PMID- 24947365
OWN - NLM
STAT- MEDLINE
DCOM- 20141118
LR  - 20211021
IS  - 1939-327X (Electronic)
IS  - 0012-1797 (Print)
IS  - 0012-1797 (Linking)
VI  - 63
IP  - 10
DP  - 2014 Oct
TI  - Cyclin D1 represses gluconeogenesis via inhibition of the transcriptional 
      coactivator PGC1alpha.
PG  - 3266-78
LID - 10.2337/db13-1283 [doi]
AB  - Hepatic gluconeogenesis is crucial to maintain normal blood glucose during 
      periods of nutrient deprivation. Gluconeogenesis is controlled at multiple levels 
      by a variety of signal transduction and transcriptional pathways. However, 
      dysregulation of these pathways leads to hyperglycemia and type 2 diabetes. While 
      the effects of various signaling pathways on gluconeogenesis are well 
      established, the downstream signaling events repressing gluconeogenic gene 
      expression are not as well understood. The cell-cycle regulator cyclin D1 is 
      expressed in the liver, despite the liver being a quiescent tissue. The most 
      well-studied function of cyclin D1 is activation of cyclin-dependent kinase 4 
      (CDK4), promoting progression of the cell cycle. We show here a novel role for 
      cyclin D1 as a regulator of gluconeogenic and oxidative phosphorylation (OxPhos) 
      gene expression. In mice, fasting decreases liver cyclin D1 expression, while 
      refeeding induces cyclin D1 expression. Inhibition of CDK4 enhances the 
      gluconeogenic gene expression, whereas cyclin D1-mediated activation of CDK4 
      represses the gluconeogenic gene-expression program in vitro and in vivo. 
      Importantly, we show that cyclin D1 represses gluconeogenesis and OxPhos in part 
      via inhibition of peroxisome proliferator-activated receptor gamma coactivator-1alpha 
      (PGC1alpha) activity in a CDK4-dependent manner. Indeed, we demonstrate that PGC1alpha is 
      novel cyclin D1/CDK4 substrate. These studies reveal a novel role for cyclin D1 
      on metabolism via PGC1alpha and reveal a potential link between cell-cycle regulation 
      and metabolic control of glucose homeostasis.
CI  - (c) 2014 by the American Diabetes Association. Readers may use this article as long 
      as the work is properly cited, the use is educational and not for profit, and the 
      work is not altered.
FAU - Bhalla, Kavita
AU  - Bhalla K
AD  - Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of 
      Medicine, Baltimore, MD.
FAU - Liu, Wan-Ju
AU  - Liu WJ
AD  - Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of 
      Medicine, Baltimore, MD.
FAU - Thompson, Keyata
AU  - Thompson K
AD  - Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of 
      Medicine, Baltimore, MD.
FAU - Anders, Lars
AU  - Anders L
AD  - Dana-Farber Cancer Institute, Boston, MA.
FAU - Devarakonda, Srikripa
AU  - Devarakonda S
AD  - Dana-Farber Cancer Institute, Boston, MA.
FAU - Dewi, Ruby
AU  - Dewi R
AD  - Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of 
      Medicine, Baltimore, MD.
FAU - Buckley, Stephanie
AU  - Buckley S
AD  - Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of 
      Medicine, Baltimore, MD.
FAU - Hwang, Bor-Jang
AU  - Hwang BJ
AD  - Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of 
      Medicine, Baltimore, MD.
FAU - Polster, Brian
AU  - Polster B
AD  - Department of Anesthesiology, University of Maryland School of Medicine, 
      Baltimore, MD.
FAU - Dorsey, Susan G
AU  - Dorsey SG
AD  - Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of 
      Medicine, Baltimore, MD Department of Organizational Systems and Adult Health, 
      University of Maryland School of Nursing, Baltimore, MD.
FAU - Sun, Yezhou
AU  - Sun Y
AD  - Institute for Genome Sciences, University of Maryland School of Medicine, 
      Baltimore, MD.
FAU - Sicinski, Piotr
AU  - Sicinski P
AD  - Dana-Farber Cancer Institute, Boston, MA Department of Genetics, Harvard Medical 
      School, Boston, MA.
FAU - Girnun, Geoffrey D
AU  - Girnun GD
AD  - Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of 
      Medicine, Baltimore, MD Department of Biochemistry and Molecular Biology, 
      University of Maryland School of Medicine, Baltimore, MD Department of Pathology, 
      Stony Brook School of Medicine, Stony Brook, NY 
      geoffrey.girnun@stonybrookmedicine.edu.
LA  - eng
GR  - K01 DK064685/DK/NIDDK NIH HHS/United States
GR  - CA169919/CA/NCI NIH HHS/United States
GR  - R01 CA169919/CA/NCI NIH HHS/United States
GR  - DK064685/DK/NIDDK NIH HHS/United States
GR  - R01 CA083688/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20140619
PL  - United States
TA  - Diabetes
JT  - Diabetes
JID - 0372763
RN  - 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha)
RN  - 0 (Ppargc1a protein, mouse)
RN  - 0 (Transcription Factors)
RN  - 136601-57-5 (Cyclin D1)
RN  - EC 2.7.11.22 (Cyclin-Dependent Kinase 4)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
CIN - Diabetes. 2014 Oct;63(10):3177-9. PMID: 25249644
MH  - Animals
MH  - COS Cells
MH  - Chlorocebus aethiops
MH  - Cyclin D1/genetics/*metabolism
MH  - Cyclin-Dependent Kinase 4/genetics/*metabolism
MH  - Eating/physiology
MH  - Fasting/metabolism
MH  - Gluconeogenesis/*genetics
MH  - Glucose/metabolism
MH  - Hep G2 Cells
MH  - Homeostasis/physiology
MH  - Humans
MH  - Liver/*metabolism
MH  - Mice
MH  - Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
MH  - Transcription Factors/genetics/*metabolism
PMC - PMC4392904
EDAT- 2014/06/21 06:00
MHDA- 2014/11/19 06:00
PMCR- 2015/10/01
CRDT- 2014/06/21 06:00
PHST- 2014/06/21 06:00 [entrez]
PHST- 2014/06/21 06:00 [pubmed]
PHST- 2014/11/19 06:00 [medline]
PHST- 2015/10/01 00:00 [pmc-release]
AID - db13-1283 [pii]
AID - 1283 [pii]
AID - 10.2337/db13-1283 [doi]
PST - ppublish
SO  - Diabetes. 2014 Oct;63(10):3266-78. doi: 10.2337/db13-1283. Epub 2014 Jun 19.