期刊
VIRCHOWS ARCHIV
卷 447, 期 3, 页码 634-642出版社
SPRINGER
DOI: 10.1007/s00428-005-1262-y
关键词
cell cycle; HIF1; renal cell carcinoma; transcription factors; VHL
类别
Renal cell carcinomas (RCCs) of the clear cell type are associated with alteration of the von Hippel-Lindau (VHL) tumour suppressor gene as well as subsequent stabilization and over-expression of hypoxia inducible factor (HIF), which causes up-regulation of cyclin D1. On the basis of their ability to interact with cyclin D1 we investigated a number of cell cycle proteins to shed further light on the downstream effects of HIF dysregulation. Expression of HIF1 alpha, cyclin D1, cyclin-dependent kinase 4 and cyclin-dependent kinase inhibitors p16, p21 and p27 was studied by immunohistochemistry. Since NF kappa B1/RelA have been shown to bind to the cyclin D1 promoter, mRNA expression of these transcription factors was further analysed by quantitative PCR. In RCCs harbouring VHL mutations/hypermethylation, over-expression of HIF1 alpha was parallelled by up-regulation of cyclin D1 and CDK4 and down-regulation of p21 and p27. Moreover, p27 expression was inversely correlated with tumour cell differentiation. Comparison of non-tumorous autologous kidney tissues revealed a significant down-regulation of NF kappa B1 mRNA expression in patients harbouring RCC with VHL mutations/hypermethylation. Our data support the notion of a link between VHL deficiency/HIF dysfunction and disturbances of cell cycle control in the tumorigenesis of VHL-negative RCC.
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