Study of Hypoxia and New Gene Reveals Early-Stage
Action of p53 Tumor Suppressor Gene
(Philadelphia, PA) – Researchers have known for a decade that the
p53 tumor suppressor gene is important for killing cells as they proliferate
under low-oxygen conditions inside tumors. As tumors grow they outstrip
their oxygen supply. If a cell has a normal p53 gene, the p53
protein will eliminate cancerous cells, keeping tumor growth at bay. Under
conditions of stress to the cell – such as radiation or chemotherapy
and hypoxia – p53 normally eliminates tumors.
however, induces p53 to mutate: The less oxygen, the more mutations
in the p53 gene, so cancer cells are not killed; instead, they
proliferate. A team led by Wafik El-Deiry, MD, PhD, Associate
Professor, Departments of Medicine, Genetics, and Pharmacology with the
Abramson Cancer Center of the University of Pennsylvania,
discovered a gene related to p53 called Bnip3L that
can also cause cell death. The gene is turned on by p53 and a second transcription
factor called hypoxia inducible factor, or HIF. (Click on thumbnail above
to view full-size images). The team silenced Bnip3L in cells
with normal p53 and exposed cells to low oxygen conditions. In
cell culture and in an animal model with implanted tumor cells, the researchers
showed that tumors with silenced Bnip3L grew more aggressively
in low oxygen conditions than cells and tumors with intact Bnip3L.
El-Deiry and first author Peiwen Fei, MD, PhD, a post-doctoral
fellow, report their findings in the December issue of Cancer Cell.
“From this, we predict in humans that another reason for tumor growth
is the silencing of Bnip3L,” says El-Deiry. “We think
one of the ways that p53 suppresses tumors at their earliest stages is
by turning on Bnip3L, and that’s new. There is no information
at present about how p53 works in the earliest stages of tumor growth,
especially as the growth begins to outstrip the supply of nutrients and
Understanding how cells die after they are starved for oxygen is important
for fighting cancer as well as other diseases. “Down the road we
would like to find strategies to turn Bnip3L back on to restore
the ability to die under hypoxia now that we know how it happens in the
first place,” says El-Deiry.
This work was funded by the Howard Hughes Medical Institute and by grants
from the National Institutes of Health.
The Abramson Cancer Center of the University of Pennsylvania
was established in 1973 as a center of excellence in cancer research,
patient care, education and outreach. Today, the Abramson Cancer Center
ranks as one of the nation’s best in cancer care, according to U.S.
News & World Report, and is one of the top five in National Cancer
Institute (NCI) funding. It is one of only 39 NCI-designated comprehensive
cancer centers in the United States. Home to one of the largest clinical
and research programs in the world, the Abramson Cancer Center of the
University of Pennsylvania has 275 active cancer researchers and 250 Penn
physicians involved in cancer prevention, diagnosis and treatment.
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high-quality patient care. PENN Medicine consists of the University of
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(created in 1993 as the nation’s first integrated academic health
Penn’s School of Medicine is ranked #3 in the nation for receipt
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schools. Supporting 1,400 fulltime faculty and 700 students, the School
of Medicine is recognized worldwide for its superior education and training
of the next generation of physician-scientists and leaders of academic
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