+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Activation of 5'-AMP-activated kinase with diabetes drug metformin induces casein kinase Iepsilon (CKIepsilon)-dependent degradation of clock protein mPer2

Activation of 5'-AMP-activated kinase with diabetes drug metformin induces casein kinase Iepsilon (CKIepsilon)-dependent degradation of clock protein mPer2

Journal of Biological Chemistry 282(29): 20794-8

Metformin is one of the most commonly used first line drugs for type II diabetes. Metformin lowers serum glucose levels by activating 5'-AMP-activated kinase (AMPK), which maintains energy homeostasis by directly sensing the AMP/ATP ratio. AMPK plays a central role in food intake and energy metabolism through its activities in central nervous system and peripheral tissues. Since food intake and energy metabolism is synchronized to the light-dark (LD) cycle of the environment, we investigated the possibility that AMPK may affect circadian rhythm. We discovered that the circadian period of Rat-1 fibroblasts treated with metformin was shortened by 1 h. One of the regulators of the period length is casein kinase I epsilon (CKI epsilon), which by phosphorylating and inducing the degradation of the circadian clock component, mPer2, shortens the period length. AMPK phosphorylates Ser-389 of CKI epsilon, resulting in increased CKI epsilon activity and degradation of mPer2. In peripheral tissues, injection of metformin leads to mPer2 degradation and a phase advance in the circadian expression pattern of clock genes in wild-type mice but not in AMPK alpha 2 knock-out mice. We conclude that metformin and AMPK have a previously unrecognized role in regulating the circadian rhythm.

Please choose payment method:

(PDF emailed within 0-6 h: $19.90)

Accession: 051341707

Download citation: RISBibTeXText

PMID: 17525164

DOI: 10.1074/jbc.c700070200

Related references

Activation of 5-AMP-activated Kinase with Diabetes Drug Metformin Induces Casein Kinase I (CKI)-dependent Degradation of Clock Protein mPer2. The Journal of Biological Chemistry 282(29): 794-8, 2007

Interactions between Casein kinase Iepsilon (CKIepsilon) and two substrates from disparate signaling pathways reveal mechanisms for substrate-kinase specificity. Plos one 4(3): E4766, 2009

The receptor tyrosine kinase Ror2 associates with and is activated by casein kinase Iepsilon. Journal of Biological Chemistry 279(48): 50102-9, 2004

SCFbeta-TRCP controls clock-dependent transcription via casein kinase 1-dependent degradation of the mammalian period-1 (Per1) protein. Journal of Biological Chemistry 280(29): 26863-26872, 2005

Synergistic activation by Ras and 14-3-3 protein of a mitogen-activated protein kinase kinase kinase named Ras-dependent extracellular signal-regulated kinase kinase stimulator. Journal of Biological Chemistry 269(37): 22917-22920, 1994

Sodium salicylate induces apoptosis via p38 mitogen-activated protein kinase but inhibits tumor necrosis factor-induced c-Jun N-terminal kinase/stress-activated protein kinase activation. Proceedings of the National Academy of Sciences of the United States of America 94(7): 2869-2873, 1997

Role of interleukin (IL)-2 receptor beta-chain subdomains and Shc in p38 mitogen-activated protein (MAP) kinase and p54 MAP kinase (stress-activated protein Kinase/c-Jun N-terminal kinase) activation. IL-2-driven proliferation is independent of p38 and p54 MAP kinase activation. Journal of Biological Chemistry 274(11): 7591-7597, 1999

Negative control of circadian clock regulator E4BP4 by casein kinase Iepsilon-mediated phosphorylation. Current Biology 14(11): 975-980, 2004

The ankyrin repeat protein Diversin recruits Casein kinase Iepsilon to the beta-catenin degradation complex and acts in both canonical Wnt and Wnt/JNK signaling. Genes and Development 16(16): 2073-2084, 2002

Activation of a nuclear Cdc2-related kinase within a mitogen-activated protein kinase-like TDY motif by autophosphorylation and cyclin-dependent protein kinase-activating kinase. Molecular and Cellular Biology 25(14): 6047-6064, 2005

Activation of AMP-activated Protein Kinase by Metformin Induces Protein Acetylation in Prostate and Ovarian Cancer Cells. Journal of Biological Chemistry 291(48): 25154-25166, 2016