title: Adaptive response to l-serine deficiency is mediated by p38 MAPK activation via 1-deoxysphinganine in normal fibroblasts.
abstract: 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.
authors.affiliation: 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.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Sayano
authors.affiliation: Department of Bioscience and Biotechnology Graduate School of Bioresource and Bioenvironmental Sciences Kyushu University Fukuoka Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kawano
authors.affiliation: Department of Bioscience and Biotechnology Graduate School of Bioresource and Bioenvironmental Sciences Kyushu University Fukuoka Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Kusada
authors.affiliation: Department of Bioscience and Biotechnology Graduate School of Bioresource and Bioenvironmental Sciences Kyushu University Fukuoka Japan.
authors.forename: Yashiho
authors.initials: Y
authors.lastname: Arimoto
authors.affiliation: 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.
authors.forename: Kayoko
authors.initials: K
authors.lastname: Esaki
authors.affiliation: Department of Bioscience and Biotechnology Graduate School of Bioresource and Bioenvironmental Sciences Kyushu University Fukuoka Japan.
authors.forename: Momoko
authors.initials: M
authors.lastname: Hamano
authors.affiliation: Department of Genetic Resources Technology Graduate School of Bioresource and Bioenvironmental Sciences Kyushu University Fukuoka Japan.
authors.forename: Miyako
authors.initials: M
authors.lastname: Udono
authors.affiliation: Department of Genetic Resources Technology Graduate School of Bioresource and Bioenvironmental Sciences Kyushu University Fukuoka Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Katakura
authors.affiliation: Department of Pharmaceutical Sciences International University of Health and Welfare Tochigi Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Ogawa
authors.affiliation: Corporate Sponsored Research Program 'Food for Life', Organization for Interdisciplinary Research Projects The University of Tokyo Japan.
authors.forename: Hisanori
authors.initials: H
authors.lastname: Kato
authors.affiliation: Laboratory for Molecular Membrane Neuroscience RIKEN Brain Science Institute Wako Saitama Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hirabayashi
authors.affiliation: 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; Department of Bioscience and Biotechnology Graduate School of Bioresource and Bioenvironmental Sciences Kyushu University Fukuoka Japan; Department of Genetic Resources Technology Graduate School of Bioresource and Bioenvironmental Sciences Kyushu University Fukuoka Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Furuya
keywords: cell proliferation; nutritional stress; p21; p38 MAPK; serine deficiency