Nicke Barbara, Bastien Julie, Khanna Sophia J, Warne Patricia H, Cowling Victoria, Cook Simon J, Peters Gordon, Delpuech Oona, Schulze Almut, Berns Katrien, Mullenders Jasper, Beijersbergen Roderick L, Bernards René, Ganesan Trivadi S, Downward Julian, Hancock David C
Signal Transduction Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom.
Mol Cell. 2005 Dec 9;20(5):673-85. doi: 10.1016/j.molcel.2005.10.038.
The ability of activated Ras to induce growth arrest of human ovarian surface epithelial (HOSE) cells via induction of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) has been used to screen for Ras pathway signaling components using a library of RNA interference (RNAi) vectors targeting the kinome. Two known Ras-regulated kinases were identified, phosphoinositide 3-kinase p110alpha and ribosomal protein S6 kinase p70(S6K1), plus the MAP kinase kinase kinase kinase MINK, which had not previously been implicated in Ras signaling. MINK is activated after Ras induction via a mechanism involving reactive oxygen species and mediates stimulation of the stress-activated protein kinase p38 MAPK downstream of the Raf/ERK pathway. p38 MAPK activation is essential for Ras-induced p21(WAF1/CIP1) upregulation and cell cycle arrest. MINK is thus a distal target of Ras signaling in the induction of a growth-arrested, senescent-like phenotype that may act to oppose oncogenic transformation in HOSE cells.
活化的Ras通过诱导细胞周期蛋白依赖性激酶抑制剂p21（WAF1/CIP1）来诱导人卵巢表面上皮（HOSE）细胞生长停滞的能力，已被用于使用靶向激酶组的RNA干扰（RNAi）载体文库筛选Ras信号通路的信号成分。鉴定出两种已知的Ras调节激酶，磷脂酰肌醇3激酶p110α和核糖体蛋白S6激酶p70（S6K1），以及丝裂原活化蛋白激酶激酶激酶激酶MINK，其以前未涉及Ras信号传导。Ras诱导后，MINK通过涉及活性氧的机制被激活，并介导Raf/ERK途径下游应激激活蛋白激酶p38 MAPK的刺激。p38 MAPK激活对于Ras诱导的p21（WAF1/CIP1）上调和细胞周期停滞至关重要。因此，MINK是Ras信号传导在诱导生长停滞、衰老样表型中的远端靶点，该表型可能起到对抗HOSE细胞致癌转化的作用。
