Dephosphorylation of the Retinoblastoma protein (Rb) inhibits cancer cell EMT via Zeb.
Dephosphorylation of the Retinoblastoma protein (Rb) inhibits cancer cell EMT via Zeb.
复制标题
DOI：
10.1080/15384047.2016.1235668
复制
发表时间：
2016-11
影响因子：
3.6
通讯作者：
Krucher NA
中科院分区：
文献类型：
--
作者：
Egger JV;Lane MV;Antonucci LA;Dedi B;Krucher NA
肿瘤抑制剂视网膜母细胞瘤（Rb）蛋白在癌细胞中高度磷酸化，这主要是由于细胞周期蛋白的过表达或细胞周期蛋白依赖性激酶抑制剂（cdki）表达的缺失。Rb的过度磷酸化促进增殖，并在细胞凋亡的调节中起作用。最近，抑制细胞周期蛋白对Rb的依赖性活性已被确定为已显示临床疗效的策略。我们利用了一种方法，通过shRNA沉默PNUTS（磷酸酶核靶向亚基），调节PP 1介导的Rb去磷酸化，诱导细胞中Rb的磷酸酶活性。在这项研究中，Rb去磷酸化对上皮间质转化（EMT）的影响进行了测定。EMT转变在具有侵袭性特征的癌细胞中观察到。在3D Matrigel培养物中生长的乳腺癌细胞中，MCF 7细胞响应Rb去磷酸化而经历凋亡，而MDA-MB-231和Hs 578 T细胞表现出EMT减少。缺乏磷酸化Rb的细胞（未转化的MCF 10A和Rb缺失的MDA-MB-468）对PNUTS耗竭缺乏任何反应，表明该效应是Rb依赖性的。此外，这些研究表明，Rb去磷酸化的高度侵袭性HT 1080细胞的3D Matrigel培养物导致EMT的抑制。此外，我们还观察到去磷酸化Rb与ZEB 1之间的关联，ZEB 1是一种锌指E盒结合转录因子，可调节E-和N-钙粘蛋白的表达。最后Rb去磷酸化导致ZEB 1转录活性的抑制，这一数据支持Rb去磷酸化调节EMT的观点。这些研究表明，靶向间充质癌细胞中的Rb磷酸化可能会降低侵袭性。
The tumor suppressor Retinoblastoma (Rb) protein is highly phosphorylated in cancer cells largely due to the overexpression of cyclins or the loss of expression of cyclin dependent kinase inhibitors (cdki). Hyperphosphorylation of Rb promotes proliferation, and plays a role in the regulation of apoptosis. Recently, inhibition of cyclin dependent activity toward Rb has been identified as a strategy that has shown clinical efficacy. We utilized a method to induce phosphatase activity toward Rb in cells by shRNA silencing of PNUTS (Phosphatase Nuclear Targeting Subunit) that regulates PP1-mediated dephosphorylation of Rb. In this study, the effect of Rb dephosphorylation on the epithelial to mesenchymal transition (EMT) was determined. The EMT transition is observed in cancer cells that have acquired invasive characteristics. In breast cancer cells grown in 3D Matrigel cultures, MCF7 cells undergo apoptosis in response to Rb dephosphorylation, whereas MDA-MB-231 and Hs578T cells exhibit a reduction in the EMT. Cells devoid of phosphorylated Rb (nontransformed MCF10A and Rb-null MDA-MB-468) lacked any response to PNUTS depletion, showing the effect is Rb-dependent. In addition, these studies showed that Rb dephosphorylation in 3D Matrigel cultures of highly invasive HT1080 cells led to the inhibition of the EMT. Furthermore we observed association between dephosphorylated Rb with ZEB1, a zinc-finger E-box-binding transcription factor that regulates expression of E- and N-cadherins. Finally Rb dephosphorylation led to inhibition of ZEB1 transcriptional activity, this data supports the notion that Rb dephosphorylation modulates the EMT. These studies suggest targeting Rb phosphorylation in mesenchymal cancer cells may decrease invasiveness.
登录
查看更多内容
影响因子：
4.8
作者：
Debnath, J;Muthuswamy, SK;Brugge, JS
通讯作者：
Brugge, JS
影响因子：
11.2
作者：
Kavela, Sridhar;Shinde, Swapnil R.;Maddika, Subbareddy
通讯作者：
Maddika, Subbareddy
影响因子：
3.5
作者：
Kreivi, JP;Trinkle-Mulcahy, L;Lamond, AI
通讯作者：
Lamond, AI
影响因子：
8
作者：
Krucher, NA;Zygmunt, A;Lee, MYWT
通讯作者：
Lee, MYWT
影响因子：
51.1
作者：
Finn, Richard S.;Crown, John P.;Slamon, Dennis J.
通讯作者：
Slamon, Dennis J.