pVHL and PTEN tumour suppressor proteins cooperatively suppress kidney cyst formation
pVHL and PTEN tumour suppressor proteins cooperatively suppress kidney cyst formation
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DOI：
10.1038/emboj.2008.96
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发表时间：
2008-06-18
期刊：
影响因子：
11.4
通讯作者：
Krek, Wilhelm
中科院分区：
文献类型：
--
作者：
Frew, Ian J.;Thoma, Claudio R.;Krek, Wilhelm
在冯希佩尔-林道（VHL）病患者中，肾囊肿和透明细胞肾细胞癌（ccRCC）起源于肾小管上皮细胞，其中含有VHL肿瘤抑制基因的双等位基因失活。然而，据推测，肾囊肿的形成及其向ccRCC的转化涉及其他位点的额外遗传变化。在这里，我们发现VHL患者肾脏的囊性病变也显示了磷脂酰肌醇-3激酶（PI3K）途径的激活。引人注目的是，在小鼠肾脏中，Vhlh和Pten肿瘤抑制基因（通常会拮抗PI3K信号）的条件失活联合在短潜伏期后引发囊肿形成，而单独失活任何一种肿瘤抑制基因都不能产生这种表型。有趣的是，内衬这些囊肿的细胞通常缺乏初级纤毛，这是一种基于微管的细胞天线，对抑制不受控制的肾上皮细胞增殖和囊肿形成很重要。我们的研究结果支持PTEN肿瘤抑制蛋白与pVHL合作抑制肾脏囊肿发展的模型。
In patients with von Hippel-Lindau (VHL) disease, renal cysts and clear cell renal cell carcinoma (ccRCC) arise from renal tubular epithelial cells containing biallelic inactivation of the VHL tumour suppressor gene. However, it is presumed that formation of renal cysts and their conversion to ccRCC involve additional genetic changes at other loci. Here, we show that cystic lesions in the kidneys of patients with VHL disease also demonstrate activation of the phosphatidylinositol-3-kinase (PI3K) pathway. Strikingly, combined conditional inactivation of Vhlh and the Pten tumour suppressor gene, which normally antagonises PI3K signalling, in the mouse kidney, elicits cyst formation after short latency, whereas inactivation of either tumour suppressor gene alone failed to produce such a phenotype. Interestingly, cells lining these cysts frequently lack a primary cilium, a microtubule-based cellular antenna important for suppression of uncontrolled kidney epithelial cell proliferation and cyst formation. Our results support a model in which the PTEN tumour suppressor protein cooperates with pVHL to suppress cyst development in the kidney.