Abstract:
: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.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Bertout JA,Patel SA,Fryer BH,Durham AC,Covello KL,Olive KP,Goldschmidt MH,Simon MCdoi
10.1158/0008-5472.CAN-08-4223subject
Has Abstractpub_date
2009-04-01 00:00:00pages
3213-20issue
7eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-08-4223journal_volume
69pub_type
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