Open AccessAdaptive response to l ‐serine deficiency is mediated by p38 MAPK activation via 1‐deoxysphinganine in normal fibroblasts
Author(s) -
Sayano Tomoko,
Kawano Yuki,
Kusada Wataru,
Arimoto Yashiho,
Esaki Kayoko,
Hamano Momoko,
Udono Miyako,
Katakura Yoshinori,
Ogawa Takuya,
Kato Hisanori,
Hirabayashi Yoshio,
Furuya Shigeki
Publication year - 2016
Publication title -
febs open bio
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.718
H-Index - 31
ISSN - 2211-5463
DOI - 10.1002/2211-5463.12038
Subject(s) - serine , embryonic stem cell , microbiology and biotechnology , p38 mitogen activated protein kinases , kinase , mapk/erk pathway , biology , cell growth , chemistry , phosphorylation , biochemistry , gene
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 .