Department of Orthopedic Oncology, Changzheng Hospital, The Second Military Medical University, Shanghai 200003, China.
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China.
Nat Commun. 2015 Apr 24;6:6875. doi: 10.1038/ncomms7875.
Here we report that mice deficient for the proteasome activator, REGγ, exhibit a marked resistance to TPA (12-O-tetradecanoyl-phorbol-13-acetate)-induced keratinocyte proliferation, epidermal hyperplasia and onset of papillomas compared with wild-type counterparts. Interestingly, a massive increase of REGγ in skin tissues or cells resulting from TPA induces activation of p38 mitogen-activated protein kinase (MAPK/p38). Blocking p38 MAPK activation prevents REGγ elevation in HaCaT cells with TPA treatment. AP-1, the downstream effector of MAPK/p38, directly binds to the REGγ promoter and activates its transcription in response to TPA stimulation. Furthermore, we find that REGγ activates Wnt/β-catenin signalling by degrading GSK-3β in vitro and in cells, increasing levels of CyclinD1 and c-Myc, the downstream targets of β-catenin. Conversely, MAPK/p38 inactivation or REGγ deletion prevents the increase of cyclinD1 and c-Myc by TPA. This study demonstrates that REGγ acts in skin tumorigenesis mediating MAPK/p38 activation of the Wnt/β-catenin pathway.
在这里，我们报告称，与野生型小鼠相比，缺乏蛋白酶体激活剂 REGγ 的小鼠对 TPA（12-O-十四烷酰佛波醇-13-醋酸酯）诱导的角质形成细胞增殖、表皮增生和乳头状瘤的发生表现出明显的抗性。有趣的是，TPA 导致皮肤组织或细胞中 REGγ 的大量增加会激活丝裂原活化蛋白激酶（MAPK/p38）。阻断 p38 MAPK 的激活可防止 TPA 处理的 HaCaT 细胞中 REGγ 的升高。AP-1 是 MAPK/p38 的下游效应物，可直接与 REGγ 启动子结合，并在 TPA 刺激下激活其转录。此外，我们发现 REGγ 通过体外和细胞内降解 GSK-3β 来激活 Wnt/β-catenin 信号通路，增加 CyclinD1 和 c-Myc 的水平，后者是β-catenin 的下游靶标。相反，MAPK/p38 的失活或 REGγ 的缺失可防止 TPA 增加 cyclinD1 和 c-Myc。这项研究表明，REGγ 在皮肤肿瘤发生中起作用，介导 MAPK/p38 激活 Wnt/β-catenin 通路。
