Transcription factor EGR-1 suppresses the growth and transformation of human HT-1080 fibrosarcoma cells by induction of transforming growth factor beta 1.

Liu, Chaoting; Adamson, Eileen D.; Mercola, Dan

doi:10.1073/pnas.93.21.11831

Cited by 148 publications

(130 citation statements)

References 42 publications

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“…In a recent report, constitutive expression of Egr1 induced apoptosis in cardiac fibroblast cells (Zins et al 2014). A number of human tumor cells lines including fibroblastoma and hepatocellular carcinoma lines have decreased Egr1 expression (Liu et al 1996;Hao et al 2002). Egr1 inhibits the growth and reverses the cancerous phenotype of v-sis transformed NIH3T3 cells (Huang et al 1994).…”

Section: Discussionmentioning

confidence: 99%

“…The mechanism of action of Egr1 for causing apoptosis appears to require the DNA-binding activity of Egr1 (Huang et al 1995). Egr1 activation of the expression of transforming growth factor beta1 (TGF-b1) is suggested to be involved in its growth inhibition activity (Liu et al 1996). In addition, transactivation of p53 and downregulation of bcl-2 involve apoptosis-inducing effects of Egr1 (Liu et al 1998;Huang et al 1998).…”

Section: Discussionmentioning

confidence: 99%

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Iron deficiency upregulates Egr1 expression

Lee

Prywes

et al. 2015

Genes Nutr

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Iron-deficient anemia is a prevalent disease among humans. We searched for genes regulated by iron deficiency and its regulated mechanism. cDNA microarrays were performed using Hepa1c1c7 cells treated with 100 lM desferrioxamine (DFO), an iron chelator. Early growth response 1 (Egr1) was upregulated with at least 20-fold increase within 4 h and lasted for 24 h, which was confirmed by qRT-PCR. This activation was not seen by ferric ammonium citrate (FAC). DFO increased the transcriptional activity of Egr1-luc (-604 to ?160) and serum response element (SRE)-luc reporters by 2.7-folds. In addition, cycloheximide lowered DFO-induced Egr1 mRNA levels. The upregulation of Egr1 by DFO was accompanied by sustained ERK signals along with phosphorylation of Elk-1. The ERK inhibitor (PD98059) prevented the DFO-induced Egr1 mRNAs. Overexpression of Elk-1 mutant (pElk-1S383A) decreased Egr1 reporter activity. DFO lowered reactive oxygen species (ROS) production and increased caspase 3/7 activity and cell death. DFO-induced iron deficiency upregulates Egr1 in part through transcriptional activation via ERK and Elk-1 signals, which may be important in the regulation of cell death in hepatoma cells. Our study demonstrated that iron depletion controlled the expression of Egr1, which might contribute to decisions about cellular fate in response to iron deficiency.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Iron deficiency upregulates Egr1 expression

Lee

Prywes

et al. 2015

Genes Nutr

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“…2,3 The promoter of the human TGFb1 gene contains at least two Egr1-binding sites, both of which can bind Egr1, leading to the activation of transcription. 4,5 The significance of this interaction in human tumor cells was shown by re-expression of Egr1 in human HT1080 fibrosarcoma cells, which do not normally express Egr1 but do exhibit functional TGFb1 RII receptors. 5 HT1080 cells that have been made to express Egr1 acquire the ability to synthesize and secrete precursor TGFb1 that becomes activated and acts in an autocrine fashion to suppress growth.…”

Section: Tgfb1mentioning

confidence: 99%

“…4,5 The significance of this interaction in human tumor cells was shown by re-expression of Egr1 in human HT1080 fibrosarcoma cells, which do not normally express Egr1 but do exhibit functional TGFb1 RII receptors. 5 HT1080 cells that have been made to express Egr1 acquire the ability to synthesize and secrete precursor TGFb1 that becomes activated and acts in an autocrine fashion to suppress growth. Chromatin immunoprecipitation of Egr1-DNA complexes has confirmed the regulation of TGFb1 by Egr1 in living cells.…”

Section: Tgfb1mentioning

confidence: 99%

The transcription factor Egr1 is a direct regulator of multiple tumor suppressors including TGFβ1, PTEN, p53, and fibronectin

Bar-On

Adamson

Calogero³

et al. 2005

Cancer Gene Ther

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Recent studies are reviewed indicating that the transcription factor early growth response-1 (Egr1) is a direct regulator of multiple tumor suppressors including TGFb1, PTEN, p53, and fibronectin. The downstream pathways of these factors display multiple nodes of interaction with each other, suggesting the existence of a functional network of suppressor factors that serve to maintain normal growth regulation and resist the emergence of transformed variants. Paradoxically, Egr1 is oncogenic in prostate cancer. In the majority of these cancers, PTEN or p53 is inactive. It is suggested that these defects in the suppressor network allow for the unopposed induction of TGFb1 and fibronectin, which favor transformation and survival of prostate tumor epithelial cells, and explain the role of Egr1 in prostate cancer. Egr1 is a novel and logical target for intervention by gene therapy methods, and targeting methods are discussed.

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“…Recently, it has been reported that PAX3/FKHR has a protein-destabilization effect (Roeb et al, 2007), as PAX3/FKHR was shown to directly interact with the early growth responsive transcription factor EGR1 thereby targeting EGR1for proteasomal degradation. EGR1 plays important roles in regulating cell growth, differentiation and development (Liu et al, 1996) and has been shown to mediate expression of p57Kip2 as one of its target genes.…”

mentioning

confidence: 99%

p21 Downregulation is an important component of PAX3/FKHR oncogenicity and its reactivation by HDAC inhibitors enhances combination treatment

et al. 2010

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A number of drugs developed against cancer-specific molecular targets have been shown to offer survival benefits alone or in combination with standard treatments, especially for those cases where tumor pathogenesis is dominated by a single molecular abnormality. One example for such a tumor type is alveolar rhabdomyosarcoma (aRMS) which is characterized by a specific translocation creating the oncogenic PAX3/FKHR transcription factor, believed to be the molecular basis of the disease.Recently, we were able to demonstrate that the small molecule inhibitor PKC412 (midostaurin) exhibits strong antitumor activity against aRMS by reducing the transcriptional activity of PAX3/FKHR.Here, we screened for combination strategies that are superior to PKC412-only treatment and found that the combination of PKC412 with histone deacetylase (HDAC) inhibitors like valproic acid (VPA) synergistically induced apoptosis resulting in suppressed aRMS tumor growth in vivo.We provide evidence that the antitumor effect upon combination treatment is achieved by VPAinduced reactivation of p21 which is downregulated in aRMS cells via destabilization of the transcriptional regulator EGR1 by PAX3/FKHR. Our study highlights a possible mechanism behind the increased efficacy and indicates that different arms of PAX3/FKHR oncogenicity can be exploited therapeutically by the specific combination of drugs to increase their therapeutic potential.

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Transcription factor EGR-1 suppresses the growth and transformation of human HT-1080 fibrosarcoma cells by induction of transforming growth factor beta 1.

Abstract: The early growth response 1 (EGR-1) gene product is a transcription factor with roles in differentiation and growth. We

Cited by 148 publications

References 42 publications

Iron deficiency upregulates Egr1 expression

Iron deficiency upregulates Egr1 expression

The transcription factor Egr1 is a direct regulator of multiple tumor suppressors including TGFβ1, PTEN, p53, and fibronectin

p21 Downregulation is an important component of PAX3/FKHR oncogenicity and its reactivation by HDAC inhibitors enhances combination treatment

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