scholarly journals Early growth response transcription factors: Key mediators of fibrosis and novel targets for anti-fibrotic therapy

2011 ◽  
Vol 30 (4) ◽  
pp. 235-242 ◽  
Author(s):  
Swati Bhattacharyya ◽  
Minghua Wu ◽  
Feng Fang ◽  
Warren Tourtellotte ◽  
Carol Feghali-Bostwick ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Growth Response ◽  
Early Growth ◽  
Early Growth Response ◽  
Novel Targets

scholarly journals Ternary Complex Factors Elk-1 and Sap-1a Mediate Growth Hormone-Induced Transcription of Egr-1 (Early Growth Response Factor-1) in 3T3-F442A Preadipocytes

1999 ◽  
Vol 13 (4) ◽  
pp. 619-631 ◽  
Author(s):  
Richard W. E. Clarkson ◽  
Catherine A. Shang ◽  
Linda K. Levitt ◽  
Tammy Howard ◽  
Michael J. Waters
Keyword(s):  
Transcription Factors ◽  
Ternary Complex ◽  
Growth Response ◽  
Early Growth ◽  
Ternary Complexes ◽  
Response Factor ◽  
Site Specific ◽  
Early Growth Response ◽  
Ets Factors ◽  
Serum Response

Abstract In our search for transcription factors induced by GH, we have analyzed immediate early gene activation in a model of GH-dependent differentiation. Here we describe the activation of early growth response factor-1 (egr-1) in GH-stimulated 3T3-F442A preadipocytes and the transcription factors responsible for its transactivation. Binding activity of egr-1 in electrophoretic mobility shift assay (EMSA) increased transiently 1 h after GH stimulation, accompanied by a concomitant increase in egr-1 mRNA. egr-1 induction appeared not to be related to proliferation since it was amplified in quiescent preadipocytes at a time when cells were refractive to GH-stimulated DNA synthesis. Truncations of the proximal 1 kb of the egr-1 promoter revealed that a 374-bp region (−624 to −250) contributes about 80% of GH inducibility in 3T3-F442A cells and approximately 90% inducibility in CHO-K1 cells. This region contains three juxtaposed SRE (serum response element)/Ets site pairs known to be important for egr-1 activity in response to exogenous stimuli. Site-specific mutations of individual SRE and Ets sites within this region each reduced GH inducibility of the promoter. Use of these site-specific mutations in EMSA showed that disruption of either Ets or SRE sites abrogated ternary complex formation at the composite sites. DNA binding of ternary complexes, but not binary complexes, in EMSA was rapidly and transiently increased by GH. EMSA supershifts indicated these ternary complexes contained serum response factor (SRF) and the Ets factors Elk-1 and Sap-1a. Coexpression of Sap-1a and Elk-1 resulted in a marked increase in GH induction of egr-1 promoter activity, although transfection with expression vectors for either Ets factor alone did not significantly enhance the GH response. We conclude that GH stimulates transcription of egr-1 primarily through activation of these Ets factors at multiple sites on the promoter and that stabilization of ternary complexes with SRF at these sites maximizes this response.

Cell-extracellular matrix interactions can regulate the switch between growth and differentiation in rat hepatocytes: reciprocal expression of C/EBP alpha and immediate-early growth response transcription factors

1994 ◽  
Vol 14 (9) ◽  
pp. 5858-5869
Author(s):  
B Rana ◽  
D Mischoulon ◽  
Y Xie ◽  
N L Bucher ◽  
S R Farmer
Keyword(s):  
Extracellular Matrix ◽  
Transcription Factors ◽  
Dna Binding ◽  
Growth Response ◽  
Isolated Hepatocytes ◽  
Early Growth ◽  
Binding Activity ◽  
Early Growth Response ◽  
Dna Binding Activity ◽  
Rat Tail

