Oncogene：p53亚型刺激血管生成和肿瘤发展

p53是一种肿瘤抑制基因（gene）。在所有恶性肿瘤中，50%以上会出现该基因的突变。由这种基因编码的蛋白质（protein）是一种转录（transcription）因子，其控制着细胞周期的启动。该基因编码一种分子量为53kDa的蛋白质，p53基因的失活对肿瘤形成起重要作用。

肿瘤抑制基因p53参与DNA修复、细胞周期阻滞和凋亡，也参与抑制血管的形成过程，血管生成对促进肿瘤的发展非常有帮助。p53基因表达12种不同的蛋白质（亚型），包括TAp53（P53或p53α）、p53β和p53γ）和Δ133p53亚型（Δ133p53α、Δ133p53β和Δ133p53γ）。

近来研究证实Δ133p53α亚型调节p53的转录活性，在多种人类肿瘤类型中都过度表达。然而，Δ133p53α在肿瘤进展中的作用还在不断探索中。最新刊登在Oncogene杂志上的一项研究着重探讨分析了Δ133p53对人脑胶质瘤U87的血管生成和肿瘤生长的作用。

研究人员收集去除Δ133p53后U87细胞的培养液，用培养液去孵育内皮细胞，结果发现该培养液不影响血管内皮细胞在体外的增殖情况，但能抑制内皮细胞的迁移和血管腔形成。去除Δ133p53后U2OS骨肉瘤细胞的培养液也导致类似的血管生成抑制功效。

此外，在异位表达Δ133p53亚型U87的培养基中，研究人员证实了Δ133p53α和Δ133p53γ能刺激血管生成，但Δ133p53β不具备刺激血管生成的功效。使用U87胶质母细胞瘤肿瘤鸡绒毛尿囊膜血管生成模型和小鼠移植瘤模型证实去除Δ133p53亚型的U87肿瘤细胞，其血管生成和体内生长都明显受到抑制。

doi:10.1038/onc.2012.242
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The p53 isoform, Δ133p53α, stimulates angiogenesis and tumour progression

H Bernard, B Garmy-Susini, N Ainaoui, L Van Den Berghe, A Peurichard, S Javerzat, A Bikfalvi, D P Lane, J C Bourdon, and A-C Prats

The tumour suppressor p53, involved in DNA repair, cell cycle arrest and apoptosis, also inhibits blood vessel formation, that is, angiogenesis, a process strongly contributing to tumour development. The p53 gene expresses 12 different proteins (isoforms), including TAp53 (p53 (or p53α), p53β and p53γ) and Δ133p53 isoforms (Δ133p53α, Δ133p53β and Δ133p53γ). The Δ133p53α isoform was shown to modulate p53 transcriptional activity and is overexpressed in various human tumours. However, its role in tumour progression is still unexplored. In the present study, we examined the involvement of Δ133p53 isoforms in tumoural angiogenesis and tumour growth in the highly angiogenic human glioblastoma U87. Our data show that conditioned media from U87 cells depleted for Δ133p53 isoforms block endothelial cell migration and tubulogenesis without affecting endothelial cell proliferation in vitro. The Δ133p53 depletion in U2OS osteosarcoma cells resulted in a similar angiogenesis blockade. Furthermore, using conditioned media from U87 cells ectopically expressing each Δ133p53 isoform, we determined that Δ133p53α and Δ133p53γ but not Δ133p53β, stimulate angiogenesis. Our in vivo data using the chicken chorio-allantoic membrane and mice xenografts establish that angiogenesis and growth of glioblastoma U87 tumours are inhibited upon depletion of Δ133p53 isoforms. By TaqMan low-density array, we show that alteration of expression ratio of Δ133p53 and TAp53 isoforms differentially regulates angiogenic gene expression with Δ133p53 isoforms inducing pro-angiogenic gene expression and repressing anti-angiogenic gene expression.