Moonlighting function of glycerol kinase causes systems-level changes in rat hepatoma cells.
Glycerol kinase (GK) is an enzyme with diverse (moonlighting) cellular functions. GK overexpression affects central metabolic fluxes substantially; therefore, to elucidate the mechanism underlying these changes, we employed a systems-level evaluation of GK overexpression in H4IIE rat hepatoma cells. Microarray analysis revealed altered expression of genes in metabolism (central carbon and lipid), which correlated with previous flux analysis, and of genes regulated by the glucocorticoid receptor (GR). Oil Red O staining showed that GK overexpression leads to increased fat storage in H4IIE cells. Network component analysis revealed that activities of peroxisome proliferator-activated receptor alpha, GR, and seven other transcription factors were altered by GK overexpression. The increased activity of GR was experimentally verified by quantitative RT-PCR of GR-responsive genes in the presence and absence of the glucocorticoid agonist, dexamethasone. This systems biology approach further emphasizes GK's essential role in central and lipid metabolism and experimentally verifies GK's alternative (moonlighting) function of affecting GR transcription factor activity.
Sriram
Ganesh
G
Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-7088, USA.
Parr
Lilly S
LS
Rahib
Lola
L
Liao
James C
JC
Dipple
Katrina M
KM
D000818:Animals; D002244:Carbon / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000378:metabolism; D005991:Glycerol Kinase; D050356:Lipid Metabolism; D047493:PPAR alpha / Q000378:metabolism; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D049490:Systems Biology; D014157:Transcription Factors / Q000378:metabolism
D002352:Carrier Proteins; D047493:PPAR alpha; D011965:Receptors, Glucocorticoid; D014157:Transcription Factors; D002244:Carbon; D003907:Dexamethasone; C485945:Gk protein, rat; D005991:Glycerol Kinase
Metab Eng. 2007 May;9(3):241-51
17240181
Mol Genet Metab. 2008 Feb;93(2):145-59
18029214
J Med Genet. 2000 Jun;37(6):434-41
10851254
Mol Genet Metab. 2001 Sep-Oct;74(1-2):45-50
11592802
Hum Genet. 2001 Jul;109(1):55-62
11479736
Mol Genet Metab. 2006 Aug;88(4):334-45
16545593
Endocrinology. 1989 Feb;124(2):675-80
2912694
Mol Genet Metab. 2009 Mar;96(3):106-12
19121967
Hum Mol Genet. 2006 Feb 1;15(3):405-15
16368706
PLoS Genet. 2005 Aug;1(2):e16
16110340
Eur J Hum Genet. 2007 Jun;15(6):646-57
17406644
Methods. 2001 Dec;25(4):402-8
11846609
Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15522-7
14673099
Am J Hum Genet. 2005 Jun;76(6):911-24
15877277
Biochem Biophys Res Commun. 1984 Jun 29;121(3):940-5
6378197
Am J Hum Genet. 2000 May;66(5):1558-68
10736265
Plant Physiol. 2004 Oct;136(2):3043-57
15466217
Endocrinology. 2004 Mar;145(3):1087-95
14670991
Biochem Biophys Res Commun. 1993 Jun 30;193(3):848-54
8323560
Bioinformatics. 2006 Aug 1;22(15):1886-94
16766556
Biochem Med. 1983 Oct;30(2):231-45
6316940
Mol Genet Metab. 2003 Dec;80(4):412-8
14654354
Mol Genet Metab. 2000 Sep-Oct;71(1-2):43-50
11001794
J Clin Invest. 2004 Jul;114(1):94-103
15232616
Nat Med. 2002 Oct;8(10):1122-8
12357248
Mol Endocrinol. 2003 Aug;17(8):1534-42
12750452
Mol Endocrinol. 2004 Apr;18(4):807-19
15044597
Metab Eng. 2007 Jan;9(1):52-67
17097906
Clin Cancer Res. 2006 Apr 1;12(7 Pt 1):1983-93
16609007
Metabolism. 2005 Oct;54(10):1282-9
16154425
J Clin Invest. 2006 Mar;116(3):615-22
16511594
J Toxicol Sci. 2006 Dec;31(5):471-90
17202761
Biochim Biophys Acta. 2004 Oct 21;1680(2):114-28
15488991
J Biol Chem. 2003 May 23;278(21):18785-90
12644461
Am J Hum Genet. 2000 Jun;66(6):1729-35
10793008
PLoS One. 2009;4(4):e5197
19381295