Trp53 通过 Mdm2 调节 Notch 4 信号通路。
Trp53 regulates Notch 4 signaling through Mdm2.
机构信息
Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
出版信息
J Cell Sci. 2011 Apr 1;124(Pt 7):1067-76. doi: 10.1242/jcs.068965.
Abstract
Notch receptors and their ligands have crucial roles in development and tumorigenesis. We present evidence demonstrating the existence of an antagonistic relationship between Notch 4 and Trp53, which is controlled by the Mdm2-dependent ubiquitylation and degradation of the Notch receptor. We show that this signal-controlling mechanism is mediated by physical interactions between Mdm2 and Notch 4 and suggest the existence of a trimeric complex between Trp53, Notch 4 and Mdm2, which ultimately regulates Notch activity. Functional studies indicate that Trp53 can suppress NICD4-induced anchorage-independent growth in mammary epithelial cells and present evidence showing that Trp53 has a pivotal role in the suppression of Notch-associated tumorigenesis in the mammary gland.
摘要
Notch 受体及其配体在发育和肿瘤发生中具有重要作用。我们提供的证据表明 Notch4 和 Trp53 之间存在拮抗关系，这种关系受 Notch 受体的 Mdm2 依赖性泛素化和降解控制。我们表明，这种信号控制机制是由 Mdm2 和 Notch4 之间的物理相互作用介导的，并提出了 Trp53、Notch4 和 Mdm2 之间存在三聚体复合物的假设，该复合物最终调节 Notch 活性。功能研究表明，Trp53 可以抑制 NICD4 诱导的乳腺上皮细胞的无锚定生长，并提供证据表明 Trp53 在抑制乳腺中 Notch 相关肿瘤发生中起着关键作用。
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