Side of p27: Scientists uncover new roles for p27 in oncogenesis and stem cell expansion In a paper published online ahead of its July 15th print date, Dr. James Roberts (FHCRC) and colleagues reveal a surprising new role for the p27 tumor suppressor in tumors and stem cells.
“p27 is one of most frequently misregulated proteins in human cancers, and this is strongly predictive of an aggressive tumor phenotype,“ explains Dr. Roberts.
Their finding, along with the novel animal model they studied, hold great promise for furthering understanding of how mutations abnormal expression ofin p27 contributes to cancer growth and the rational design of drugs to combat p27 dysfunction.
P27 is a cell cycle regulator – more specifically a cyclin-dependent kinase (CDK) inhibitor -- meaning that it can inactivate cyclin-CDK protein complexes and specific CDK enzymes essential for cell division cause cell cycle arrest in the G1 phase of cell growth and thereby stop cell proliferation. P27 is thus a CDK-dependent tumor suppressor: Its inactivation promotes uncontrolled cell growth.
As published previously, p27-kockout mice (mice completely lacking p27) display multi-organ hyperplasia and pituitary tumors. But is has been a mystery as to why the p27 knockout mouse failed to recapitulate the widespread and potent role that p27 has in human cancer.
Dr. Roberts and colleagues generated a new strain of p27-mutant mice: p27 that cannot bind to cyclin-CDK, but otherwise functions normally. These p27CK- mice, as they are known, enabled researchers to probe the CDK-independent functions of p27. What they found was “totally unexpected,” according to Dr. Roberts.
As it turned out, p27 has a strong CDK-independent oncogenic effect. Unlike the p27-null mice, P27CK- mice developed aggressive spontaneous tumors in multiple, diverse organs. Furthermore, the tumors of the lungs and retina were associated with an expansion of the stem cell populations of these tissues. Thus, p27 can function as a CDK-dependent tumor suppressor, as well as a CDK-independent oncogene.
Comparison of the p27CK- and p27-null phenotypes led the researchers to conclude that the p27CK- mice may, in fact, represent a more faithful model of the dual role of p27 in human tumorigenesis. Dr. Roberts says that the p27CK- mouse not only eliminates the tumor suppressing function of p27, but also liberates its oncogenic activity, thus allowing it full effect on tumorigenesis to be revealed.
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