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The cell death gene BNIP3 is mutated in astrocytic tumors
Teralee Burton, Priti Baijal, Shunzhen Zhang, Elizabeth
Henson, Spencer B. Gibson, David D. Eisenstat
Manitoba Institute of Cell
Biology, Winnipeg, MB, Canada and CancerCare Manitoba, Winnipeg, MB, Canada.
E-mail: teraleeb@hotmail.com
The BCL2-Nineteen Kilodalton Interacting protein, BNIP3, is a Bcl-2 family
member that is up-regulated in hypoxic regions in
many solid tumors.
BNIP3 is activated by the transcription factor HIF-1α.
BNIP3 mediates cell death in a caspase-independent manner through its
interaction with the mitochondria.
This is facilitated by binding of BNIP3
to the mitochondrial membrane through its transmembrane (TM) domain.
Astrocytic
tumors are the most commonly diagnosed brain tumor in children and adults.
Glioblastoma multiforme (GBM, WHO grade IV) represents the most malignant form
of astrocytoma with a time to progression of 12 weeks without therapeutic
intervention and 12-15 months survival with combined modality therapy, including
surgery, radiation and chemotherapy.
Response to therapy fails, in part, due to
tumor hypoxia facilitating resistance to radiation and chemotherapy.
In this
study we have determined that BNIP3 is up-regulated in glioblastoma multiforme
compared to normal brain and is expressed in malignant astrocytes.
This
increased expression in GBM correlates with increased expression of
HIF-1α that is an indicator for hypoxic regions in tumors.
In glioma cell
lines, BNIP3 expression is increased under hypoxic conditions over a 72 hour
time course.
In 33% of primary (or de novo) GBM we have detected
mutations in the PEST and conserved (CD) domains of BNIP3 that predict a
truncated protein without a functional TM domain.
These cDNA mutations have been
confirmed by SSCP analysis or by allele-specific PCR and DNA sequencing.
Over-expression of BNIP3 into malignant glioma cells induces cell death, whereas
treatment of these cells with antisense constructs against BNIP3, expression of
a dominant negative form of BNIP3 or expression of mutant (PEST or CD domain)
BNIP3 block hypoxia-induced cell death.
This blockage of cell death is due to
failure to localize with mitochondria and inhibition of BNIP3-mediated
mitochondrial dysfunction, such as changes in membrane potential.
Our results
suggest that BNIP3 acts as a tumor suppressor and selective pressure within the
tumor generates BNIP3 mutations providing a survival advantage.
This could
explain why treatments for malignant gliomas are often ineffective in hypoxic
regions of these tumors.
Copyright © 2004 American Association for Cancer Research. All rights
reserved.
Source: http://aacr04.agora.com/planner/displayabstract.asp?presentationid=1780
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