Parathyroid hormone-related protein inhibits DKK1 expression through c-Jun-mediated inhibition of β-catenin activation of the DKK1 promoter in prostate cancer.
Parathyroid hormone-related protein inhibits DKK1 expression through c-Jun-mediated inhibition of β-catenin activation of the DKK1 promoter in prostate cancer.
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作者：
前列腺癌骨转移的独特之处在于，它们中的大多数通过不明确的机制诱导过度矿化骨基质，与大多数其他癌症诱导骨吸收相反。甲状旁腺激素相关蛋白（PTHrP）由前列腺癌细胞产生，间歇性接触PTHrP具有骨合成代谢作用，表明PTHrP可能导致过度骨矿化。Wnt是前列腺癌细胞产生的骨生成因子，Wnt抑制剂DKK1已被证明可促进前列腺癌的进展。这些发现，再加上观察到PTHrP的表达随着前列腺癌的进展而增加，而DKK1的表达减少，导致PTHrP可能是前列腺癌细胞中DKK1表达的负调节因子，从而使wnt的成骨活性得以实现。为了验证这一点，我们首先证明了PTHrP下调DKK1 mRNA和蛋白的表达。然后，我们通过多个突变的DKK1启动子分析发现，PTHrP通过c-Jun激活，通过tcf反应元件位点下调DKK1启动子。此外，染色质免疫沉淀（ChIP）和reChIP分析显示，pthrp通过诱导c-Jun结合转录激活因子复合物（由β-catenin组成，结合最近的DKK1启动子tcf反应元件）介导了这种作用。总之，这些结果证明了PTHrP和Wnt信号通路之间的一种新的信号联系，这种信号联系导致Wnt抑制剂的下调，从而使Wnt活性能够促进前列腺癌的成骨性质。
Prostate cancer bone metastases are unique in that that majority of them induce excessive mineralized bone matrix, through undefined mechanisms, as opposed to most other cancers that induce bone resorption. Parathyroid hormone-related protein (PTHrP) is produced by prostate cancer cells and intermittent PTHrP exposure has bone anabolic effects suggesting PTHrP could contribute to the excess bone mineralization. Wnts are bone productive factors produced by prostate cancer cells and the Wnt inhibitor DKK1 has been shown to promote prostate cancer progression. These findings, in conjunction with the observation that PTHrP expression increases and DKK1 expression decreases as prostate cancer progresses led to the hypothesis that PTHrP could be a negative regulator of DKK1 expression in prostate cancer cells, and hence allow the osteoblastic activity of Wnts to be realized. To test this, we first demonstrated that PTHrP downregulated DKK1 mRNA and protein expression. We then found through multiple mutated DKK1 promoter assays that PTHrP, through c-Jun activation, downregulated the DKK1 promoter through a TCF-response element site. Furthermore, chromatin immunoprecipitation (ChIP) and reChIP assays revealed that PTHrP-mediated this effect through inducing c-Jun to bind to a transcriptional activator complex consisting of β-catenin that binds the most proximal DKK1 promoter TCF-response element. Together, these results demonstrate a novel signaling linkage between PTHrP and Wnt signaling pathways that results in downregulation of a Wnt inhibitor allowing for Wnt activity that could contribute the osteoblastic nature of prostate cancer.
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影响因子：
2.8
作者：
Hall, Christopher L.;Daignault, Stephanie D.;Shah, Rajal B.;Pienta, Kenneth J.;Keller, Evan T.
通讯作者：
Keller, Evan T.
影响因子：
9.7
作者：
Koppen, Arjen;Ait-Aissa, Rachida;Valentijn, Linda J.
通讯作者：
Valentijn, Linda J.
影响因子：
11.4
作者：
Grotewold, L;Rüther, U
通讯作者：
Rüther, U
DOI：
10.1016/j.bbrc.2004.11.162
发表时间：
2005-02-11
影响因子：
3.1
作者：
Deftos, LJ;Barken, I;Geller, J
通讯作者：
Geller, J
影响因子：
5.3
作者：
HENDERSON, E;STEIN, R
通讯作者：
STEIN, R