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Iron Deficiency Sparks Dramatic Changes In Gene Expression

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Duke Health News 919-660-1306

DURHAM, N.C. -- Researchers at Duke University Medical Center have
demonstrated for the first time what happens inside a cell when it is
deprived of the essential nutrient iron. Iron is found abundantly in
red meats, shellfish dried fruits, whole grains, spinach, seeds and
other foods.

Their study in yeast cells demonstrated that
iron-starved cells preserve the little iron they possess by shutting
down the major iron users in order to maintain the cell's essential
functions, said Dennis J. Thiele, Ph.D., professor of Pharmacology and
Cancer Biology at Duke. He said their discovery could aid in the
diagnosis and ultimately the treatment of serious disorders caused by
low iron levels.

Results of his study, funded by the National
Institutes of Health, are published in the Jan. 14, 2005, issue of the
journal Cell.

Iron deficiency is the most prevalent and severe
nutritional disorder world wide, affecting more than 2 billion people.
The most widely recognized symptom is anemia, in which too few red
blood cells are produced, and the body is deprived of oxygen needed for
energy metabolism. Iron deficiency causes wide-ranging symptoms from
fatigue, weakness and cognitive deficits to serious heart complications
and developmental disorders. Iron deficiency also contributes to the
pathology of hereditary blood disorders, Parkinson's disease and
certain cancers and develops during a number of chronic diseases, the
researchers said.

Until now, however, a cell's response to iron
deprivation was poorly understood. In the Duke study, Thiele and his
Duke colleagues at the Sarah W. Stedman Nutrition and Metabolism Center
demonstrated that the activity of more than 80 different genes was
dramatically reduced in response to iron deprivation. The function of
many of these genes is unknown, meaning that side effects from iron
deprivation may go unattributed to their root cause. Other genes
affected by iron starvation are known to be vital in generating energy,
copying the cell's genetic code and protecting the cell from free
radicals and aging, said Thiele.

"We discovered that iron
deprivation actually reprograms the metabolism of the entire cell,"
said Thiele. "Literally hundreds of proteins require iron to carry out
their proper function, so without this nutrient, there is a complete
reorganization of how cellular processes occur."

The cellular
player responsible for the metabolic reprogramming is a protein called
Cth2. Thiele's team found that iron-deprived cells overproduce Cth2.
This protein binds to the gene expression machinery of more than 80
different genes and targets these molecules, called messenger RNA, to
be destroyed or degraded. Without messenger RNA, a gene cannot
translate its genetic code into proteins that carry out its intended
functions.

Thiele said the same scenario may occur in human
cells, as well, to an even greater degree. His study was conducted in
yeast cells because their genome is remarkably similar to that of a
human cell. In fact, the Cth2 protein in yeast is quite similar to a
family of three proteins in humans. When the human proteins are
substituted in place of Cth2 in yeast, they actually assume its
function in yeast cells, said Thiele.

"Yeast cells illuminate for
us what to look for in human cells," said Thiele. "Current diagnostic
markers for iron deficiency aren't very sensitive, unless the
deficiency is severe. Pinpointing the genes affected by iron
deprivation should provide us with a genetic fingerprint of what
patients with varying levels of iron deprivation look like."

A
patient's blood could easily be tested for specific diagnostic markers
that would indicate his level of iron deprivation, he said. With
diagnostic markers in place, physicians could translate the severity of
the disease into the appropriate treatment.

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