Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha.
Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha.
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DOI：
10.1101/gad.14.1.34
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发表时间：
2000-01
影响因子：
10.5
通讯作者：
R. Ravi;B. Mookerjee;Z. Bhujwalla;C. H. Sutter;D. Artemov;Qinwen Zeng;L. Dillehay;A. Madan;
中科院分区：
文献类型：
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作者：
R. Ravi;B. Mookerjee;Z. Bhujwalla;C. H. Sutter;D. Artemov;Qinwen Zeng;L. Dillehay;A. Madan;
向血管生成表型的转变是肿瘤生长和肿瘤进展的基本决定因素。我们证明，在人类癌细胞系中通过同源重组纯合缺失p53肿瘤抑制基因，可促进裸鼠肿瘤异种移植物的新生血管和生长。我们发现p53促进mdm2介导的泛素化和缺氧诱导因子1 （HIF-1）的HIF-1 α亚基的蛋白酶体降解，HIF-1是一种异二聚体转录因子，在缺氧反应中调节细胞能量代谢和血管生成。肿瘤细胞中p53的缺失增强了hif -1 α水平，并增强了hif -1依赖性的血管内皮生长因子（VEGF）基因的转录激活，以应对缺氧。在表达p53的肿瘤细胞中强迫表达hif -1 α可增加缺氧诱导的VEGF表达，增强肿瘤异种移植物的新生血管和生长。这些结果表明，通过p53功能的丧失，hif -1对缺氧的正常依赖性反应的扩增有助于肿瘤发生过程中的血管生成开关。
The switch to an angiogenic phenotype is a fundamental determinant of neoplastic growth and tumor progression. We demonstrate that homozygous deletion of the p53 tumor suppressor gene via homologous recombination in a human cancer cell line promotes the neovascularization and growth of tumor xenografts in nude mice. We find that p53 promotes Mdm2-mediated ubiquitination and proteasomal degradation of the HIF-1alpha subunit of hypoxia-inducible factor 1 (HIF-1), a heterodimeric transcription factor that regulates cellular energy metabolism and angiogenesis in response to oxygen deprivation. Loss of p53 in tumor cells enhances HIF-1alpha levels and augments HIF-1-dependent transcriptional activation of the vascular endothelial growth factor (VEGF) gene in response to hypoxia. Forced expression of HIF-1alpha in p53-expressing tumor cells increases hypoxia-induced VEGF expression and augments neovascularization and growth of tumor xenografts. These results indicate that amplification of normal HIF-1-dependent responses to hypoxia via loss of p53 function contributes to the angiogenic switch during tumorigenesis.