The Transcription Factors Egr1 and Egr2 Have Opposing Influences on Adipocyte Differentiation

Overview

Journal Cell Death Differ

Specialty Cell Biology

Date 2009 Feb 21

PMID 19229250

Citations 55

Authors

K B Boyle

D Hadaschik

S Virtue

W P Cawthorn

S H Ridley

S ORahilly

K Siddle

Affiliations

Soon will be listed here.

Abstract

The zinc finger-containing transcription factors Egr1 (Krox24) and Egr2 (Krox20) have been implicated in the proliferation and differentiation of many cell types. Egr2 has earlier been shown to play a positive role in adipocyte differentiation, but the function of Egr1 in this context is unknown. We compared the roles of Egr1 and Egr2 in the differentiation of murine 3T3-L1 adipocytes. Egr1 protein was rapidly induced after addition of differentiation cocktail, whereas Egr2 protein initially remained low before increasing on days 1 and 2, concomitant with the disappearance of Egr1. In marked contrast to the effects of Egr2, differentiation was inhibited by ectopic expression of Egr1 and potentiated by knockdown of Egr1. The pro-adipogenic effects of Egr1 knockdown were particularly notable when isobutylmethylxanthine (IBMX) was omitted from the differentiation medium. However, knockdown of Egr1 did not affect CCAAT/enhancer binding protein (C/EBP)beta protein expression or phosphorylation of CREB Ser133. Further, Egr1 did not directly affect the activity of promoters for the master adipogenic transcription factors, C/EBPalpha or peroxisome proliferator-activated receptor-gamma2, as assessed in luciferase reporter assays. These data indicate that Egr1 and Egr2 exert opposing influences on adipocyte differentiation and that the careful regulation of both is required for maintaining appropriate levels of adipogenesis. Further, the pro-differentiation effects of IBMX involve suppression of the inhibitory influence of Egr1.

Citing Articles

Overexpression of Egr1 Transcription Regulator Contributes to Schwann Cell Differentiation Defects in Neural Crest-Specific Knockout Mice.

Zerad L, Gacem N, Gayda F, Day L, Sinigaglia K, Richard L Cells. 2024; 13(23).

PMID: 39682701 PMC: 11639873. DOI: 10.3390/cells13231952.

Shift work promotes adipogenesis via cortisol-dependent downregulation of EGR3-HDAC6 pathway.

Wan X, Wang L, Khan M, Peng L, Zhang K, Sun X Cell Death Discov. 2024; 10(1):129.

PMID: 38467615 PMC: 10928160. DOI: 10.1038/s41420-024-01904-9.

Genomic Prediction and Genome-Wide Association Study for Boar Taint Compounds.

Faggion S, Boschi E, Veroneze R, Carnier P, Bonfatti V Animals (Basel). 2023; 13(15).

PMID: 37570259 PMC: 10417264. DOI: 10.3390/ani13152450.

Diversity and heterogeneity in human breast cancer adipose tissue revealed at single-nucleus resolution.

Tang L, Li T, Xie J, Huo Y Front Immunol. 2023; 14:1158027.

PMID: 37153595 PMC: 10160491. DOI: 10.3389/fimmu.2023.1158027.

Comparative three-dimensional genome architectures of adipose tissues provide insight into human-specific regulation of metabolic homeostasis.

Liu P, Li D, Zhang J, He M, Gao D, Wang Y J Biol Chem. 2023; 299(6):104757.

PMID: 37116707 PMC: 10245122. DOI: 10.1016/j.jbc.2023.104757.

References

Yamauchi T, Oike Y, Kamon J, Waki H, Komeda K, Tsuchida A . Increased insulin sensitivity despite lipodystrophy in Crebbp heterozygous mice. Nat Genet. 2002; 30(2):221-6. DOI: 10.1038/ng829. View

Decker E, Nehmann N, Kampen E, Eibel H, Zipfel P, Skerka C . Early growth response proteins (EGR) and nuclear factors of activated T cells (NFAT) form heterodimers and regulate proinflammatory cytokine gene expression. Nucleic Acids Res. 2003; 31(3):911-21. PMC: 149206. DOI: 10.1093/nar/gkg186. View

Milbrandt J . A nerve growth factor-induced gene encodes a possible transcriptional regulatory factor. Science. 1987; 238(4828):797-9. DOI: 10.1126/science.3672127. View

Clarke S, ROBINSON C, Gimble J . CAAT/enhancer binding proteins directly modulate transcription from the peroxisome proliferator-activated receptor gamma 2 promoter. Biochem Biophys Res Commun. 1997; 240(1):99-103. DOI: 10.1006/bbrc.1997.7627. View

