An AIDS-Related Virus Tricks Cells
to Become Tumors, New Penn Study Finds
Researchers at the University of Pennsylvania
School of Medicine have discovered how the
Kaposi’s sarcoma-associated herpesvirus (KSHV)
subverts a normal cell process in order to promote
tumor growth. The finding, published in the most
recent issue of PLoS Pathogens, offers new
potential strategies for treating Kaposi’s sarcoma and
other cancers associated with viruses.
KSHV is an opportunistic pathogen that rarely affects
individuals with normal immune systems. However,
HIV/AIDS patients and those who are immune suppressed
such as organ transplant patients are at high risk for
developing Kaposi’s sarcoma and another cancer called
primary effusion lymphoma.
The study describes how a KSHV-encoded protein, called
latency-associated nuclear antigen, or LANA, tricks
the cell into destroying two major suppressors of
tumor growth called von Hippel Lindau (VHL) and p53.
“In addition, we have shown that when LANA expression
was blocked, the tumor suppressors again become stable
suggesting a direct role of the viral protein in
regulation of these major cell proteins,” says lead
author Erle Robertson, PhD, Professor
of Microbiology and the Director of Tumor Virology at
Penn’s Abramson Cancer Center.
Marked for Disposal
The trick is played out in a cell process called
ubiquitylation. This refers to a pathway in all cells
whereby a protein aptly named ubiquitin binds to
cellular proteins and marks them for degradation. This
process can be likened to putting out the garbage for
disposal.
Ubiquitylation and degradation involve a complex set
of proteins in addition to ubiquitin. “We found that
the viral LANA has an amino acid motif that mimics
non-viral cell proteins usually involved in the
ubiquitylation process,” says Robertson. This motif,
or stretch of amino acids, normally enables LANA to
bind to tumor suppressors p53 or VHL, thus bringing
them into the active ubiquitylation complex. Once in
the complex, the tumor suppressors are targeted for
degradation.
Tumor suppressors, as their name implies, prevent or
limit the growth of tumors in numerous ways. One way
the tumor suppressors p53 and VHL work is to mark a
key protein that controls the blood supply in a tumor
mass. Once marked, this protein called hypoxia-induced
factor 1a (HIF-1a) is degraded through ubiquitylation
before it can start the process of activating genes
responsible for inducing growth of more blood vessels
to supply the tumor with oxygen. However, in a KSHV-infected
cell, p53 and VHL themselves would be targeted for
degradation and HIF-1a would then be free to activate
genes involved in growth of blood vessels to increase
the blood supply to the tumor.
“Use of such proteosome inhibitors as Bortezomib as
cancer therapeutic agents has been ongoing for the
last four to five years and this study provides
crucial step in understanding the mechanism for anti-tumorigenic
activity against KSHV-associated human cancers,”
concludes Robertson. “Additionally, we can now use
compounds known to inhibit proteosome activity to
determine their effectiveness in inhibiting the
Kaposi’s viral-induced degradation of these two major
tumor suppressors.” This, he says, is important in
finding or designing drugs that can be specifically
used against KSHV, and potentially, other
virus-associated cancers.
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Source: |
University of Pennsylvania School of Medicine |
Published on 19th November 2006
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