New Steps Found In Deadly Path Of Cancer-Causing Virus: Findings Suggest Novel Method Of Stopping Cervical Cancer In Its Tracks

April 15, 1997

BOSTON--Few microbes are capable of wreaking greater long-term havoc in the human body than the human papillomaviruses. While the majority invade the cells of the body and form tiny tumors, or warts, which are a nuisance but not life-threatening, a small number can produce cervical cancers. Nearly 5,000 American women die of cervical cancer each year.

How, exactly, do these deadlier strains cause their destruction? Two Harvard Medical School scientists have uncovered an unexpected answer.

Researchers have known that cancer-causing strains of human papillomavirus (HPV) splice two viral genes into the DNA of cervical cells, both of which must be activated to result in cancer. One of these genes, called E6, produces the E6 protein that teams up with a second protein, E6-AP, to carry out its carcinogenic work. The pair targets and destroys the tumor-suppressor protein, p53, inside the cell, freeing the cell to divide uncontrollably.

The other viral gene, E7, produces the E7 protein, which was thought to work quite differently. While it targets a tumor-suppressor called retinoblastoma protein (pRB), the binding of E7 to pRB was believed to result in a blocking of pRB's actions rather than an actual degradation of that protein.

This assumption appears to be wrong, according to researchers Karl Munger, assistant professor of pathology, and Leanne Jones, research fellow in pathology and lead author of a study that appears in the April Journal of Virology. In their investigation, the researchers infected human cells with normal and mutant E7 genes. In all cases where the normal and mutant E7 genes were known to turn human cells cancerous, pRB levels were reduced--and the remaining pRB was degraded at a more rapid rate than pRB in normal cells.

Virologists have long wondered why certain other E7 mutants that are able to bind pRB are not able to transform cells. In their study, Munger and Jones show that such E7 mutants are unable to induce pRB degradation. The findings suggest that while binding of E7 to pRB is necessary, it is not enough: Some other step--namely, destabilization of pRB--is required for E7 to transform a cell.

"To me as someone who has been in the field for 10 years, that's the biggest 'Aha' experience I've had for a very long time. It tells me, in part, that what the mutated sequences do is somehow interfere with the stability of pRB," says Munger.

How these sequences cause the destabilization of pRB is not clear. One possibility is that they may enable E7 to team up with another protein--just as E6 teams up with E6-AP to target p53. In fact, the researchers have already identified several candidate "partner" proteins.

Until now, pharmaceutical companies such as Merck have been trying--unsuccessfully--to develop molecules that interfere with the binding of E7 and pRB. A better idea may be to stabilize or bolster pRB once it has been targeted, says Munger.

Ironically, the recent findings topple a theory that Munger helped to erect. It was Munger who helped to establish the importance of binding between E7 and pRB, while he was a postdoctoral fellow at the National Cancer Institute in the lab of Peter Howley, who is now George Fabyan Professor of Comparative Pathology at HMS. In 1992, Munger discovered that the E7 proteins of cancer-causing HPVs differ from their wart-causing cousins by a single amino acid in their pRB-binding region.

Yet even then, binding between E7 and pRB did not appear to be the whole answer to E7's role in cervical cancer. First, pRB is a plentiful protein in the body while E7 molecules are expressed in much lower levels. How could they effectively target pRB when they were so vastly outnumbered? Then there was also the question of the E7 mutants that could bind pRB but did not lead to cancer.

To explore the question of how E7 causes cancers to form, Jones and Munger measured pRB levels in cells expressing normal and mutant E7 genes. Not only did the level and half-life of pRB decrease in cells known to undergo transformation, the decrease appeared the moment E7 was expressed. The timing suggested the drop in pRB levels was actually due to E7 expression.

A better understanding of how pRB is destabilized by E7 could lead to better therapies for treating cervical cancer. "We can go after defining compounds that can restabilize pRB--we don't have to target a specific protein-protein interaction," says Munger.

Could the findings lead to new treatments for the far more common, less serious, but quite difficult to treat HPV affliction--warts? Wart-causing E7 proteins appear to bind pRB less well than cancer-causing forms, but restabilizing pRB may be a possible strategy for therapies.

The researchers say it is still too early to tell. "Both low- and high-risk viruses somehow have to reactivate inactive replicatory machinery in their target cells. So that is going to be a common mechanism. How does E7 do this? That's what we are looking at," says Jones.

Harvard Medical School

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