The discovery of a novel cellular
"switch " in the popular laboratory research worm, C.
elegans by a University of Colorado at Boulder team may provide
researchers with a new means...
Click here for more information.
A research team led by the University of Colorado at Boulder has
discovered a previously unknown cellular "switch" that may provide
researchers with a new means of triggering programmed cell death,
findings with implications for treating cancer.
The new results are a big step forward in understanding
programmed cell death, or apoptosis, a cell suicide process that
involves a series of biochemical events leading to changes like
cell body shrinkage, mitochondria destruction and chromosome
fragmentation, said CU-Boulder Professor Ding Xue. But unlike
traumatic cell death from injury, programmed cell death is a
naturally occurring aspect of animal development that may help
prevent human diseases like cancer and autoimmune disorders, said
Xue, lead author on the new study.
In the new study, Xue and his team found that a well-known
cellular molecule called caspase – known as the "executioner
enzyme" for apoptosis because of its primary role of cutting up and
destroying cellular proteins -- has an entirely different effect on
a particular enzyme called Dicer. The team found that when caspase
cleaves Dicer, it does not kill it but instead changes its
function, causing Dicer to break up chromosomes -- pieces of coiled
DNA containing thousands of genes -- and kill the cells that house
them.
"This finding was totally unexpected," said Xue of CU-Boulder's
molecular, cellular and developmental biology department. "We
believe that by understanding this mechanism, we may be able to
develop a new way to trigger cell death in a controlled manner as a
way to treat disease."
A paper on the subject appears in the March 12 issue of
Science. Co-authors on the study included CU-Boulder
postdoctoral researchers Akihisa Nakagawa and Yong Shi and Tokyo
Women's Medical University researchers Eriko Kage-Nakadai and
Shohei Mitani.
The normal function of Dicer is to snip strands of RNA into
smaller pieces that attach to messenger RNA molecules -- which
carry DNA's genetic messages from the nucleus of cells to make
specific proteins in cell cytoplasm -- and silence their activity,
said Xue. But when caspase comes in contact with Dicer, it takes
away Dicer's ability to cleave RNA and it replaces it with the
ability to snip up and destroy DNA-laden chromosomes.
The experiments were undertaken on a common, eyelash-sized
nematode known as Caenorhabditis elegans, a popular
laboratory organism for genetic and biomedical experiments. The
study of cell death in C. elegans is providing critical
information to scientists trying to understand cell death
mechanisms in humans and identify ways to combat human diseases
caused by "inappropriate apoptosis," Xue said.
"There are many enzymes whose job it is to cut RNA, and many
unrelated enzymes whose job it is to cut DNA," said CU-Boulder MCD
Biology Department Chair Tom Blumenthal, who studies RNA processing
in C. elegans and who was not involved in the study. "But
this is the first time that anyone has shown that it is possible to
cleave an RNA-cutter enzyme and thereby convert it to a DNA-cutter
enzyme."
As part of the study, the team "knocked out" the C.
elegans gene that encodes the Dicer enzyme. The removal of the
gene compromised the apoptosis process and blocked the
fragmentation of chromosomes, said Xue.
Genetic studies of C. elegans have identified many genes
that are important for the five sequential steps of programmed cell
death, Xue said. They include the specification of which cells
should die, the activation of the cell death program, the onset of
the killing process, the engulfment of cell "corpses" and the
degradation of cellular debris, said Xue.
"Our findings initially seemed too good to be true," said Xue,
who said the team has been working on the project for five years.
"We wound up looking at the results from a number of angles,
including genetics, cell biology and biochemistry. Eventually we
reached the only logical conclusions we could make."
"This is a completely novel finding, and all of the players in
this story are well known, well studied aspects of a very important
process in our lives," said Blumenthal. "The minute I saw the
results, I knew it was a very, very important finding with wide
implications."
Since the failure of apoptosis is one of the main contributors
to the development of tumors, many biomedical researchers believe
that a better understanding of the programmed cell death process
could lead to potential therapeutic agents for those suffering from
a number of diseases caused by abnormal apoptosis, said Xue. "The
biomedical potential here is for researchers to be able turn a
pro-survival enzyme into an enzyme that is pro-death," Xue
said.
The Science study by Xue and his team was funded by the
Burroughs Wellcome Fund and the National Institutes of Health.
The researchers are now investigating whether human cells have
the mechanisms to convert the function of Dicer enzyme in the same
manner as C. elegans cells, said Xue. Nearly half of the
genes found in C. elegans are believed to have functional
counterparts in humans, he said.
C. elegans is a key organism for scientists to study for
several reasons, according to Xue. It was the first organism whose
genome was completely sequenced, and its transparency under
microscopes has allowed scientists to study many aspects of
cellular and developmental biology, as well as genetics. Nobel
prizes for C. elegans biomedical research were awarded in
2002, 2006 and 2008.
SOURCE