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

7 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

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p38 Mitogen-Activated Protein Kinases
Fibroblasts
Serine
Chemical activation
Phosphoglycerate Dehydrogenase
Cell proliferation
Cells
Cell Proliferation
Protein Kinases
1-deoxysphinganine
Cell Survival
Cell Cycle
MAP Kinase Kinase 4
Cyclin-Dependent Kinases
Heat-Shock Proteins
Ablation
Gene expression
Alanine
Availability
Databases

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Adaptive response to l-serine deficiency is mediated by p38 MAPK activation via 1-deoxysphinganine in normal fibroblasts. / Sayano, Tomoko; Kawano, Yuki; Kusada, Wataru; Arimoto, Yashiho; Esaki, Kayoko; Hamano, Momoko; Udono, Miyako; Katakura, Yoshinori; Ogawa, Takuya; Kato, Hisanori; Hirabayashi, Yoshio; Furuya, Shigeki.

In: FEBS Open Bio, Vol. 6, No. 4, 01.04.2016, p. 303-316.

Research output: Contribution to journalArticle

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, vol. 6, no. 4, pp. 303-316. https://doi.org/10.1002/2211-5463.12038
Sayano, Tomoko ; Kawano, Yuki ; Kusada, Wataru ; Arimoto, Yashiho ; Esaki, Kayoko ; Hamano, Momoko ; Udono, Miyako ; Katakura, Yoshinori ; Ogawa, Takuya ; Kato, Hisanori ; Hirabayashi, Yoshio ; Furuya, Shigeki. / Adaptive response to l-serine deficiency is mediated by p38 MAPK activation via 1-deoxysphinganine in normal fibroblasts. In: FEBS Open Bio. 2016 ; Vol. 6, No. 4. pp. 303-316.
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