Identification of vitamin D receptor as a target of p63
Identification of vitamin D receptor as a target of p63
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DOI：
10.1038/sj.onc.1209412
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发表时间：
2006-06-22
期刊：
影响因子：
8
通讯作者：
Kadakia, M. P.
中科院分区：
文献类型：
--
作者：
Kommagani, R.;Caserta, T. M.;Kadakia, M. P.
p53的同系物P63已被证明在发育和癌症中发挥作用。P63对于外胚层向层状上皮的转化以及上皮干细胞的增殖潜能都是至关重要的。P63基因敲除小鼠出生时具有严重的发育缺陷和缺乏上皮来源的器官。此外，p63还通过对肿瘤抑制基因和转移相关基因的差异调控，在癌症发展中发挥作用。为了了解p63在癌症和发展中的作用，鉴定了由p63而不是p53特异性调节的基因。在本研究中，我们提供了p63 γ特异性上调维生素D受体（VDR）的证据。相反，p53似乎不参与VDR表达的上调。此外，我们证明了自然存在的p63错义突变体p63c （R279H）和p14（ARF）都以显性负向方式抑制p63 γ介导的VDR上调。此外，通过染色质免疫沉淀实验，我们证明了p63在体内直接与VDR启动子结合。我们的研究结果清楚地表明，VDR是p63的直接靶点，并表明p63可能通过调节VDR途径在癌症和分化中发挥作用。
p63, a p53 homolog has been shown to play a role in development and cancer. p63 is essential for both commitment of ectoderm to stratified epithelia and for the proliferative potential of epithelial stem cells. p63 knockout mice are born with severe development defects and lack organs of epithelial origin. In addition, p63 has also been shown to play a role in cancer development through the differential regulation of genes with tumor suppressor function and genes involved in metastasis. In order to understand the role of p63 in cancer and development, genes that are specifically regulated by p63 but not p53 were identified. In this study, we provide evidence that p63 gamma specifically upregulates vitamin D Receptor ( VDR). In contrast, p53 does not appear to be involved in upregulation of VDR expression. Additionally, we demonstrate that a naturally occurring p63 missense mutant, p63c ( R279H) and p14(ARF), both act in a dominant negative manner to inhibit p63 gamma-mediated upregulation of VDR. Furthermore, using chromatin immunoprecipitation assays, we demonstrated that p63 directly binds to the VDR promoter in vivo. Our findings clearly demonstrate that VDR is a direct target of p63 and suggests that p63 may play a role in cancer and differentiation through modulation of the VDR pathway.