February 27, 1998
Stepping Off the Brake
The E7 peptide from human papilloma virus (yellow) reaches into the retinoblastoma pocket domain (red and blue) to shut down retinoblastoma's tumor-suppressing ability.
It's one thing to theorize how a virus knocks a tumor suppressor protein out of commission, but it's quite another to see inactivation in action. That's now possible for the intensely studied retinoblastoma
(Rb) protein, the first tumor suppressor identified.
A Hughes research team at Memorial Sloan-Kettering Cancer Institute in
New York has crystallized Rb protein just as it is being handcuffed by a
fragment of the human papilloma virus (HPV) that is associated with 90
percent of all cervical cancers. The research is reported in the
February 26 issue of
Nature.
The business end of the Rb protein visualized by Hughes
investigator
Nikola Pavletich
and colleagues contains the crucial
"pocket domain." This is where viral proteins attach and where mutations
can occur. "The pocket domain is at the center of a biochemical pathway
that is altered in a majority of cancers," Pavletich said.
The three-dimensional view of the pocket domain now opens a window into
how the alteration of Rb contributes to the development of many types of
cancers, including lung, breast, and bladder carcinoma, Pavletich said.
Almost all of the body's cells express the Rb protein; it
appears to act as one of the main brakes for the cell division cycle.
When exposed to growth factors, the
Rb
gene is turned off by
phosphorylation. The cell then enters a growth stage and begins to
divide. Without the presence of such growth signals,
Rb
remains
unphosphorylated and binds strongly to key regulatory proteins,
preventing those proteins from promoting DNA replication in the nucleus.
For a tumor to grow, these regulatory proteins need to free
themselves of Rb's restraint. Some cancer-promoting viruses do this by
handcuffing Rb and preventing it from blocking cell division. The virus
then commandeers the host cell's DNA synthesis machinery, causing the
cell to divide recklessly, and possibly producing cancer.
HPV disarms Rb by inserting the E7 peptide from HPV into the
pocket domain of Rb. This interference causes Rb to release the E2F
transcription factors, which are required for the expression of genes
involved in DNA replication.
Now that researchers can better visualize the union of Rb and
E7, they may now be able to understand a more global problem: How does
Rb inhibit E2F transcription factors?
Pavletich suggests that in the future, dysfunctional stages in this
growth regulatory pathway may be fixed therapeutically to prevent the
cancer from ever starting. "Each element of this regulatory pathway
inhibits the next one, and if we truly understand the cascade of events,
we may be able to restore normal function," he said.
Tyler Jacks, a Hughes investigator at the Massachusetts
Institute of Technology, said that the structure of the Rb pocket domain
will provide insights "related to basic questions about normal cellular
regulation and tumorigenesis. It may also be possible to use this
information in the future to design specific inhibitors of the viral
oncoproteins for use in cancer treatment."
Image: Jie-Oh Lee/Pavletich Laboratory
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