Progesterone receptor activates Msx2 expression by downregulating TNAP/Akp2 and activating the Bmp pathway in EpH4 mouse mammary epithelial cells.
Progesterone receptor activates Msx2 expression by downregulating TNAP/Akp2 and activating the Bmp pathway in EpH4 mouse mammary epithelial cells.
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DOI：
10.1371/journal.pone.0034058
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Vonderhaar BK
中科院分区：
文献类型：
--
作者：
Fleming JM;Ginsburg E;Goldhar AS;Plant J;Vonderhaar BK
以前，我们证明，EpH 4小鼠乳腺上皮细胞诱导的同源异型盒转录因子Msx 2无论是与孕激素受体（PR）转染时，或与Bmp 2/4治疗时。Msx 2上调不受Wnt抑制剂s-FRP或Dkk 1的影响，但受到BMP拮抗剂Noggin的抑制。因此，我们假设PR信号传导至Msx 2通过Bmp受体途径起作用。在此，我们证实，转录Alk 2/ActR 1A，一个非典型的BmpR I型，上调乳腺上皮细胞过表达PR（EpH 4-PR）。在EpH 4-PR细胞中，观察到Smads 1、5、8（Alk 2和其它BmpR I型蛋白的已知底物）的磷酸化增加，以及它们向细胞核的移位。分析还显示，组织非特异性碱性磷酸酶（TNAP/Akp 2）也被发现在EpH 4-PR细胞中下调。当含有1/2 PRE位点的Akp 2启动子-报告基因构建体转染到EpH 4-PR细胞中时，其表达下调。此外，siRNA介导的Akp 2敲低增加了Alk 2和Msx 2的表达。总的来说，这些数据表明，Akp 2的PR抑制导致Alk 2活性增加，Smads 1、5、8磷酸化增加，并最终上调Msx 2。这些研究表明，Akp 2基因的重新激活可能有助于下调PR+乳腺癌中Msx 2的异常表达。
Previously we demonstrated that EpH4 mouse mammary epithelial cells induced the homeobox transcription factor Msx2 either when transfected with the progesterone receptor (PR) or when treated with Bmp2/4. Msx2 upregulation was unaffected by Wnt inhibitors s-FRP or Dkk1, but was inhibited by the Bmp antagonist Noggin. We therefore hypothesized that PR signaling to Msx2 acts through the Bmp receptor pathway. Herein, we confirm that transcripts for Alk2/ActR1A, a non-canonical BmpR Type I, are upregulated in mammary epithelial cells overexpressing PR (EpH4-PR). Increased phosphorylation of Smads 1,5, 8, known substrates for Alk2 and other BmpR Type I proteins, was observed as was their translocation to the nucleus in EpH4-PR cells. Analysis also showed that Tissue Non-Specific Alkaline Phosphatase (TNAP/Akp2) was also found to be downregulated in EpH4-PR cells. When an Akp2 promoter-reporter construct containing a ½PRE site was transfected into EpH4-PR cells, its expression was downregulated. Moreover, siRNA mediated knockdown of Akp2 increased both Alk2 and Msx2 expression. Collectively these data suggest that PR inhibition of Akp2 results in increased Alk2 activity, increased phosphorylation of Smads 1,5,8, and ultimately upregulation of Msx2. These studies imply that re-activation of the Akp2 gene could be helpful in downregulating aberrant Msx2 expression in PR+ breast cancers.
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影响因子：
11.2
作者：
Deckers, M;van Dinther, M;ten Dijke, P
通讯作者：
ten Dijke, P
影响因子：
2.5
作者：
Hovey, RC;Trott, JF;Vonderhaar, BK
通讯作者：
Vonderhaar, BK
影响因子：
5.8
作者：
Hofseth, LJ;Raafat, AM;Haslam, SZ
通讯作者：
Haslam, SZ
DOI：
10.1083/jcb.132.6.1115
发表时间：
1996-03
期刊：
The Journal of cell biology
影响因子：
--
作者：
Fialka I;Schwarz H;Reichmann E;Oft M;Busslinger M;Beug H
通讯作者：
Beug H
影响因子：
6
作者：
Harmey, D;Hessle, L;Millán, JL
通讯作者：
Millán, JL