Page 282 - Read Online
P. 282
Magee et al. Egr1 in liver metabolism and cancer
sensitivity to chemotherapeutics could be applied Ethics approval
as a novel approach for HCC therapy. In addition, Not applicable.
whether the current discrepancies on Egr1 function in
HCC could be due to a dual role of Egr1 during HCC REFERENCES
development, first acting as an activator and then as
a repressor, still remains elusive and requires further 1. Milbrandt J. A nerve growth factor-induced gene encodes a possible
investigation. transcriptional regulatory factor. Science 1987;238:797-9.
2. Kaufmann K, Bach K, Thiel G. The extracellular signal-regulated
protein kinases Erk1/Erk2 stimulate expression and biological activity
CONCLUSION of the transcriptional regulator Egr-1. Biol Chem 2001;382:1077-81.
3. Gashler AL, Swaminathan S, Sukhatme VP. A novel repression
As a Zinc-finger transcription factor, Egr1 has a module, an extensive activation domain, and a bipartite nuclear
diverse range of functions implicated in various cell localization signal defined in the immediate-early transcription factor
Egr-1. Mol Cell Biol 1993;13:4556-71.
types. The major roles of Egr1 in liver diseases are 4. Cui L, Schoene NW, Zhu L, Fanzo JC, Alshatwi A, Lei KY. Zinc
summarized and depicted in Figure 2. Research depletion reduced Egr-1 and HNF-3beta expression and apolipoprotein
efforts using various animal models such as fatty liver, A-I promoter activity in Hep G2 cells. Am J Physiol Cell Physiol
liver injury and fibrosis have contributed greatly to the 2002;283:C623-30.
elucidation of Egr1 liver-specific function. However, in 5. Duclot F, Kabbaj M. The role of early growth response 1 (EGR1) in
some instances, such as in insulin signaling as well brain plasticity and neuropsychiatric disorders. Front Behav Neurosci
2017;11:35.
as HCC studies, the data regarding the role of Egr1 6. Swirnoff AH, Apel ED, Svaren J, Sevetson BR, Zimonjic DB,
are contradictory. Hence, much progress is required Popescu NC, Milbrandt J. Nab1, a corepressor of NGFI-A (Egr-1),
to uncover and characterize the role of Egr1 in various contains an active transcriptional repression domain. Mol Cell Biol
types of cells in the regulation of normal liver function. 1998;18:512-24.
For example, studying the effects of insulin signaling, 7. Sevetson BR, Svaren J, Milbrandt J. A novel activation function
for NAB proteins in EGR-dependent transcription of the luteinizing
APAP, ethanol, or CCL 4 in hepatocyte-specific or hormone beta gene. J Biol Chem 2000;275:9749-57.
macrophage-specific Egr1 knockout models are 8. Li XJ, Wang KM, Xu Y, Wang ZH, Xia AD, Chen SS, Qian GX.
greatly appreciated. Utilization of primary cell cultures Ionizing radiation-regulated killing of human hepatoma cells by
(such as hepatocytes, stellate cells, and macrophages) liposome-mediated CDglyTK gene delivery. Sheng Wu Hua Xue Yu
from normal liver to assess Egr1 functions may also Sheng Wu Wu Li Xue Bao (Shanghai) 2003;35:64-70. (in Chinese)
aid in elucidation of liver-specific Egr1 regulation. On 9. Keeton AB, Bortoff KD, Bennett WL, Franklin JL, Venable DY,
Messina JL. Insulin-regulated expression of Egr-1 and Krox20:
the other hand, due to its regulation of key fibrotic dependence on ERK1/2 and interaction with p38 and PI3-kinase
mediators, Egr1 may be a promising target for anti- pathways. Endocrinology 2003;144:5402-10.
fibrotic therapy. Overall, much progress is required to 10. Chen SJ, Ning H, Ishida W, Sodin-Semrl S, Takagawa S, Mori Y,
uncover and characterize the cell-type specific role of Varga J. The early-immediate gene EGR-1 is induced by transforming
Egr1 in the liver. Improving our understanding of Egr1 growth factor-beta and mediates stimulation of collagen gene
expression. J Biol Chem 2006;281:21183-97.
in liver metabolism and liver cancer may provide new 11. Zhang Y, Bonzo JA, Gonzalez FJ, Wang L. Diurnal regulation of the
insights to facilitate developing novel treatments or early growth response 1 (Egr-1) protein expression by hepatocyte
prevention strategies for liver diseases. nuclear factor 4alpha (HNF4alpha) and small heterodimer partner
(SHP) cross-talk in liver fibrosis. J Biol Chem 2011;286:29635-43.
DECLARATIONS 12. Zhang Y, Xu N, Xu J, Kong B, Copple B, Guo GL, Wang L. E2F1 is
a novel fibrogenic gene that regulates cholestatic liver fibrosis through
the Egr-1/SHP/EID1 network. Hepatology 2014;60:919-30.
Authors’ contributions 13. Zhu HY, Bai WD, Wang HT, Xie ST, Tao K, Su LL, Liu JQ, Yang
Reviewed the literature and wrote the manuscript: N. XK, Li J, Wang YC, He T, Han JT, Hu DH. Peroxisome proliferator-
Magee, Y. Zhang activated receptor-gamma agonist inhibits collagen synthesis in
human keloid fibroblasts by suppression of early growth response-1
Financial support and sponsorship expression through upregulation of miR-543 expression. Am J Cancer
Res 2016;6:1358-70.
This work was supported by the National Institutes 14. Dussmann P, Pagel JI, Vogel S, Magnusson T, Zimmermann R,
of Health grants NCIK22CA184146, P20GM103549, Wagner E, Schaper W, Ogris M, Deindl E. Live in vivo imaging
P20GM103418, P30GM118247, and T32ES007079. of Egr-1 promoter activity during neonatal development, liver
regeneration and wound healing. BMC Dev Biol 2011;11:28.
Conflicts of Interest 15. Christy B, Nathans D. DNA binding site of the growth factor-inducible
The authors declare no conflicts of interest. protein Zif268. Proc Natl Acad Sci U S A 1989;86:8737-41.
16. Fagerberg L, Hallstrom BM, Oksvold P, Kampf C, Djureinovic
D, Odeberg J, Habuka M, Tahmasebpoor S, Danielsson A, Edlund
Patient consent K, Asplund A, Sjostedt E, Lundberg E, Szigyarto CA, Skogs M,
Not applicable. Takanen JO, Berling H, Tegel H, Mulder J, Nilsson P, Schwenk JM,
274 Hepatoma Research ¦ Volume 3 ¦ November 20, 2017