Ehrenreiter Karin, Kern Florian, Velamoor Vanishree, Meissl Katrin, Galabova-Kovacs Gergana, Sibilia Maria, Baccarini Manuela
Max F. Perutz Laboratories, Department of Microbiology and Immunobiology, University of Vienna, Vienna, Austria.
Cancer Cell. 2009 Aug 4;16(2):149-60. doi: 10.1016/j.ccr.2009.06.008.
Ras activation is common to many human cancers and promotes cell proliferation and survival by initiating multiple signaling cascades. Accordingly, Ras-transformed cells are generally considered too resourceful to become addicted to a single effector. In contrast to this tenet, we now demonstrate an absolute, cell autonomous requirement for Raf-1 in the development and maintenance of Ras-induced skin epidermis tumors. Mechanistically, Raf-1 functions as an endogenous inhibitor dimming the activity of the Rho-dependent kinase Rok-alpha in the context of a Ras-induced Raf-1:Rok-alpha complex. Raf-1-induced Rok-alpha inhibition allows the phosphorylation of STAT3 and Myc expression and promotes dedifferentiation in Ras-induced tumors. These data link the Raf-1:Rok-alpha complex to STAT3/Myc activation and delineate a pathway crucial for cell fate decision in Ras-induced tumorigenesis.
Ras激活在许多人类癌症中很常见，并通过启动多个信号级联反应来促进细胞增殖和存活。因此，Ras转化的细胞通常被认为过于足智多谋，不会依赖单一效应器。与这一原则相反，我们现在证明在Ras诱导的皮肤表皮肿瘤的发生和维持过程中，Raf-1对细胞具有绝对的自主需求。从机制上讲，在Ras诱导的Raf-1:Rok-α复合物的背景下，Raf-1作为一种内源性抑制剂，减弱Rho依赖性激酶Rok-α的活性。Raf-1诱导的Rok-α抑制允许STAT3磷酸化和Myc表达，并促进Ras诱导肿瘤中的去分化。这些数据将Raf-1:Rok-α复合物与STAT3/Myc激活联系起来，并描绘了一条对Ras诱导的肿瘤发生中细胞命运决定至关重要的途径。
