WT1 induction of mitogen-activated protein kinase phosphatase 3 represents a novel mechanism of growth suppression.
WT1 induction of mitogen-activated protein kinase phosphatase 3 represents a novel mechanism of growth suppression.
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WT1 诱导丝裂原激活蛋白激酶磷酸酶 3 代表了一种新的生长抑制机制。
DOI：
10.1158/1541-7786.mcr-08-0078
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发表时间：
2008
期刊：
影响因子：
--
通讯作者：
Licht,JonathanD
中科院分区：
文献类型：
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作者：
Morrison,DebraJ;Kim,MarianneKH;Berkofsky-Fessler,Windy;Licht,JonathanD
In its role as a tumor suppressor, WT1 transactivates several genes that are regulators of cell growth and differentiation pathways. For instance, WT1 induces the expression of the cell cycle regulator p21, the growth-regulating glycoprotein amphiregulin, the proapoptotic geneBak, and the Ras/mitogen-activated protein kinase (MAPK) inhibitor Sprouty1. Here, we show that WT1 transactivates another important negative regulator of the Ras/MAPK pathway, MAPK phosphatase 3 (MKP3). In a WT1-inducible cell line that exhibits decreased cell growth and increased apoptosis on expression of WT1, microarray analysis showed thatMKP3is the most highly induced gene. This was confirmed by real-time PCR whereMKP3and other members of the fibroblast growth factor 8 syn expression group, which includesSprouty 1and the Ets family of transcription factors, were induced rapidly following WT1 expression. WT1 induction was associated with a block in the phosphorylation of extracellular signal-regulated kinase in response to epidermal growth factor stimulation, an effect mediated by MKP3. In the presence of a dominant-negative MKP3, WT1 could no longer block phosphorylation of extracellular signal-regulated kinase. Lastly, when MKP3 expression is down-regulated by short hairpin RNA, WT1 is less able to block Ras-mediated transformation of 3T3 cells. (Mol Cancer Res 2008;6(7):1225–31)
