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Berkeley Lab cell biologist
Kunxin Luo leads a research team that is investigating the reasons
why a normal epithelial cell turns cancerous. |
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A protein long known to play a vital role in the process by which a living
cell divides into two new "daughter" cells has now been shown
to also play an important role in cancer. Researchers with Lawrence Berkeley
National Laboratory (Berkeley Lab) have shown that the anaphase-promoting
complex (APC) of proteins that breaks apart the connections between daughter
cells during cell division also breaks apart a protein complex within
the cell nucleus that is important for maintaining normal cell growth.
"Until now, the only role known for APC is that it unglues the chromatids,
or chromosome strands, to allow the separation of two daughter cells during
mitosis," says Kunxin Luo, a cell biologist with Berkeley Lab's Life
Sciences Division, who led this research. "Our studies reveal a novel
role for APC in the regulation of TGF-beta signaling as well."
TGF-beta, which stands for transforming growth factor-beta, is an extracellular
protein responsible for controlling the growth and differentiation of
epithelial cellsthe cells that line the skin, kidney, glands, lungs,
gastrointestinal tract, bladder, and blood vessels.
The TGF-beta signal activates genes that, among other things, instruct
an epithelial cell to stop growing. If something goes awry, causing the
TGF-beta signal to be blocked, cell growth can continue unchecked, giving
rise to cancerous tumors. Nearly 90 percent of all human cancers involve
epithelial cells.
Luo, who holds a joint appointment as an assistant adjunct professor
with the University of California at Berkeley (UCB), led a previous study
a year ago which reported that the TGF-beta signal can be blocked by "Ski"
and "Sno," two closely-related proteins, long-suspected of being
major contributors to the development of a number of cancers. Luo's research
group demonstrated that the Ski and Sno oncoproteins interact with a family
of tumor-suppressing proteins called "Smad" to regulate the
TGF-beta signal.
"Our work suggested that cancer development is a delicate balancing
act in which the balance gets tipped the wrong way," Luo said at
the time. To this protein balancing act, she and her colleagues have now
added APCand in the process have uncovered new evidence that the
signals regulating vital cell processes arise from a highly sophisticated
network of interacting proteins.
"We've now shown that APC is a key component in the Smad-induced
degradation of Sno protein," Luo says, "and this mechanism can
help provide insights into what causes a normal cell to become cancerous."
![](assets/images/2002/Mar-31-2002/sno-ski.jpg) |
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To send a message to a cell's DNA, TGF-beta proteins dock with
receptors in the cell's outer membrane, triggering the release of
a chemical signal that is picked up by Smad proteins in the cytoplasm
and transported into the nucleus. The TGF-beta message can be blocked
by abnormally high levels of Sno or Ski proteins, a problem that
can result in the cell becoming cancerous.
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TGF-beta proteins cannot themselves enter a living cell and must therefore
transmit their signals by attaching themselves to receptor proteins on
a cell's outer surface. The signal generated by this interaction is then
ferried across the cell membrane, through the cytoplasm, and into the
nucleus via Smad proteins. Luo and her colleagues had previously shown
that a normal level of Sno inside the nucleus blunts TGF-beta signals,
but as the number of Smad proteins increases, the level of Sno degrades
until it is low enough for the signals to take effect. With the results
of this latest study, they now understand the mechanism by which the degradation
of SnoN, the most predominant form of the Sno protein, takes place.
"When the Smad proteins enter the nucleus they pick up APC proteins
and bring them along to chop up the SnoN," explains Luo. "The
SnoN contains a region called a destruction box that the APC targets.
This is a similar molecular motif to what the APC targets in cyclins and
other cell cycle-regulated proteins."
![](assets/images/2002/Mar-31-2002/SMAD-APC.jpg) |
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Smad proteins must get
past SnoN (the most common Sno protein) to deliver the TGF-beta message
to a cell's DNA. To do this, Smad proteins enlist the services of
APC proteins, which break down the SnoN by binding to it at a molecular
motif called the D Box (destruction box). CDH1 is the targeting area
of APC that recognizes the D Box motif. |
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With the levels of SnoN reduced, TGF-beta signals get through and their
target genes become activated. After about two hours, the TGF-beta signal
has resulted in a marked increase in the expression of the Sno gene, which
causes the level of SnoN to once again rise until there's enough present
to block the signal and allow cell growth to resume. The mechanism is a
negative feedback loop that must be maintained for normal growth activity.
The next step, Luo says, is to determine whether high levels of Ski and
Sno proteins alone are enough to cause a normal epithelial cell to become
cancerous. It is known that mice cannot survive long if the Ski and Sno
genes are entirely removed, so she and her colleagues have developed a
mouse that carries mutant forms of the genes, which produce proteins that
cannot block the TGF-beta signal. They anticipate results later this year.
Members of Luo's team included Shannon Stroschein, who is with Berkeley
Lab and UC Berkeley, and Shirin Bonni and Jeffrey Wrana, from the Samuel
Lunenfield Research Institute in Toronto.
Additional information:
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