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 | | From: | Kofi | | Subject: | beta-arrestin2 and hedgehog | | Date: | Sun, 23 Jan 2005 13:13:05 GMT |
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 | http://www.sciencedaily.com/releases/2005/01/050111174304.htm
Source:
Duke University Medical Center
Date:
2005-01-12
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Fundamental Finding Yields Insight Into Stem Cells, Cancer; Opens Door
To Drug Discovery
DURHAM, N.C. New research by investigators at Duke University Medical
Center has provided insight into a fundamental cellular control
mechanism that governs tissue regeneration, stem cell renewal and cancer
growth. In humans, malfunctions in the pathway have been implicated in
skin and brain cancers, as well as certain developmental defects,
according to the researchers.
The team found that the protein beta-arrestin2, earlier linked to a
variety of inhibitory functions, also plays a critical role in
activating the so-called hedgehog (Hh) signaling pathway, which plays a
central role in early development and normal cell proliferation. When
left unchecked, uncontrolled cell growth spurred by the hedgehog pathway
can lead to the development of cancerous tumors.
The researchers report their findings in the Dec. 24, 2004, issue of
Science. The work was funded by the National Institutes of Health.
"Studies have found a wide breadth of functions for beta-arrestins, but
none had revealed a role for these proteins in development," said James
B. Duke Professor Marc Caron, Ph.D., a researcher in the department of
cell biology, the Duke Institute for Genome Sciences and Policy and
senior author of the study. "The involvement of beta-arrestin2 in the
hedgehog signaling pathway provides a previously unappreciated paradigm
for its role in promoting growth, differentiation, and malignancies."
The finding in zebrafish could lead to new drugs that block the growth
of tumors by disrupting the beta-arrestin2 protein's normal function,
the researchers said. In other cases, drugs that activate beta-arrestin2
might also drive the proliferation of therapeutic stem cells, they added.
Hh proteins play a central role in cell proliferation and embryonic
patterning. In humans, inhibitory mutations in the pathway result in
developmental defects such as holoprosencephaly an often fatal
condition characterized by abnormal brain development and facial
deformities. In contrast, mutations that spur overactivity of the
pathway lead to basal cell carcinoma, the most common form of skin
cancer, and medulloblastoma, an aggressive form of brain cancer. About
one in five childhood brain tumors are medulloblastomas.
In their experiments, the researchers injected zebrafish embryos with a
chemical that specifically blocked the function of beta-arrestin2.
Humans and zebrafish, both vertebrates, share fundamental developmental
pathways, the researchers said. Zebrafish embryos are an ideal model for
study because their transparent embryos allow researchers to easily
observe their early development.
The injected embryos, which almost completely lacked the beta-arrestin2
protein, exhibited characteristics earlier linked to defects in the Hh
signaling pathway, including curved bodies, underdeveloped heads and
abnormal muscle development, the researchers reported. Furthermore,
injected embryos exhibited reduced activity of other genes that respond
to Hh activity compared to normal embryos, suggesting that loss of
beta-arrestin2 blocked their activity, the researchers found. Injection
of other substances that activate the Hh pathway restored normal
development in embryos lacking beta-arrestin2.
"It appears that beta-arrestin2 is a positive force in Hh signaling in
living organisms," Caron said. "The current finding opens up new avenues
for study of normal developmental regulation and the manner in which
abnormalities in that regulation can lead to cancer. Drugs that disrupt
the function of beta-arrestin2 might also offer an alternative approach
to cancer therapy."
Another experimental system developed by the researchers -- which
includes cells with fluorescently tagged beta-arrestin2 -- might offer a
useful tool for identifying drug compounds that either disrupt or
promote the protein's activity, said Gregory Fralish, Ph.D., of Duke,
co-author of the study. Beta-arrestin2 normally concentrates at the
periphery of cells as it binds to activated receptors nestled in the
cell membrane, including a component of the Hh pathway known as
Smoothened, he explained. Quantifying changes in the amount of
fluorescent beta-arrestin2 at the cell surface in the presence of other
compounds would therefore identify those that modify Hh pathway activity
compounds of potential therapeutic use.
In a companion paper in the same issue of Science, researchers led by
Howard Hughes Medical Institute investigator and James B. Duke Professor
Robert Lefkowitz, M.D., also at Duke, demonstrated that beta-arrestin2
does indeed interact with activated Smoothened in cells. That
interaction promotes the internalization of activated Smoothened, a
finding entirely consistent with the protein's newly recognized role in
the signaling pathway, Lefkowitz said.
"The system offers the opportunity to screen for Hh pathway antagonists
that might control cancer and, alternatively, for compounds that promote
the pathway's activity a function that might be of use in stimulating
the growth of therapeutic stem cells," Fralish said.
Collaborators on the study include lead author Alyson Wilbanks, Margaret
Kirby, Larry Barak, and Yin-Xiong Li. Collaborators on the companion
study include lead author Wei Chen, Xiurong Ren, Christopher Nelson,
Larry Barak, all of Duke; James Chen and Philip Beachy of HHMI and Johns
Hopkins University and Frederic de Sauvage from Genentech of South San
Francisco.
Editor's Note: The original news release can be found here.
------------------------------------------------------------------------
This story has been adapted from a news release issued by Duke
University Medical Center.
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