Transcriptional regulation of tissue-specific genes by the ERK5 mitogen-activated protein kinase.
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.
Sohn
Sue J
SJ
Department of Molecular and Cell Biology, Division of Immunology and Cancer Research Laboratory, University of California, Berkeley, 465 Life Science Addition, Berkeley, CA 94720-3200, USA.
Li
Dongling
D
Lee
Linda K
LK
Winoto
Astar
A
D020816:Amino Acid Motifs; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D002319:Cardiovascular System / Q000196:embryology; D048429:Cell Size; D002470:Cell Survival; D047369:Chromatin Immunoprecipitation; D003001:Cloning, Molecular; D004247:DNA / Q000737:chemistry; D018076:DNA, Complementary / Q000378:metabolism; D015536:Down-Regulation; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D005799:Genes, Dominant; D017930:Genes, Reporter; D006801:Humans; D000860:Hypoxia; D015151:Immunoblotting; D017403:In Situ Hybridization; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D048054:Mitogen-Activated Protein Kinase 7 / Q000378:metabolism / Q000502:physiology*; D008969:Molecular Sequence Data; D009389:Neovascularization, Pathologic; D020411:Oligonucleotide Array Sequence Analysis; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D015854:Up-Regulation
D018076:DNA, Complementary; C096161:KLF2 protein, human; D051741:Kruppel-Like Transcription Factors; D034741:RNA, Small Interfering; D004247:DNA; D048054:Mitogen-Activated Protein Kinase 7