Le Gallic L, Sgouras D, Beal G, Mavrothalassitis G
IMBB-FORTH, University of Crete, Voutes, Heraklion, Crete 714-09, Greece.
Mol Cell Biol. 1999 Jun;19(6):4121-33. doi: 10.1128/MCB.19.6.4121.
A limited number of transcription factors have been suggested to be regulated directly by Erks within the Ras/mitogen-activated protein kinase signaling pathway. In this paper we demonstrate that ERF, a ubiquitously expressed transcriptional repressor that belongs to the Ets family, is physically associated with and phosphorylated in vitro and in vivo by Erks. This phosphorylation determines the ERF subcellular localization. Upon mitogenic stimulation, ERF is immediately phosphorylated and exported to the cytoplasm. The export is blocked by specific Erk inhibitors and is abolished when residues undergoing phosphorylation are mutated to alanine. Upon growth factor deprivation, ERF is rapidly dephosphorylated and transported back into the nucleus. Phosphorylation-defective ERF mutations suppress Ras-induced tumorigenicity and arrest the cells at the G0/G1 phase of the cell cycle. Our findings strongly suggest that ERF may be important in the control of cellular proliferation during the G0/G1 transition and that it may be one of the effectors in the mammalian Ras signaling pathway.
在Ras/丝裂原活化蛋白激酶信号通路中，已有少数转录因子被认为可由细胞外信号调节激酶（Erks）直接调控。在本文中，我们证明了ERF（一种属于Ets家族的普遍表达的转录抑制因子）在体外和体内均与Erks发生物理结合并被其磷酸化。这种磷酸化决定了ERF的亚细胞定位。在有丝分裂原刺激下，ERF立即被磷酸化并转运至细胞质。这种转运被特异性Erk抑制剂阻断，且当发生磷酸化的残基突变为丙氨酸时，转运被消除。在生长因子剥夺时，ERF迅速去磷酸化并运回细胞核。磷酸化缺陷型ERF突变抑制Ras诱导的肿瘤发生，并使细胞停滞在细胞周期的G0/G1期。我们的研究结果强烈表明，ERF在G0/G1期转换过程中对细胞增殖的控制可能很重要，并且它可能是哺乳动物Ras信号通路中的效应器之一。
