Studies on the mechanism of functional food components at molecular basis focusing on phosphorylation hub protein.

食用一定量的蔬菜和水果与生活方式相关疾病（包括癌症）的发病率呈负相关。为了从分子基础上阐明蔬菜和水果植物化学物质的抗癌作用，我们重点研究了将各种细胞内刺激转化为磷酸化信号的磷酸化枢纽蛋白。凋亡信号调节激酶1（Apoptosis signal- regulatory kinase 1, ASK1）是位于应激负责激酶SAPK/JNK上游的典型磷酸化枢纽蛋白，可将细胞内刺激转化为磷酸化信号；ASK1也是MAPKK的一种。在静止细胞中，细胞内ASK1与硫氧还蛋白（Trx）结合使其生物活性失活；Trx中半胱氨酸残基的氧化导致ASK1的激活。在这项研究中，我们首次证明了大蒜衍生的抗癌化合物二烯丙基三硫化物在Trx分子的半胱氨酸残基之间形成二硫键，随后在白血病细胞中激活ASK1并形成所谓的信号体。这种由三硫二烯丙基对半胱氨酸残基的氧化修饰是导致细胞凋亡的原因。

Consumption of a certain amount of vegetables and fruits negatively correlates with the incidence of life-style related diseases including cancer. To clarify the anti-cancer effect of phytochemicals derived from vegetables and fruits at molecular basis, we focused on phosphorylation-hub protein which converts various intracellular stimuli into the phosphorylation signals. Apoptosis signal-regulating kinase 1(ASK1), a typical phosphorylation hub protein locating at the up-stream of stress-responsible kinase, SAPK/JNK, converts the intracellular stimuli to phosphorylation signals ; ASK1 is also a sort of MAPKK. In the quiescent cells, intracellular ASK1 binds with thioredoxin(Trx) to inactivate its biological activity ; oxidation of cysteine residues in Trx causes the activation of ASK1. In this study, we demonstrated for the first time that garlic derived anti-cancer compound, diallyl trisulfide, formed disulfide bond between cysteine residues in Trx molecule, followed by activation of ASK1 and formation of so-called signalsome in leukemic cells. This oxidative modification by diallyl trisulfide of the cysteine residues is a causative of apoptosi in the cells.