Scientists examine protein linked to mesotheliomaThe mutated genetic origins of malignant pleural mesothelioma (MPM) are, at best, a tangle of DNA damage, genere repeats and protein over- and under-expression. To say the least, it has been tough for researchers to pick this knot apart. But they've begun to do just that, with many exciting successes along the way.
For instance, a team of oncologists and molecular biologists at the University of California, San Francisco (UCSF) recently found that a particular protein, called Cullin 4A (Cul4A) is overproduced in mesothelioma. The group theorized that the damage gene responsible for excess Cul4A might make a good target for MPM treatments.
Protein may inhibit tumor suppressors
With funding from the National Institutes of Health and the Kazan, McClain, Abrams, Fernandez, Lyons, Greenwood, Harley and Oberman Foundation, researchers from the UCSF Thoracic Oncology Lab examined the expression of Cul4A in mesothelioma cells.
Cul4A is a small protein that helps control the cell cycle. It also interacts with several other proteins, including tumor-suppressors like Merlin (short for "Moesin-Ezrin-Radixin-Like Protein") and cyclin-dependent kinase inhibitor 1 (p21).
Why did the team focus on this particular protein? First, it is overproduced in many mesothelioma tissues - the authors estimated that 64 percent of all MPM cases involve Cul4A overexpression. And second, researchers have found it in abundance in other common tumors, particularly in breast cancer.
Considering its clear association with malignancy, the UCSF obtained MPM cell samples and fiddled with the gene that encodes Cul4A. They did so to watch what happens when the production of Cul4A is amped up or downregulated. What the team found was that this protein appears to encourage malignant growth by blocking tumor-suppressing proteins like Merlin and p21.
Genetic 'knockouts' reveal overactivity
Scientists began by "knocking out" the Cul4A gene in MPM tissue samples. The group then observed what other proteins arose in greater abundance. Researchers found that the cell lines began to produce more p21 and p27, two common tumor suppressors.
To be sure of this finding, the UCSF group then tried the opposite, cranking up the production of Cul4A in MPM cells. This time, they noticed that p21 and p27 production dropped sharply.
Researchers concluded that Cul4A, which is essential for cell cycle control in healthy cells, can go haywire in MPM tissue, prolonging cell life, increasing malignant growth and preventing other proteins from suppressing tumor expansion. The team added that, someday, the Cul4A gene may provide a target for novel mesothelioma treatments.
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