In 1997, Dr. Pagano's group and other research teams separately reported that low levels of p27 correlated with a poor prognosis among patients with colorectal and breast cancers, regardless of tumor size. Since then, numerous reports have extended these original findings to many other types of tumors. In more recent studies, researchers have discovered that p27 and Skp2 were inversely correlated in certain tumors, so when Skp2 levels were high, p27 levels were low.
However, no one knew what controlled the cellular abundance of Skp2, which is now considered an oncogene. Alterations in oncogenes often lead to uncontrolled cell growth, and to cancer. Now, with this latest report in Nature, Dr. Pagano's group has figured out that levels of Skp2 are controlled by APC; APC actually induces the degradation of Skp2.
Although this seeming alphabet soup of protein acronyms can be confusing to lay people, these proteins are of utmost interest to cancer researchers because they play an essential role in the cell cycle.
Disruptions in the breakdown of proteins associated with the cell cycle can lead to cancer, the uncontrolled growth of cells. In normal cells, Skp2 needs to be degraded in order for the cell to remain in a quiescent, or resting, state. When it isn't degraded, its levels rise and then the cell is pushed into the initial stage of cell division, called the S phase, in which the cell synthesizes its DNA in preparation for replicating its genome.
In Dr. Pagano's latest study, his group demonstrated that cells with high levels of a mutated form of Skp2 promoted the degradation of p27. As a result, these cells entered the S phase of the cell cycle faster than control cells with unmutated Skp2.
The premature entry of a cell into the S phase is a potential cause of genetic instability, which in turn can propel a cell into uncontrolled proliferation, res
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Contact: Pamela McDonnell
Pamela.McDonnell@med.nyu.edu
212-404-5555
New York University Medical Center and School of Medicine
10-Mar-2004