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p27 protein’s role in halting cancer probed
The development of cancer is sometimes likened to a car that is out of control because of a stuck accelerator, a broken brake or, more often, a combination of both.
In this scenario, the protein products of tumor suppressor genes normally act as brakes, stopping abnormal cells from continuing to grow and divide and often triggering their death. Loss of the suppressor activity can result in the runaway cell growth that characterizes cancers.
A group of Vanderbilt-Ingram Cancer Center investigators recently reported that the protein p27, previously thought to be only a tumor suppressor, can halt or promote cell growth under different circumstances.
“The current dogma has been that p27 is a classic tumor suppressor,” said Dr. Rebecca S. Muraoka, research assistant professor of Cancer Biology and lead author of the report in the journal Molecular and Cellular Biology. “Our studies suggest a more complex role for p27. We found that p27’s role as a tumor suppressor requires two functional copies of the gene, since the loss of a single copy of p27 results in increased susceptibility to breast tumor formation. However, loss of both p27 alleles results in decreased growth of breast epithelium, and a reduced frequency of breast tumor formation.”
The cycle through which a cell moves as it divides and replicates itself is tightly regulated to control cell growth. A group of chemicals called cyclins and the partners that catalyze their activity, the cyclin dependent kinases (Cdks) are instrumental in driving the cell cycle forward. Cyclin D1/Cdk4 complexes function early in the cell cycle, while cyclin E/Cdk2 complexes funtion later.
The authors noted that while p27 acts as an inhibitor of Cdk2 activity, it also is required early in the cell cycle for the assembly of cyclin D1/Cdk4 complexes. This suggested that p27 permits early progression but restrains later progression of the cell cycle.
The Vanderbilt investigators found that breast epithelial cells were more susceptible to transformation induced by the breast cancer-associated gene HER2/neu in the context of only one functional copy of p27, versus the normal two copies. The group also demonstrated that the loss of both copies of p27 results in substantially delayed tumor formation.
“Our results suggest that in the absence of both p27 alleles, the ability of p27 to drive the cell cycle forward is lost,” the authors wrote. “But in the presence of a single allele, the forward progression of the cell cycle is maintained while p27 is unable to suppress the cell cycle.”
As a result, the authors suggest, levels of p27 within a given mammary epithelial cell may determine p27 function within that cell at that time.
Muraoka said the findings suggest therapeutic approaches targeting p27 may be more complicated than previously thought.
“If we try to target p27 in therapy, this suggests that we will have to be very careful to make sure that p27 is completely wiped out,” she said.
Muraoka’s colleagues in the work were Brian Law and Elizabeth Hamilton in Cancer Biology; Anne E.G. Lenferink, Dana M. Brantley and L. Renee Roebuck in the Department of Medicine, and Carlos Arteaga, Ingram Professor of Cancer Research and professor of Medicine, Cancer Biology and Cell Biology.
The research was funded by the National Institutes of Health and the Susan G. Komen Foundation.