TY - JOUR
T1 - The expression of p53-target genes in the hypoxia-tolerant subterranean mole-rat is hypoxia-dependent and similar to expression patterns in solid tumors
AU - Band, Mark
AU - Ashur-Fabian, Osnat
AU - Avivi, Aaron
N1 - Funding Information:
This study was supported by the US-Israel Binational Science Foundation (BSF) Grant No. 2005346 to A.A. and M.B. We wish to thank Ms. Alma Joel for her dedicated technical assistance.
PY - 2010/8/15
Y1 - 2010/8/15
N2 - The tumor suppressor gene, p53, in response to DNA damage/hypoxia, induces growth arrest and/or apoptosis. Inactivation of p53, by mutations and/or overexpression of the mdm2 gene, confers a selective advantage to tumor cells under hypoxic microenvironment during tumor progression. The mole rat, Spalax, spends its life underground at low-oxygen tensions and hence has developed a wide range of respiratory/molecular adaptations to hypoxic stress. We previously reported that the highly conserved p53 Arg(R)-174 is substituted by lysine (K) in Spalax, identical to a tumor-associated mutation. Functionality assays revealed that Spalax p53 and human R174K-mutated p53 were unable to induce human/Spalax apaf1, an apoptotic target gene, while over-activating the mdm2 gene. Moreover, cells transfected with human p53 underwent more extensive apoptosis (44.8%) as compared to Spalax p53 (23.2%) transfected cells. To support our hypothesis that the pattern of activity in Spalax is related to hypoxia tolerance, we quantified apaf1 and mdm2 mRNA levels under normoxia (21% O2), short-acute hypoxic stress (5 h at 6% O2) and long-mild hypoxic insult (44 h at 10% O2). Results were compared to those of rats under similar conditions. Following hypoxia, Spalax apaf1 mRNA levels decreased significantly, but increased in rats. apip mRNA levels, a negative regulator of apaf1, increased in Spalax and decreased in rats. mdm2 mRNA levels under hypoxia were significantly higher in Spalax. We conclude that, similar to our previous in-vitro work, two parallel hypoxia-adaptive mechanisms evolved in Spalax: mutated p53 and p53 response element leading to a bias against apoptosis and increased mdm2, which are analogous to observations in tumor development.
AB - The tumor suppressor gene, p53, in response to DNA damage/hypoxia, induces growth arrest and/or apoptosis. Inactivation of p53, by mutations and/or overexpression of the mdm2 gene, confers a selective advantage to tumor cells under hypoxic microenvironment during tumor progression. The mole rat, Spalax, spends its life underground at low-oxygen tensions and hence has developed a wide range of respiratory/molecular adaptations to hypoxic stress. We previously reported that the highly conserved p53 Arg(R)-174 is substituted by lysine (K) in Spalax, identical to a tumor-associated mutation. Functionality assays revealed that Spalax p53 and human R174K-mutated p53 were unable to induce human/Spalax apaf1, an apoptotic target gene, while over-activating the mdm2 gene. Moreover, cells transfected with human p53 underwent more extensive apoptosis (44.8%) as compared to Spalax p53 (23.2%) transfected cells. To support our hypothesis that the pattern of activity in Spalax is related to hypoxia tolerance, we quantified apaf1 and mdm2 mRNA levels under normoxia (21% O2), short-acute hypoxic stress (5 h at 6% O2) and long-mild hypoxic insult (44 h at 10% O2). Results were compared to those of rats under similar conditions. Following hypoxia, Spalax apaf1 mRNA levels decreased significantly, but increased in rats. apip mRNA levels, a negative regulator of apaf1, increased in Spalax and decreased in rats. mdm2 mRNA levels under hypoxia were significantly higher in Spalax. We conclude that, similar to our previous in-vitro work, two parallel hypoxia-adaptive mechanisms evolved in Spalax: mutated p53 and p53 response element leading to a bias against apoptosis and increased mdm2, which are analogous to observations in tumor development.
KW - Cancer
KW - Hypoxia
KW - Subterranean mole rat
KW - p53-targeted genes
UR - http://www.scopus.com/inward/record.url?scp=77955744209&partnerID=8YFLogxK
U2 - 10.4161/cc.9.16.12712
DO - 10.4161/cc.9.16.12712
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C2 - 20703075
AN - SCOPUS:77955744209
SN - 1538-4101
VL - 9
SP - 3367
EP - 3372
JO - Cell Cycle
JF - Cell Cycle
IS - 16
ER -