Previous investigations have shown that culture of freshly isolated hepatocytes under conventional conditions, i.e., on dried rat tail collagen in the presence of growth factors, facilitates cell growth but also causes an extensive down-regulation of most liver-specific functions. This dedifferentiation process can be prevented if the cells are cultured on a reconstituted basement membrane gel matrix derived from the Englebreth-Holm-Swarm mouse sarcoma tumor (EHS gel). To gain insight into the mechanisms regulating this response to extracellular matrix, we are analyzing the activities of two families of transcription factors, C/EBP and AP-1, which control the transcription of hepatic and growth-responsive genes, respectively. We demonstrate that isolation of hepatocytes from the normal quiescent rat liver by collagenase perfusion activates the immediate-early growth response program, as indicated by increased expression of c-jun, junB, c-fos, and c-myc mRNAs. Adhesion of these activated cells to dried rat tail collagen augments the elevated levels of these mRNAs for the initial 1 to 2 h postplating; junB and c-myc mRNA levels then drop steeply, with junB returning to normal quiescence and the c-myc level remaining slightly elevated during the 3-day culture period. Levels of c-jun mRNA and AP-1 DNA binding activity, however, remain elevated from the outset, while C/EBP alpha mRNA expression is down-regulated, resulting in a decrease in the steady-state levels of the 42- and 30-kDa C/EBP alpha polypeptides and C/EBP alpha DNA binding activity. In contrast, C/EBP beta mRNA production remains at near-normal hepatic levels for 5 to 8 days of culture, although its DNA binding activity decreases severalfold during this time. Adhesion of hepatocytes to the EHS gel for the same period of time dramatically alters this program: it arrests growth and inhibits AP-1 DNA binding activity and the expression of c-jun, junB, and c-myc mRNAs, but, in addition, it restores C/EBP alpha mRNA and protein as well as C/EBP alpha and C/EBP beta DNA binding activities to the abundant levels present in freshly isolated hepatocytes. These changes are not due merely to growth inhibition, because suppression of hepatocyte proliferation on collagen by epidermal growth factor starvation or addition of transforming growth factor beta does not inhibit AP-1 activity or restore C/EBP alpha DNA binding activity to normal hepatic levels. These data suggest that expression of the normal hepatic phenotype requires that hepatocytes exist in a G0 state of growth arrest, facilitated here by adhesion of cells to the EHS gel, in order to express high levels of hepatic transcription factors such as C/EBP alpha.

scholarly journals O-032. The role of early growth response family of transcription factors in male fertility

1999 ◽  
Vol 14 (Suppl_3) ◽  
pp. 18-18
Author(s):  
C. Müller ◽  
A. Auyeung ◽  
C. Dorn ◽  
W. Tourtellotte ◽  
J. Milbrandt
Keyword(s):  
Transcription Factors ◽  
Male Fertility ◽  
Growth Response ◽  
Early Growth ◽  
Early Growth Response

scholarly journals The Neuroplasticity-Associated Arc Gene Is a Direct Transcriptional Target of Early Growth Response (Egr) Transcription Factors

2005 ◽  
Vol 25 (23) ◽  
pp. 10286-10300 ◽  
Author(s):  
Lin Li ◽  
John Carter ◽  
Xiaoguang Gao ◽  
Jennifer Whitehead ◽  
Warren G. Tourtellotte
Keyword(s):  
Transcription Factors ◽  
Synaptic Plasticity ◽  
Learning And Memory ◽  
Growth Response ◽  
Long Term Potentiation ◽  
Early Growth ◽  
Synaptic Activity ◽  
Early Growth Response ◽  
Arc Gene

ABSTRACT Early growth response (Egr) transcription factors (Egr1 to Egr4) are synaptic activity-inducible immediate early genes (IEGs) that regulate some aspects of synaptic plasticity-related to learning and memory, yet the target genes regulated by them are unknown. In particular, Egr1 is essential for persistence of late-phase long-term potentiation (L-LTP), for hippocampus-dependent long-term memory formation, and for reconsolidation of previously established memories. Here, we show that Egr1 and Egr3 directly regulate the plasticity-associated activity-regulated cytoskeletal-related (Arc) gene, a synaptic activity-induced effector molecule which is also required for L-LTP and hippocampus-dependent learning and memory processing. Moreover, Egr1-deficient and Egr3-deficient mice lack Arc protein in a subpopulation of neurons, while mice lacking both Egr1 and Egr3 lack Arc in all neurons. Thus, Egr1 and Egr3 can indirectly modulate synaptic plasticity by directly regulating Arc and the plasticity mechanisms it mediates in recently activated synapses.

scholarly journals Cell-extracellular matrix interactions can regulate the switch between growth and differentiation in rat hepatocytes: reciprocal expression of C/EBP alpha and immediate-early growth response transcription factors.

