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Publication
Cyclin D1-Cdk4 controls glucose metabolism independently of cell cycle
progression.
Authors Lee Y, Dominy JE, Choi YJ, Jurczak M, Tolliday N, Camporez JP, Chim H, Lim JH,
Ruan HB, Yang X, Vazquez F, Sicinski P, Shulman GI, Puigserver P
Submitted By Submitted Externally on 7/24/2015
Status Published
Journal Nature
Year 2014
Date Published 6/26/2014
Volume : Pages 510 : 547 - 551
PubMed Reference 24870244
Abstract Insulin constitutes a principal evolutionarily conserved hormonal axis for
maintaining glucose homeostasis; dysregulation of this axis causes diabetes.
PGC-1a (peroxisome-proliferator-activated receptor-? coactivator-1a) links
insulin signalling to the expression of glucose and lipid metabolic genes. The
histone acetyltransferase GCN5 (general control non-repressed protein 5)
acetylates PGC-1a and suppresses its transcriptional activity, whereas sirtuin 1
deacetylates and activates PGC-1a. Although insulin is a mitogenic signal in
proliferative cells, whether components of the cell cycle machinery contribute
to its metabolic action is poorly understood. Here we report that in mice
insulin activates cyclin D1-cyclin-dependent kinase 4 (Cdk4), which, in turn,
increases GCN5 acetyltransferase activity and suppresses hepatic glucose
production independently of cell cycle progression. Through a cell-based
high-throughput chemical screen, we identify a Cdk4 inhibitor that potently
decreases PGC-1a acetylation. Insulin/GSK-3ß (glycogen synthase kinase 3-beta)
signalling induces cyclin D1 protein stability by sequestering cyclin D1 in the
nucleus. In parallel, dietary amino acids increase hepatic cyclin D1 messenger
RNA transcripts. Activated cyclin D1-Cdk4 kinase phosphorylates and activates
GCN5, which then acetylates and inhibits PGC-1a activity on gluconeogenic genes.
Loss of hepatic cyclin D1 results in increased gluconeogenesis and
hyperglycaemia. In diabetic models, cyclin D1-Cdk4 is chronically elevated and
refractory to fasting/feeding transitions; nevertheless further activation of
this kinase normalizes glycaemia. Our findings show that insulin uses components
of the cell cycle machinery in post-mitotic cells to control glucose homeostasis
independently of cell division.








Genes
SymbolDescription
Ccnd1cyclin D1

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