Sayano Tomoko, Kawano Yuki, Kusada Wataru, Arimoto Yashiho, Esaki Kayoko, Hamano Momoko, Udono Miyako, Katakura Yoshinori, Ogawa Takuya, Kato Hisanori, Hirabayashi Yoshio, Furuya Shigeki
Laboratory of Functional Genomics and Metabolism Department of Innovative Science and Technology for Bio-industry Graduate School of Bioresource and Bioenvironmental Sciences Kyushu University Fukuoka Japan; Laboratory for Molecular Membrane Neuroscience RIKEN Brain Science Institute Wako Saitama Japan.
Department of Bioscience and Biotechnology Graduate School of Bioresource and Bioenvironmental Sciences Kyushu University Fukuoka Japan.
FEBS Open Bio. 2016 Mar 3;6(4):303-16. doi: 10.1002/2211-5463.12038. eCollection 2016 Apr.
Reduced availability of l-serine limits cell proliferation and leads to an adaptation to l-serine-deficient environment, the underlying molecular mechanism of which remain largely unexplored. Genetic ablation of 3-phosphoglycerate dehydrogenase (Phgdh), which catalyzes the first step of de novo l-serine synthesis, led to diminished cell proliferation and the activation of p38 MAPK and stress-activated protein kinase/Jun amino-terminal kinase in mouse embryonic fibroblasts under l-serine depletion. The resultant l-serine deficiency induced cyclin-dependent kinase inhibitor 1a (Cdkn1a; p21) expression, which was mediated by p38 MAPK. Survival of the Phgdh-deficient mouse embryonic fibroblasts was markedly reduced by p38 MAPK inhibition under l-serine depletion, whereas p38 MAPK could be activated by 1-deoxysphinganine, an atypical alanine-derived sphingoid base that was found to accumulate in l-serine-depleted mouse embryonic fibroblasts. These observations provide persuasive evidence that when the external l-serine supply is limited, l-serine synthesized de novo in proliferating cells serves as a metabolic gatekeeper to maintain cell survival and the functions necessary for executing cell cycle progression.
Gene Expression Omnibus, accession number GSE55687.
L-丝氨酸可用性降低会限制细胞增殖，并导致细胞适应L-丝氨酸缺乏的环境，但其潜在的分子机制在很大程度上仍未被探索。3-磷酸甘油酸脱氢酶（Phgdh）催化L-丝氨酸从头合成的第一步，在L-丝氨酸耗竭的情况下，对小鼠胚胎成纤维细胞进行Phgdh基因敲除会导致细胞增殖减少以及p38丝裂原活化蛋白激酶（MAPK）和应激激活蛋白激酶/ Jun氨基末端激酶的激活。由此产生的L-丝氨酸缺乏诱导细胞周期蛋白依赖性激酶抑制剂1a（Cdkn1a；p21）表达，这是由p38 MAPK介导的。在L-丝氨酸耗竭的情况下，p38 MAPK抑制会显著降低Phgdh缺陷型小鼠胚胎成纤维细胞的存活率，而p38 MAPK可被1-脱氧鞘氨醇激活，1-脱氧鞘氨醇是一种非典型的源自丙氨酸的鞘脂碱，发现在L-丝氨酸耗竭的小鼠胚胎成纤维细胞中积累。这些观察结果提供了有说服力的证据，即当外部L-丝氨酸供应受到限制时，增殖细胞中从头合成的L-丝氨酸作为代谢守门人来维持细胞存活以及执行细胞周期进程所需的功能。
基因表达综合数据库，登录号GSE55687。
