Senescence-inducing stress promotes proteolysis of phosphoglycerate mutase via ubiquitin ligase Mdm2.
J Cell Biol
; 204(5): 729-45, 2014 Mar 03.
Article
em En
| MEDLINE
| ID: mdl-24567357
ABSTRACT
Despite the well-documented clinical significance of the Warburg effect, it remains unclear how the aggressive glycolytic rates of tumor cells might contribute to other hallmarks of cancer, such as bypass of senescence. Here, we report that, during oncogene- or DNA damage-induced senescence, Pak1-mediated phosphorylation of phosphoglycerate mutase (PGAM) predisposes the glycolytic enzyme to ubiquitin-mediated degradation. We identify Mdm2 as a direct binding partner and ubiquitin ligase for PGAM in cultured cells and in vitro. Mutations in PGAM and Mdm2 that abrogate ubiquitination of PGAM restored the proliferative potential of primary cells under stress conditions and promoted neoplastic transformation. We propose that Mdm2, a downstream effector of p53, attenuates the Warburg effect via ubiquitination and degradation of PGAM.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Estresse Fisiológico
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Senescência Celular
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Fosfoglicerato Mutase
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Proteínas Proto-Oncogênicas c-mdm2
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article