A new mechanism that may trigger the onset of cancer has been described by scientists at Cold Spring Harbour Laboratory (CSHL).
Using a common virus called adenovirus, as a tool for investigating abnormal cell proliferation, the team has succeeded in expounding an intricate series of biochemical steps that shed light on a way that cancer can begin.
Adenovirus is a type of virus that causes the common cold in people, but its genome contains known oncogenes, genes whose expression can promote cancer under certain conditions.
"Adenovirus carries a number of cooperating genes that modulate cell growth in ways we're interested in," said William Tansey, Ph.D, co-leader and study author.
The team focused its study on an adenoviral oncogene called E1A, and a protein that it codes for with the same name.
A DNA virus like adenovirus is little more than a tiny, double-stranded segment of DNA enclosed within a protein shell. It must find a way to enter the nucleus of a living cell and hijack the cell's reproductive machinery in order to reproduce itself.
"It's not adenovirus itself, but the things it does when it enters a cell, that really interest us," said Tansey
"By looking, in particular, at the activity of the proteins adenovirus codes for -- proteins like E1A -- we are tapping into a kind of natural growth-control mechanism," he added.
To hijack the reproductive machinery, the tumour virus forces the host cell to enter the reproductive, or S-phase, of its cycle.
Past studies have shown has that a protein called E2F is central in the process by which S-phase is activated. When the cell is not reproducing, E2F is known to be inhibited by its binding to another protein, called Rb, or retinoblastoma protein.
"It's this regulated association of E2F and Rb that is one of the primary mechanisms through which cells normally progress into S-phase," Tansey said.
"The E1A protein, after binding Rb, is capable of physically pulling it off the E2F molecule. This unleashes the cell to replicate its DNA. And this, in turn, can promote transformations associated with cancer," he added.
He also studied protein Myc , an oncoprotein, which is important in a great many regulatory processes in the cell, and which, when over-expressed, can cause dysregulation that leads to cancer.
E1A's cancer-promoting activity also involves a gene-regulating protein called p400. The team knew from prior studies that when the E1A and p400 proteins were bound to one another, cellular growth control was disrupted.
The study showed that "the piece of the E1A protein that was important for stabilizing Myc was the same piece that bound to p400," Dr. Tansey said.
And just as E1A can pull the Rb protein away from E2F, initiating a cascade of pathologies potentially leading to oncogenesis, so does the ability of E1A to bind p400 and via that connection to engage Myc, stabilize that oncoprotein and open the door to tumorigenesis.
The study appears in Proceedings of the National Academy of Sciences.