Jin Hua, Hwang Soon-Kyung, Yu Kyungnam, Anderson Hanjo K, Lee Yeon-Sook, Lee Kee Ho, Prats Anne-Catherine, Morello Dominique, Beck George R, Cho Myung-Haing
Laboratory of Toxicology, College of Veterinary Medicine and School of Agricultural Biotechnology, Seoul National University, Seoul 151-742, Korea.
Toxicol Sci. 2006 Mar;90(1):221-9. doi: 10.1093/toxsci/kfj066. Epub 2005 Dec 7.
Inorganic phosphate (Pi) plays a key role in diverse physiological functions. Recently, considerable progress has been made in our understanding of the function and regulation of the brain-specific sodium-dependent inorganic phosphate transporter 1 (NPT1), which is found to exist principally in cerebrum and cerebellum. The potential importance of Pi as a novel signaling molecule and the poor prognosis of diverse neurodegenerative diseases that involve brain-specific NPT1 have prompted us to define the pathways by which Pi affects mouse brain growth. A high phosphate diet caused an increase in serum Pi accompanied by a decrease in calcium, and a decrease in body weight coupled with a decreased relative weight of cerebellum. A high phosphate diet caused a significant increase in protein expression of NPT1, both in cerebrum and cerebellum. Additionally, the high phosphate diet increased Homo sapiens v-akt murine thymoma viral oncogene homolog 1 (Akt) phosphorylation at Ser473 in cerebrum and cerebellum, whereas suppression of Akt phosphorylation at Thr308 was observed only in cerebellum. Selective suppression of eukaryotic translation initiation factor-binding protein (eIF4E-BP1) in cerebrum was induced by high levels of Pi, which induced cap-dependent and cap-independent protein translation in cerebrum and cerebellum, respectively. Phosphorylation of extracellular regulated kinase 1 (ERK1) in comparison with that of ERK2 was significantly reduced in both cerebrum and cerebellum. High levels of Pi reduced protein expressions of proliferating cell nuclear antigen (PCNA) and cyclin D1 in cerebrum and cerebellum. In conclusion, the results indicate that high dietary Pi can perturb normal brain growth, possibly through Akt-ERK signaling in developing mice.
无机磷酸盐（Pi）在多种生理功能中发挥着关键作用。最近，我们对脑特异性钠依赖性无机磷酸盐转运体1（NPT1）的功能和调节的理解取得了显著进展，发现其主要存在于大脑和小脑中。Pi作为一种新型信号分子的潜在重要性以及涉及脑特异性NPT1的多种神经退行性疾病的不良预后促使我们确定Pi影响小鼠脑生长的途径。高磷饮食导致血清Pi升高，同时钙降低，体重下降以及小脑相对重量降低。高磷饮食导致大脑和小脑中NPT1的蛋白表达显著增加。此外，高磷饮食增加了大脑和小脑中人类v-akt小鼠胸腺瘤病毒癌基因同源物1（Akt）在Ser473处的磷酸化，而仅在小脑中观察到Akt在Thr308处的磷酸化受到抑制。大脑中高水平的Pi诱导了真核翻译起始因子结合蛋白（eIF4E-BP1）的选择性抑制，这分别在大脑和小脑中诱导了帽依赖性和帽非依赖性蛋白翻译。与细胞外调节激酶2（ERK2）相比，细胞外调节激酶1（ERK1）在大脑和小脑中的磷酸化均显著降低。高水平的Pi降低了大脑和小脑中增殖细胞核抗原（PCNA）和细胞周期蛋白D1的蛋白表达。总之，结果表明高膳食Pi可能通过发育中小鼠的Akt-ERK信号传导扰乱正常的脑生长。
