β-Catenin/TCF/LEF1 can directly regulate phenylephrine-induced cell hypertrophy and Anf transcription in cardiomyocytes

β-Catenin/TCF/LEF1 signaling is implicated in cardiac hypertrophy. We demonstrate that knockdown of β-catenin attenuates phenylephrine (PE)-induced cardiomyocyte hypertrophy and the up-regulation of the fetal gene Anf. We explore the mechanism through which β-catenin regulates Anf expression and find a consensus binding sequence on the Anf promoter for TCF/LEF1 family members. LEF1 binds directly to the Anf promoter via this sequence, which shows functional significance, and PE stimulation enhances recruitment of β-catenin onto the Anf promoter. Thus, we document a direct positive role of β-catenin on PE-induced cardiomyocyte hypertrophy and identify a new target gene for β-catenin/TCF/LEF1.     

Fhl1 as a downstream target of Wnt signaling to promote myogenesis of C2C12 cells

Previous studies have shown that Wnt signaling is involved in postnatal mammalian myogenesis; however, the downstream mechanism of Wnt signaling is not fully understood. This study reports that the murine four-and-a-half LIM domain 1 (Fhl1) could be stimulated by β-catenin or LiCl treatment to induce myogenesis. In contrast, knockdown of the Fhl1 gene expression in C2C12 cells led to reduced myotube formation. We also adopted reporter assays to demonstrate that either β-catenin or LiCl significantly activated the Fhl1 promoter, which contains four putative consensus TCF/LEF binding sites. Mutations of two of these sites caused a significant decrease in promoter activity by luciferase reporter assay. Thus, we suggest that Wnt signaling induces muscle cell differentiation, at least partly, through Fhl1 activation.     

蛋白质修饰对Wnt信号通路的调控

Wnt信号通路与细胞的生长发育和分化等密切相关,是细胞中重要的信号转导途径,在 多种癌症中,都有该通路的异常改变.Wnt信号通路主要是通过一系列蛋白将Wnt信号传导至β连环蛋白（β-catenin,β-cat）,使后者入核并与转录因子T细胞因子/淋巴细胞增 强因子（T cell factor / lymphoid enhancer factor,TCF/LEF）结合,从而促进下游基因的转录,进而调控细胞的多种生理过程.在该通路中,涉及轴蛋白（Axin）、结肠腺瘤样息 肉病蛋白(adenomatous polyposis coli,APC)、糖原合酶激酶3β (glycogen synthase kinase-3β, GSK-3β)、β连环蛋白和酪蛋白激酶I (casein kinase I,CKI)等众多调节因子,这些因子能发生多种化学修饰,如磷酸化、泛素化（ubiquitylation）、苏素化 (small ubiquitin related moditier,SUMO)和乙酰化等,从而影响β连环蛋白、T细胞因子的稳定性、细胞定位以及活性,最终起到调节Wnt信号通路的作用.     

Wnt/β-catenin信号通路对靶基因转录的调控

Wnt/β-catenin信号通路又被称为经典Wnt信号通路,在早期胚胎发育、成体组织稳态维持、干细胞干性调控和肿瘤发生等过程中均发挥重要作用.经典Wnt信号通路的核心信号转导因子β-catenin与核内转录因子TCF/LEF家族成员结合后,通过募集或替换一系列协同作用因子,诱导染色质结构变化,调控Wnt信号靶基因的转录.本文将从Wnt信号靶基因转录调控的基本模式、分子机制、表观遗传学调控和意义等方面,总结近年来有关Wnt信号靶基因转录调控的研究成果,方便读者更好地理解Wnt信号通路靶基因的转录调控.     

Topical Application of Oleuropein Induces Anagen Hair Growth in Telogen Mouse Skin

We observed that oleuropein, the main constituent of the leaves and unprocessed olive drupes of Olea europaea, protected mice from high-fat diet-induced adiposity by up-regulation of genes involved in Wnt10b-mediated signaling in adipose tissue. The activation of Wnt/β-catenin pathway is also well established to positively regulate the anagen phase of hair growth cycle in mice skin.

Methodology and Principal Findings

Oleuropein promoted cultured human follicle dermal papilla cell proliferation and induced LEF1 and Cyc-D1 mRNA expression and β-catenin protein expression in dermal papilla cells. Nuclear accumulation of β-catenin in dermal papilla cells was observed after oleuropein treatment. Topical application of oleuropein (0.4 mg/mouse/day) to C57BL/6N mice accelerated the hair-growth induction and increased the size of hair follicles in telogenic mouse skin. The oleuropein-treated mouse skin showed substantial upregulation of Wnt10b, FZDR1, LRP5, LEF1, Cyc-D1, IGF-1, KGF, HGF, and VEGF mRNA expression and β-catenin protein expression.

Conclusions and Significance

These results demonstrate that topical oleuroepin administration induced anagenic hair growth in telogenic C57BL/6N mouse skin. The hair-growth promoting effect of oleuropein in mice appeared to be associated with the stimulation of the Wnt10b/β-catenin signaling pathway and the upregulation of IGF-1, KGF, HGF, and VEGF gene expression in mouse skin tissue.