1994 ◽  
Vol 14 (9) ◽  
pp. 5858-5869 ◽  
Author(s):  
B Rana ◽  
D Mischoulon ◽  
Y Xie ◽  
N L Bucher ◽  
S R Farmer
Keyword(s):  
Extracellular Matrix ◽  
Transcription Factors ◽  
Dna Binding ◽  
Growth Response ◽  
Isolated Hepatocytes ◽  
Early Growth ◽  
Binding Activity ◽  
Early Growth Response ◽  
Dna Binding Activity ◽  
Rat Tail

Previous investigations have shown that culture of freshly isolated hepatocytes under conventional conditions, i.e., on dried rat tail collagen in the presence of growth factors, facilitates cell growth but also causes an extensive down-regulation of most liver-specific functions. This dedifferentiation process can be prevented if the cells are cultured on a reconstituted basement membrane gel matrix derived from the Englebreth-Holm-Swarm mouse sarcoma tumor (EHS gel). To gain insight into the mechanisms regulating this response to extracellular matrix, we are analyzing the activities of two families of transcription factors, C/EBP and AP-1, which control the transcription of hepatic and growth-responsive genes, respectively. We demonstrate that isolation of hepatocytes from the normal quiescent rat liver by collagenase perfusion activates the immediate-early growth response program, as indicated by increased expression of c-jun, junB, c-fos, and c-myc mRNAs. Adhesion of these activated cells to dried rat tail collagen augments the elevated levels of these mRNAs for the initial 1 to 2 h postplating; junB and c-myc mRNA levels then drop steeply, with junB returning to normal quiescence and the c-myc level remaining slightly elevated during the 3-day culture period. Levels of c-jun mRNA and AP-1 DNA binding activity, however, remain elevated from the outset, while C/EBP alpha mRNA expression is down-regulated, resulting in a decrease in the steady-state levels of the 42- and 30-kDa C/EBP alpha polypeptides and C/EBP alpha DNA binding activity. In contrast, C/EBP beta mRNA production remains at near-normal hepatic levels for 5 to 8 days of culture, although its DNA binding activity decreases severalfold during this time. Adhesion of hepatocytes to the EHS gel for the same period of time dramatically alters this program: it arrests growth and inhibits AP-1 DNA binding activity and the expression of c-jun, junB, and c-myc mRNAs, but, in addition, it restores C/EBP alpha mRNA and protein as well as C/EBP alpha and C/EBP beta DNA binding activities to the abundant levels present in freshly isolated hepatocytes. These changes are not due merely to growth inhibition, because suppression of hepatocyte proliferation on collagen by epidermal growth factor starvation or addition of transforming growth factor beta does not inhibit AP-1 activity or restore C/EBP alpha DNA binding activity to normal hepatic levels. These data suggest that expression of the normal hepatic phenotype requires that hepatocytes exist in a G0 state of growth arrest, facilitated here by adhesion of cells to the EHS gel, in order to express high levels of hepatic transcription factors such as C/EBP alpha.

scholarly journals Early Growth Response Transcription Factors Are Required for Development of CD4−CD8−Thymocytes to the CD4+CD8+Stage

2002 ◽  
Vol 168 (4) ◽  
pp. 1649-1658 ◽  
Author(s):  
Michael Carleton ◽  
Mariëlle C. Haks ◽  
Sigrid A. A. Smeele ◽  
Allan Jones ◽  
Stanley M. Belkowski ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Growth Response ◽  
Early Growth ◽  
Early Growth Response
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