Loss of protein phosphatase 6 in mouse keratinocytes enhances K-ras(G12D) -driven tumor promotion.
Loss of protein phosphatase 6 in mouse keratinocytes enhances K-ras(G12D) -driven tumor promotion.
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DOI：
10.1111/cas.13638
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发表时间：
2018-07
期刊：
影响因子：
5.7
通讯作者：
Shima H
中科院分区：
文献类型：
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作者：
Kurosawa K;Inoue Y;Kakugawa Y;Yamashita Y;Kanazawa K;Kishimoto K;Nomura M;Momoi Y;Sato I;Chiba N;Suzuki M;Ogoh H;Yamada H;Miura K;Watanabe T;Tanuma N;Tachi M;Shima H
在这里，我们研究了蛋白磷酸酶6 （PP6）缺失在角化细胞中K - ras启动的肿瘤发生中的作用。为此，我们开发了他莫昔芬诱导的双突变（表达K - ras G12D和Ppp6c缺陷）小鼠，其中K - ras G12D的表达由细胞角蛋白14 （K14）启动子驱动。双突变小鼠在嘴唇、乳头、外生殖器、肛门和手掌中显示出早期肿瘤形成，并且必须在他莫昔芬诱导后3周内被杀死，而同样处理的表达K - ras G12D的小鼠则没有。安乐死前的H&E染色显示所有的唇部肿瘤都是乳头状瘤，其中一些含有局灶性鳞状细胞癌。免疫组织化学分析显示，双突变体与K - ras G12D小鼠的唇部细胞增殖和细胞大小比表达K - ras G12D的小鼠增加了约2倍，唇部组织表皮厚度也比仅表达K - ras G12D的小鼠大大增加。此外，AKT磷酸化在表达K - ras G12D - /Ppp6c -缺陷的细胞中增加，下游效应物4EBP1、S6和GSK3的磷酸化也增加，表明双突变小鼠唇部组织中的蛋白质合成和存活信号增强。最后，双突变小鼠的基底上层中K14阳性细胞数量增加，表明角质细胞分化异常，γH2AX阳性细胞积累，表明DNA修复受到干扰。综上所述，Ppp6c缺失增强了K - ras G12D依赖性肿瘤促进作用。
Here, we address the function of protein phosphatase 6 (PP6) loss on K‐ras‐initiated tumorigenesis in keratinocytes. To do so, we developed tamoxifen‐inducible double mutant (K‐ras G12D‐expressing and Ppp6c‐deficient) mice in which K‐ras G12D expression is driven by the cytokeratin 14 (K14) promoter. Doubly‐mutant mice showed early onset tumor formation in lips, nipples, external genitalia, anus and palms, and had to be killed by 3 weeks after induction by tamoxifen, while comparably‐treated K‐ras G12D‐expressing mice did not. H&E‐staining of lip tumors before euthanasia revealed that all were papillomas, some containing focal squamous cell carcinomas. Immunohistochemical analysis of lips of doubly‐mutant vs K‐ras G12D mice revealed that cell proliferation and cell size increased approximately 2‐fold relative to K‐ras G12D‐expressing mutants, and epidermal thickness of lip tissue greatly increased relative to that seen in K‐ras G12D‐only mice. Moreover, AKT phosphorylation increased in K‐ras G12D‐expressing/Ppp6c‐deficient cells, as did phosphorylation of the downstream effectors 4EBP1, S6 and GSK3, suggesting that protein synthesis and survival signals are enhanced in lip tissues of doubly‐mutant mice. Finally, increased numbers of K14‐positive cells were present in the suprabasal layer of doubly‐mutant mice, indicating abnormal keratinocyte differentiation, and γH2AX‐positive cells accumulated, indicating perturbed DNA repair. Taken together, Ppp6c deficiency enhances K‐ras G12D‐dependent tumor promotion.
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影响因子：
30.8
作者：
Krauthammer, Michael;Kong, Yong;Ha, Byung Hak;Evans, Perry;Bacchiocchi, Antonella;McCusker, James P.;Cheng, Elaine;Davis, Matthew J.;Goh, Gerald;Choi, Murim;Ariyan, Stephan;Narayan, Deepak;Dutton-Regester, Ken;Capatana, Ana;Holman, Edna C.;Bosenberg, Marcus;Sznol, Mario;Kluger, Harriet M.;Brash, Douglas E.;Stern, David F.;Materin, Miguel A.;Lo, Roger S.;Mane, Shrikant;Ma, Shuangge;Kidd, Kenneth K.;Hayward, Nicholas K.;Lifton, Richard P.;Schlessinger, Joseph;Boggon, Titus J.;Halaban, Ruth
通讯作者：
Halaban, Ruth
影响因子：
64.5
作者：
Manning BD;Toker A
通讯作者：
Toker A
影响因子：
4.8
作者：
Hosing, Amol S.;Valerie, Nicholas C. K.;Larner, James M.
通讯作者：
Larner, James M.
影响因子：
5.4
作者：
Wu, Nannan;Liu, Xuyuan;Tang, Hua
通讯作者：
Tang, Hua
影响因子：
14.8
作者：
通讯作者：
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