Reciprocal regulation of p53 and NF-κB by diacylglycerol kinase ζ.
Adv Biol Regul
; 60: 15-21, 2016 Jan.
Article
de En
| MEDLINE
| ID: mdl-26521214
ABSTRACT
Diacylglycerol kinase (DGK) participates in lipid mediated-signal transduction. It phosphorylates diacylglycerol (DG) to phosphatidic acid (PA), thereby regulating the balanced control of these second messenger actions. Previous reports have described that one DGK family, DGKζ, is closely involved in stress responses under various conditions. Cellular stress response, a physiological process enabling cells to cope with an altered environment, is finely tuned through various signaling cascades and their molecular crosstalk. The major components of stress response are p53 and NF-κB. p53 generally serves as a proapoptotic transcriptional factor, whereas NF-κB promotes resistance to programmed cell death under most circumstances. Recent studies have suggested that DGKζ facilitates p53 degradation in cytoplasm through ubiquitin proteasome system and that DGKζ deletion upregulates p53 protein levels under basal and DNA-damage conditions. Counter-intuitively, however, DGKζ deletion suppresses p53 transcriptional activity despite increased p53 levels. In contrast, DGKζ knockdown engenders enhancement of NF-κB pathway in response to cytokines such as TNF-α and IL-1ß. In response to these cytokines, DGKζ downregulation accelerates phosphorylation of the p65 subunit and its nuclear translocation, thereby enhancing NF-κB transcriptional activity. Furthermore, DGKζ deficiency is shown to promote increased association of p65 subunit with the transcriptional cofactor CBP. It is particularly interesting that this association is observed even under basal conditions in the absence of stimulation. These findings suggest that DGKζ plays a role in sequestration of the limiting pool of CBP/p300 between the NF-κB p65 subunit and p53, and that DGKζ downregulation shifts CBP/p300 toward the NF-κB subunit to regulate reciprocally antagonistic phenotypes of these transcription factors.
Mots clés
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Régulation de l'expression des gènes
/
Facteur de transcription NF-kappa B
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Protéine p53 suppresseur de tumeur
/
Diacylglycérol kinase
Limites:
Animals
/
Humans
Langue:
En
Journal:
Adv Biol Regul
Année:
2016
Type de document:
Article
Pays de publication:
ENGLAND
/
ESCOCIA
/
GB
/
GREAT BRITAIN
/
INGLATERRA
/
REINO UNIDO
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SCOTLAND
/
UK
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UNITED KINGDOM