Department of Molecular and Cellular Oncology, The University of Texas, M D Anderson Cancer Center, Houston, TX 77030, USA.
Biochem Biophys Res Commun. 2010 Dec 3;403(1):103-7. doi: 10.1016/j.bbrc.2010.10.126. Epub 2010 Oct 30.
While p21 is well known to inhibit cyclin-CDK activity in the nucleus and it has also been demonstrated to have oncogenic properties in different types of human cancers. In vitro studies showed that the oncogenic function of p21is closely related to its cytoplasmic localization. However, it is unclear whether cytoplasmic p21 contributes to tumorigenesis in vivo. To address this question, we generated transgenic mice expressing the Akt-phosphorylated form of p21 (p21T145D) in the mammary epithelium. The results showed that Akt-activated p21 was expressed in the cytoplasm of mammary epithelium. Overexpression of Akt-activated p21 accelerated tumor onset and promoted lung metastasis in MMTV/neu mice, providing evidence that p21, especially cytoplasmic phosphorylated p21, has an oncogenic role in promoting mammary tumorigenesis and metastasis.
虽然 p21 已被证实可抑制细胞核中环肽依赖性激酶的活性，并且在不同类型的人类癌症中也显示出致癌特性。体外研究表明，p21 的致癌功能与其细胞质定位密切相关。然而，细胞质 p21 是否有助于体内肿瘤发生尚不清楚。为了解决这个问题，我们在乳腺上皮细胞中生成了表达 Akt 磷酸化形式 p21（p21T145D）的转基因小鼠。结果表明，Akt 激活的 p21在乳腺上皮细胞的细胞质中表达。Akt 激活的 p21 的过表达加速了 MMTV/neu 小鼠的肿瘤发生，并促进了肺转移，这为 p21，特别是细胞质磷酸化 p21，在促进乳腺肿瘤发生和转移方面具有致癌作用提供了证据。
