Heterozygosity for Hypoxia Inducible Factor 1α Decreases the Incidence of Thymic Lymphomas in a p53 Mutant Mouse Model
Heterozygosity for Hypoxia Inducible Factor 1α Decreases the Incidence of Thymic Lymphomas in a p53 Mutant Mouse Model
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DOI：
10.1158/0008-5472.can-08-4223
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发表时间：
2009-04-01
期刊：
影响因子：
11.2
通讯作者：
Simon, M. Celeste
中科院分区：
文献类型：
--
作者：
Bertout, Jessica A.;Patel, Shetal A.;Simon, M. Celeste
缺氧诱导因子（hypoxia inducible factors，HIF）是细胞对氧分压降低的反应的重要介质，在许多肿瘤中过度表达。尽管HIF 1 α和HIF 2 α具有高度的序列同源性，但最近的研究表明，这两种α亚基对肿瘤生长具有对比性和组织特异性作用。为了直接比较每个HIF α亚基在自发性肿瘤发生中的作用，我们将HIF 2 α表达扩增的小鼠模型和HIF 1 α（+/-）小鼠培育为p53中R270 H突变的纯合子。在这里，我们报告说，p53（R270 H/R270 H）小鼠，这是以前没有描述过的，发展一个独特的肿瘤谱相对于p53（p270 H/-）小鼠，包括胸腺淋巴瘤的高发病率。Hif 1 α的杂合性显著降低了在该模型中观察到的胸腺淋巴瘤的发病率。此外，HIF 1 α水平降低与活化的Notch 1稳定性降低以及Notch靶基因Dtx 1和Nrarp表达降低相关。这些观察结果揭示了HIF 1 α在T细胞淋巴瘤发生过程中Notch通路活化中的新作用。[Cancer Res 2009;69（7）：3213-20]
Hypoxia inducible factors (HIF) are critical mediators of the cellular response to decreased oxygen tension and arc over-expressed in a number of tumors. Although HIF1 alpha and HIF2 alpha 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 HIF alpha subunit in spontaneous tumorigenesis, we bred a mouse model of expanded HIF2 alpha expression and Hif1 alpha(+/-) 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(p270H/-) mice, including a high incidence of thymic lymphomas. Heterozygosity for Hif1 alpha significantly reduced the incidence of thymic lymphomas observed in this model. Moreover, reduced Hif1 alpha 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 HIF1 alpha in Notch pathway activation during T-cell lymphomagenesis. [Cancer Res 2009;69(7):3213-20]