Paul C, Lacroix M, Iankova I, Julien E, Schäfer B W, Labalette C, Wei Y, Le Cam A, Le Cam L, Sardet C
Institut de Génétique Moleculaire, UMR 5535/IFR122, CNRS, Montpellier, France.
Oncogene. 2006 Sep 7;25(40):5475-84. doi: 10.1038/sj.onc.1209567. Epub 2006 May 1.
The E1A-targeted transcription factor E4F1 is a key player in the control of mammalian embryonic and somatic cell proliferation and survival. Mouse embryos lacking E4F die at an early developmental stage, whereas enforced expression of E4F1 in various cell lines inhibits cell cycle progression. E4F1-antiproliferative effects have been shown to depend on its capacity to repress transcription and to interact with pRb and p53. Here we show that full-length E4F1 protein (p120(E4F1)) but not its E1A-activated and truncated form (p50(E4F1)), interacts directly in vitro and in vivo with the LIM-only protein FHL2, the product of the p53-responsive gene FHL2/DRAL (downregulated in rhabdomyosarcoma Lim protein). This E4F1-FHL2 association occurs in the nuclear compartment and inhibits the capacity of E4F1 to block cell proliferation. Consistent with this effect, ectopic expression of FHL2 inhibits E4F1 repressive effects on transcription and correlates with a reduction of nuclear E4F1-p53 complexes. Overall, these results suggest that FHL2/DRAL is an inhibitor of E4F1 activity. Finally, we show that endogenous E4F1-FHL2 complexes form in U2OS cells upon UV-light-induced nuclear accumulation of FHL2.
靶向E1A的转录因子E4F1是控制哺乳动物胚胎和体细胞增殖及存活的关键因子。缺乏E4F的小鼠胚胎在早期发育阶段死亡，而在各种细胞系中强制表达E4F1会抑制细胞周期进程。E4F1的抗增殖作用已被证明取决于其抑制转录以及与pRb和p53相互作用的能力。在此我们表明，全长E4F1蛋白（p120(E4F1)）而非其E1A激活的截短形式（p50(E4F1)），在体外和体内都直接与仅含LIM结构域的蛋白FHL2相互作用，FHL2是p53反应基因FHL2/DRAL（在横纹肌肉瘤中下调的Lim蛋白）的产物。这种E4F1 - FHL2的结合发生在细胞核内，并且抑制了E4F1阻断细胞增殖的能力。与此效应一致，FHL2的异位表达抑制了E4F1对转录的抑制作用，并与核内E4F1 - p53复合物的减少相关。总体而言，这些结果表明FHL2/DRAL是E4F1活性的抑制剂。最后，我们表明在U2OS细胞中，紫外线诱导FHL2在核内积累后会形成内源性E4F1 - FHL2复合物。
