Heterozygosity for hypoxia inducible factor 1alpha decreases the incidence of thymic lymphomas in a p53 mutant mouse model.
Hypoxia inducible factors (HIF) are critical mediators of the cellular response to decreased oxygen tension and are overexpressed in a number of tumors. Although HIF1alpha and HIF2alpha share a high degree of sequence homology, recent work has shown that the two alpha subunits can have contrasting and tissue-specific effects on tumor growth. To directly compare the role of each HIFalpha subunit in spontaneous tumorigenesis, we bred a mouse model of expanded HIF2alpha expression and Hif1alpha(+/-) mice to homozygotes for the R270H mutation in p53. Here, we report that p53(R270H/R270H) mice, which have not been previously described, develop a unique tumor spectrum relative to p53(R270H/-) mice, including a high incidence of thymic lymphomas. Heterozygosity for Hif1alpha significantly reduced the incidence of thymic lymphomas observed in this model. Moreover, reduced Hif1alpha levels correlated with decreased stabilization of activated Notch1 and expression of the Notch target genes, Dtx1 and Nrarp. These observations uncover a novel role for HIF1alpha in Notch pathway activation during T-cell lymphomagenesis.
Bertout
Jessica A
JA
Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Patel
Shetal A
SA
Fryer
Benjamin H
BH
Durham
Amy C
AC
Covello
Kelly L
KL
Olive
Kenneth P
KP
Goldschmidt
Michael H
MH
Simon
M Celeste
MC
D000367:Age Factors; D000483:Alleles; D000818:Animals; D005260:Female; D016158:Genes, p53; D006579:Heterozygote; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D008223:Lymphoma / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D051881:Receptor, Notch1 / Q000096:biosynthesis / Q000235:genetics; D013953:Thymus Neoplasms / Q000235:genetics* / Q000378:metabolism
C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1