(Philadelphia, PA) - Researchers at the University
of Pennsylvania School of Medicine have identified a second
molecular pathway that promotes cell survival in low-oxygen conditions.
By teasing apart the details of cellular adaptation during oxygen
deprivation, or hypoxia, the researchers hope to gain a better understanding
of the abnormal hypoxic environments that are characteristic of
many diseases, including solid-tumor cancers and stroke.
Oxygen sensing, the ability of a cell to gauge the oxygen concentrations
in its environment and to protect itself through internal regulation,
is a fundamental process in most species of animals that depend
entirely on oxygen to maintain cellular function. There are multiple,
oxygen-dependent pathways in the cell that are regulated by changes
in oxygen levels.
starving human cells of oxygen, Celeste Simon, PhD,
Professor of Cell and Developmental Biology at Penn and a Howard
Hughes Medical Institute (HHMI) Investigator, and colleagues discovered
an oxygen-sensitive cellular pathway that leads to a decrease in
protein synthesis. This finding is the second hypoxic cellular pathway
to be identified by this research team. Simon, who is also a member
of Penn’s Abramson Cancer Center, and colleagues
report their most recent findings in the February issue of Molecular
In order to promote cellular adaptations to hypoxia, the cell must
first recognize the presence of a low-oxygen environment. Previous
genetic studies from Simon’s laboratory helped to establish
that the mitochondria-the energy center of the cell-play a major
role in oxygen sensing. Like an alarm, mitochondria alert the cells
when oxygen levels fall too low, resulting in hypoxic cells activating
a protein called hypoxia-inducible factor (HIF). HIF, in turn, signals
for physiological changes in nearby tissue that serve to protect
oxygen-deprived cells. These changes include an increase in the
number of red blood cells and blood vessels, the dilation of vessels,
and changes in cell motility.
“These physiological changes make biological sense,”
explains Simon. “The changes allow the affected cell, or tissue,
to withstand the stress of low oxygen. Changes in the blood cells
and vasculature enhance the ability of the blood stream to carry
oxygen to the effected regions.”
In their most recent studies, Simon’s group revealed the ability
of cells to adapt to low-oxygen concentrations through a second
molecular pathway. In order to protect itself during hypoxic conditions,
a cell will conserve energy by greatly reducing protein synthesis.
By exposing human cells to low-oxygen conditions, the researchers
observed the inactivation of mTOR, a central regulator of global
protein synthesis. Further genetic testing revealed that the mTOR
pathway operates independent of the HIF pathway.
Though paradoxical, Simon’s findings suggest that the HIF
pathway leads to the activation and translation of nearly 200 target
genes essential to the cell’s protective physiological changes,
while the second and most recently discovered pathway-the mTOR pathway-inhibits
protein synthesis. “The cell needs to take what energy it
has to redirect to the molecular response that results in the necessary
physiological changes,” Simon suggests.
“There is something about the messenger RNAs present in the
HIF pathway that allows them to escape inhibition of global protein
synthesis,” Simon notes. She believes that the directions
for these mRNAs to move forward and make protein, while many are
left behind, lies in the genetic makeup of mRNA. Her lab is currently
working to identify these molecular directions.
Although hypoxic conditions exist throughout early embryonic development,
the presence of hypoxic environments in adult tissue is often a
response to disease. As Simon explains, “A lot of the major
Western world scourges involve a decrease in oxygen availability
that falls below the threshold that cells need to remain healthy
and carry out their functions.” Hypoxia is a prominent component
of solid tumors, myocardial infarctions, stroke, diabetic retinopathy,
inflammation, and atherosclerosis.
In addition to hypoxia, solid cancer tumors are comprised of abnormal
cells and convoluted blood vessels, which allow the tumors to resist
chemotherapy and radiation treatments. New treatments for cancer
are now aiming to turn off HIF and mTOR activity, halting the ability
of the cell to signal its low-oxygen alert system and undergo protein
“If we are able to create a treatment for tumors by inactivating
the factor that is promoting cell survival and tumor cell motility
- a key regulator of tumor metastasis - we may have another option
to treat solid tumors,” notes Simon.
Study co-authors are Liping Liu, Timothy P. Cash, Russell G. Jones,
Brian Keith and Craig B. Thompson, all from the Abramson Family
Cancer Research Institute (AFCRI). The research was funded by the
National Institutes of Health, HHMI, and AFCRI.
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