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

Research output: Contribution to journalArticle

8 Citations (Scopus)

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. 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.

Original languageEnglish
Pages (from-to)303-316
Number of pages14
JournalFEBS Open Bio
Volume6
Issue number4
DOIs
Publication statusPublished - Apr 1 2016

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'Adaptive response to l-serine deficiency is mediated by p38 MAPK activation via 1-deoxysphinganine in normal fibroblasts'. Together they form a unique fingerprint.

  • Cite this

    Sayano, T., Kawano, Y., Kusada, W., Arimoto, Y., Esaki, K., Hamano, M., Udono, M., Katakura, Y., Ogawa, T., Kato, H., Hirabayashi, Y., & Furuya, S. (2016). Adaptive response to l-serine deficiency is mediated by p38 MAPK activation via 1-deoxysphinganine in normal fibroblasts. FEBS Open Bio, 6(4), 303-316. https://doi.org/10.1002/2211-5463.12038