A team of cell biologists led by Eugene Chin, M.D., a research
professor at The Warren Alpert Medical School of Brown University and
a staff researcher at Rhode Island Hospital, reports its findings in
the journal Cell. Their results are surprising.
Scientists have long known that phosphorylation, an amino acid
modifying process in proteins, is critical for switching receptors on
and off on the surface of cells. Chin and his team studied how type 1
interferon binds to a receptor complex, known as the IFN-α receptor,
on the cell surface to trigger an immune response. Chin and his team
found that acetylation, another chemical process that modifies amino
acids, plays a central role in activating interferon receptors.
Interferons play a crucial role in the body�s defense against
infection and uncontrolled cell growth. Type 1 interferon is widely
used to treat hepatitis B and C and cancers such as melanoma and
leukemia.
�This is a major discovery in the field of signal transduction,� Chin
said. �Tyrosine phosphorylation has so far been considered the major
player in signal transduction. But what we discovered challenges this
concept. We found another player � acetylation � in the process.�
In their experiments, Chin and his team looked at how cells respond to
type 1 interferon, a protein produced in response to a viral infection
or other immune trigger. The researchers found that type 1 interferon
receptors, which are found in every cell in the body, call up
cytoplasmic CREB-binding protein, or CBP, to move up to the cell
surface. CPB acetylates these receptors. That, in turn, sparks a
biochemical cascade that attracts more proteins to create a complex
called ISGF3. To activate this protein complex, Chin found,
acetylation is required. Once that occurs, the complex travels to the
cell nucleus to switch on anti-viral or tumor-suppressing genes.
The discovery of the acetylation of cytokine receptors marks a
milestone in the study of signal transduction, the process of how
cells receive and respond to chemical messages.
Many diseases, such as diabetes, cancer and heart disease, occur when
signal transduction goes awry. That is why some drugs either inhibit
or amplify signaling inside cells by targeting tyrosine
phosphorylation. By showing that another chemical process is critical
to signal transduction, Chin�s findings may explain why some
anti-cancer or anti-viral drugs do not work for everyone. The findings
provide an important new target for therapies that fight cancer and
viral infectious diseases.
The Brown research team also included Xiaoli Tang, Jin-Song Gao, and
Ying-jie Guan, all post-doctoral research associates in Chin�s Rhode
Island Hospital laboratory. Bharat Ramratnam, associate professor of
medicine at Brown, also assisted with the research along with Katya
McLane, a scientist with Upstate/Chemicon International Inc.
The National Cancer Institute funded the work.
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