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Transcriptional Regulation of Tissue-Specific Genes by the ERK5 Mitogen-Activated Protein Kinase

机译：ERK5丝裂原活化蛋白激酶对组织特异性基因的转录调控。

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The ERK5 mitogen-activated protein kinase (MAPK) differs from other MAPKs in possessing a potent transcriptional activation domain. ERK5?/? embryos die from angiogenic defects, but the precise physiological role of ERK5 remains poorly understood. To elucidate molecular functions of ERK5 in the development of vasculature and other tissues, we performed gene profile analyses of erk5?/? mouse embryos and erk5?/? fibroblast cells reconstituted with ERK5 or ERK5(1-740), which lacks the transactivation domain. These experiments revealed several potential ERK5 target genes, including a proapoptotic gene bnip3, known angiogenic genes flt1 and lklf (lung Krüppel-like factor), and genes that regulate cardiovascular development. Among these, LKLF, known for its roles in angiogenesis, T-cell quiescence, and survival, was found to be absolutely dependent on ERK5 for expression in endothelial and T cells. We show that ERK5 drives lklf transcription by activating MEF2 transcription factors. Expression of erk5 short hairpin or a dominant-negative form of the ERK5 upstream activator, MEK5, in T cells led to downregulation of LKLF, increased cell size and upregulation of activation markers. Thus, through its kinase and transcriptional activation domains, ERK5 regulates transcriptional responses of cell survival and quiescence critical for angiogenesis and T-cell function.
机译：ERK5丝裂原激活的蛋白激酶（MAPK）与其他MAPK的不同之处在于具有强大的转录激活域。 ERK5 ？/？胚胎死于血管生成缺陷，但对ERK5的确切生理作用仍知之甚少。为了阐明ERK5在脉管系统和其他组织发育中的分子功能，我们对 erk5 ？/？小鼠胚胎和 erk5 进行了基因概况分析？/？成纤维细胞用缺少反式激活域的ERK5或ERK5（1-740）重构。这些实验揭示了几个潜在的ERK5靶基因，包括促凋亡基因 bnip3 ，已知的血管生成基因 flt1 和 lklf （肺Krüppel样因子）和调控心血管发育的基因。其中，以其在血管生成，T细胞静止和存活中的作用而闻名的LKLF被发现完全依赖ERK5在内皮细胞和T细胞中的表达。我们表明，ERK5通过激活MEF2转录因子来驱动 lklf 转录。 T细胞中 erk5 短发夹或ERK5上游激活剂MEK5的显性负型表达导致LKLF的下调，细胞大小增加和激活标记的上调。因此，ERK5通过其激酶和转录激活域调节细胞存活和静止的转录反应，这对于血管生成和T细胞功能至关重要。

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