Reusch J, Colton L, Klemm D . CREB activation induces adipogenesis in 3T3-L1 cells. Mol Cell Biol. 2000; 20(3):1008-20. PMC: 85218. DOI: 10.1128/MCB.20.3.1008-1020.2000. View

Klemm D, Leitner J, Watson P, Nesterova A, Reusch J, Goalstone M . Insulin-induced adipocyte differentiation. Activation of CREB rescues adipogenesis from the arrest caused by inhibition of prenylation. J Biol Chem. 2001; 276(30):28430-5. DOI: 10.1074/jbc.M103382200. View

Carter J, Lefebvre J, Wiest D, Tourtellotte W . Redundant role for early growth response transcriptional regulators in thymocyte differentiation and survival. J Immunol. 2007; 178(11):6796-805. DOI: 10.4049/jimmunol.178.11.6796. View

Topilko P, Levi G, Merlo G, Mantero S, Desmarquet C, Mancardi G . Differential regulation of the zinc finger genes Krox-20 and Krox-24 (Egr-1) suggests antagonistic roles in Schwann cells. J Neurosci Res. 1998; 50(5):702-12. DOI: 10.1002/(SICI)1097-4547(19971201)50:5<702::AID-JNR7>3.0.CO;2-L. View

Ge K, Guermah M, Yuan C, Ito M, Wallberg A, Spiegelman B . Transcription coactivator TRAP220 is required for PPAR gamma 2-stimulated adipogenesis. Nature. 2002; 417(6888):563-7. DOI: 10.1038/417563a. View

10.

Farmer S . Transcriptional control of adipocyte formation. Cell Metab. 2006; 4(4):263-73. PMC: 1958996. DOI: 10.1016/j.cmet.2006.07.001. View

11.

Hamm J, Pilch P, Farmer S . Reconstitution of insulin-sensitive glucose transport in fibroblasts requires expression of both PPARgamma and C/EBPalpha. J Biol Chem. 1999; 274(12):7946-51. DOI: 10.1074/jbc.274.12.7946. View

12.

Tang Q, Jiang M, Lane M . Repression of transcription mediated by dual elements in the CCAAT/enhancer binding protein alpha gene. Proc Natl Acad Sci U S A. 1998; 94(25):13571-5. PMC: 28347. DOI: 10.1073/pnas.94.25.13571. View

13.

Nguyen H, Liebermann D . The zinc finger transcription factor Egr-1 is essential for and restricts differentiation along the macrophage lineage. Cell. 1993; 72(2):197-209. DOI: 10.1016/0092-8674(93)90660-i. View

14.

Birsoy K, Chen Z, Friedman J . Transcriptional regulation of adipogenesis by KLF4. Cell Metab. 2008; 7(4):339-47. PMC: 2430156. DOI: 10.1016/j.cmet.2008.02.001. View

15.

Collins S, Lutz M, Zarek P, Anders R, Kersh G, Powell J . Opposing regulation of T cell function by Egr-1/NAB2 and Egr-2/Egr-3. Eur J Immunol. 2008; 38(2):528-36. PMC: 3598016. DOI: 10.1002/eji.200737157. View

16.

Rosen E, MacDougald O . Adipocyte differentiation from the inside out. Nat Rev Mol Cell Biol. 2006; 7(12):885-96. DOI: 10.1038/nrm2066. View

17.

Lau L, Nathans D . Expression of a set of growth-related immediate early genes in BALB/c 3T3 cells: coordinate regulation with c-fos or c-myc. Proc Natl Acad Sci U S A. 1987; 84(5):1182-6. PMC: 304390. DOI: 10.1073/pnas.84.5.1182. View

18.

Christy R, Kaestner K, Geiman D, Lane M . CCAAT/enhancer binding protein gene promoter: binding of nuclear factors during differentiation of 3T3-L1 preadipocytes. Proc Natl Acad Sci U S A. 1991; 88(6):2593-7. PMC: 51279. DOI: 10.1073/pnas.88.6.2593. View

19.

Takahashi N, Kawada T, Yamamoto T, Goto T, Taimatsu A, Aoki N . Overexpression and ribozyme-mediated targeting of transcriptional coactivators CREB-binding protein and p300 revealed their indispensable roles in adipocyte differentiation through the regulation of peroxisome proliferator-activated receptor gamma. J Biol Chem. 2002; 277(19):16906-12. DOI: 10.1074/jbc.M200585200. View

20.

Fox K, Fankell D, Erickson P, Majka S, Crossno Jr J, Klemm D . Depletion of cAMP-response element-binding protein/ATF1 inhibits adipogenic conversion of 3T3-L1 cells ectopically expressing CCAAT/enhancer-binding protein (C/EBP) alpha, C/EBP beta, or PPAR gamma 2. J Biol Chem. 2006; 281(52):40341-53. DOI: 10.1074/jbc.M605077200. View