Adaptive response to l-serine deficiency is mediated by p38 MAPK activation via 1-deoxysphinganine in normal fibroblasts

Tomoko Sayano, Yuki Kawano, Wataru Kusada, Yashiho Arimoto, Kayoko Esaki, Momoko Hamano, Miyako Udono, Yoshinori Katakura, Takuya Ogawa, Hisanori Kato, Yoshio Hirabayashi, Shigeki Furuya

研究成果: ジャーナルへの寄稿学術誌査読

11 被引用数 (Scopus)

抄録

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. Database: Gene Expression Omnibus, accession number GSE55687. Using 3-phosphoglycerate dehydrogenase (Phgdh)-deficient mouse embryonic fibroblasts, we explored l-serine deficiency. Cell proliferation was reduced, but Cdkn1a/p21 expression was induced, mediated by p38 MAPK. These observations suggest 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.

本文言語英語
ページ(範囲)303-316
ページ数14
ジャーナルFEBS Open Bio
6
4
DOI
出版ステータス出版済み - 4月 1 2016

!!!All Science Journal Classification (ASJC) codes

  • 生化学、遺伝学、分子生物学(全般)

フィンガープリント

「Adaptive response to l-serine deficiency is mediated by p38 MAPK activation via 1-deoxysphinganine in normal fibroblasts」の研究トピックを掘り下げます。これらがまとまってユニークなフィンガープリントを構成します。

引用スタイル