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首页> 外文期刊>Molecular and Cellular Biology >Ubiquitin-Independent Proteasomal Degradation of Fra-1 Is Antagonized by Erk1/2 Pathway-Mediated Phosphorylation of a Unique C-Terminal Destabilizer
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Ubiquitin-Independent Proteasomal Degradation of Fra-1 Is Antagonized by Erk1/2 Pathway-Mediated Phosphorylation of a Unique C-Terminal Destabilizer

机译：通过Erk1 / 2途径介导的独特的C末端去稳定剂的磷酸化拮抗Fra-1的泛素依赖性蛋白酶体降解。

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Fra-1, a transcription factor that is phylogenetically and functionally related to the proto-oncoprotein c-Fos, controls many essential cell functions. It is expressed in many cell types, albeit with differing kinetics and abundances. In cells reentering the cell cycle, Fra-1 expression is transiently stimulated albeit later than that of c-Fos and for a longer time. Moreover, Fra-1 overexpression is found in cancer cells displaying high Erk1/2 activity and has been linked to tumorigenesis. One crucial point of regulation of Fra-1 levels is controlled protein degradation, the mechanism of which remains poorly characterized. Here, we have combined genetic, pharmacological, and signaling studies to investigate this process in nontransformed cells and to elucidate how it is altered in cancer cells. We report that the intrinsic instability of Fra-1 depends on a single destabilizer contained within the C-terminal 30 to 40 amino acids. Two serines therein, S252 and S265, are phosphorylated by kinases of the Erk1/2 pathway, which compromises protein destruction upon both normal physiological induction and tumorigenic constitutive activation of this cascade. Our data also indicate that Fra-1, like c-Fos, belongs to a small group of proteins that may, under certain circumstances, undergo ubiquitin-independent degradation by the proteasome. Our work reveals both similitudes and differences between Fra-1 and c-Fos degradation mechanisms. In particular, the presence of a single destabilizer within Fra-1, instead of two that are differentially regulated in c-Fos, explains the much faster turnover of the latter when cells traverse the G0/G1-to-S-phase transition. Finally, our study offers further insights into the signaling-regulated expression of the other Fos family proteins.
机译：Fra-1是与原癌蛋白c-Fos系统发育和功能相关的转录因子，它控制许多基本细胞功能。它以多种细胞类型表达，尽管具有不同的动力学和丰度。在重新进入细胞周期的细胞中，Fra-1的表达被短暂刺激，尽管比c-Fos的表达晚并且持续了更长的时间。此外，在具有高Erk1 / 2活性的癌细胞中发现Fra-1过表达，并与肿瘤发生有关。调节Fra-1含量的一个关键点是蛋白质降解的控制，其机理仍然很差。在这里，我们结合了遗传学，药理学和信号学研究，以研究未转化细胞中的这一过程，并阐明其在癌细胞中的变化。我们报告说，Fra-1的固有不稳定性取决于C端30至40个氨基酸中所含的单个去稳定剂。其中的两个丝氨酸S252和S265被Erk1 / 2途径的激酶磷酸化，在正常的生理诱导和该级联的致癌性组成性激活后，蛋白质破坏都受到损害。我们的数据还表明，Fra-1与c-Fos一样，属于一小组蛋白质，在某些情况下可能会受到蛋白酶体的泛素依赖性降解。我们的工作揭示了Fra-1和c-Fos降解机制之间的相似性和差异。特别是，Fra-1中存在单个去稳定剂，而不是在c-Fos中受到差异调节的两个去稳定剂，这说明了当细胞穿过G 0 / G < sub> 1 到S相的过渡。最后，我们的研究为其他Fos家族蛋白的信号传导表达提供了进一步的见识。

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