Cooperative cell transformation by Myc/Mil(Raf) involves induction of AP-1 and activation of genes implicated in cell motility and metastasis

Hartl, Markus; Karagiannidis, Antonios I.; Bister, Klaus

doi:10.1038/sj.onc.1209441

Cited by 31 publications

(42 citation statements)

References 64 publications

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“…5B). The cMyc protein is not detectable in cells that contain high levels of v-Myc or v/hy-Myc, which is due to negative transcriptional regulation of c-myc by v-Myc (35). Ectopic expression of Hydra Max did not cause any significant cellular alterations, and Hydra Myc1 induced only a marginal increase in cell proliferation.…”

Section: Hydra Myc1 and Max Genes Are Activated In The Interstitial Smentioning

confidence: 92%

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Stem cell-specific activation of an ancestral myc protooncogene with conserved basic functions in the early metazoan Hydra

Hartl¹,

Mitterstiller

Valovka³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

143

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The c-myc protooncogene encodes a transcription factor (Myc) with oncogenic potential. Myc and its dimerization partner Max are bHLH-Zip DNA binding proteins controlling fundamental cellular processes. Deregulation of c-myc leads to tumorigenesis and is a hallmark of many human cancers. We have identified and extensively characterized ancestral forms of myc and max genes from the early diploblastic cnidarian Hydra, the most primitive metazoan organism employed so far for the structural, functional, and evolutionary analysis of these genes. Hydra myc is specifically activated in all stem cells and nematoblast nests which represent the rapidly proliferating cell types of the interstitial stem cell system and in proliferating gland cells. In terminally differentiated nerve cells, nematocytes, or epithelial cells, myc expression is not detectable by in situ hybridization. Hydra max exhibits a similar expression pattern in interstitial cell clusters. The ancestral Hydra Myc and Max proteins display the principal design of their vertebrate derivatives, with the highest degree of sequence identities confined to the bHLH-Zip domains. Furthermore, the 314-amino acid Hydra Myc protein contains basic forms of the essential Myc boxes I through III. A recombinant Hydra Myc/Max complex binds to the consensus DNA sequence CACGTG with high affinity. Hybrid proteins composed of segments from the retroviral v-Myc oncoprotein and the Hydra Myc protein display oncogenic potential in cell transformation assays. Our results suggest that the principal functions of the Myc master regulator arose very early in metazoan evolution, allowing their dissection in a simple model organism showing regenerative ability but no senescence.cell proliferation | cnidaria | development | transcription factor

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Section: Hydra Myc1 and Max Genes Are Activated In The Interstitial Smentioning

confidence: 92%

“…EMSA analysis was performed as described (33,35). DNA binding reactions (20 μL) were performed at 25°C for 45 min in a buffer containing 10 mM Tris HCl pH 7.5, 0.5 mM EDTA, 65 mM KCl, 5 mM MgCl 2 , 1 mM DTT, 100 μg∕mL BSA, 10% (vol∕vol) glycerol.…”

Section: Methodsmentioning

confidence: 99%

Stem cell-specific activation of an ancestral myc protooncogene with conserved basic functions in the early metazoan Hydra

Hartl¹,

Mitterstiller

Valovka³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

143

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“…ChIP was carried out as described (Hartl et al, 2006). The antisera a-Myc and a-Max (see above), a-Gag directed against avian retroviral Gag proteins (Hartl et al, 2001), and a-C/EBPa (Mink et al, 1999) were used.…”

Section: Protein Analysismentioning

confidence: 99%

“…To generate the expression vector pRc-C/EBPa, a 1419-bp EcoRI-XbaI fragment encompassing the coding region of the chicken C/EBPa gene was excised from the plasmid pcDNA3-chC/EBPa (Mink et al, 1999) and ligated into HindIII/XbaI-digested pRc/RSV. DNA transfer into cells by the calcium phosphate method, CATanalysis, and quantification of radioactive signals were done as described (Hartl et al, 2001(Hartl et al, , 2003(Hartl et al, , 2006. DNA transfer into cells by the nucleofection technology (Amaxa Biosystems Inc., Cologne, Germany) was performed as described (Hartl et al, 2001(Hartl et al, , 2003.…”

Section: Transactivation Analysismentioning

confidence: 99%

WS5, a direct target of oncogenic transcription factor Myc, is related to human melanoma glycoprotein genes and has oncogenic potential

et al. 2006

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We have isolated a gene (WS5) that is specifically expressed at the mRNA and protein level in avian fibroblasts transformed by the v-myc oncogene of avian acute leukemia virus MC29. In a conditional cell transformation system, WS5 gene expression was tightly correlated with v-myc activation. The WS5 gene contains 11 exons, encoding a 733-amino acid protein with a transmembrane region and a polycystic kidney disease (PKD) domain. Near the transcriptional start site, the WS5 promoter contains a cluster of four binding sites for the Myc-Max complex and a binding site for transcription factor C/EBPa. Electrophoretic mobility shift assays and chromatin immunoprecipitation showed that Myc, Max and C/EBPa bind specifically to these sites. Functional promoter analyses revealed that both the Myc-binding site cluster and the C/EBPa-binding site are essential for strong transcriptional activation, and that Myc and C/EBPa synergistically activate the WS5 promoter. Ectopic expression of WS5 led to cell transformation documented by anchorage-independent growth. The human melanoma antigen Pmel17, a type I transmembrane glycoprotein, is the mammalian protein with the highest amino acid sequence identity (38%) to WS5. The Pmel17 gene is regulated by the MITF protein, a bHLHZip transcription factor with DNA binding specificities similar to those of Myc/Max. WS5 is also related to human glycoprotein GPNMB expressed in metastatic melanoma cells and implicated in the progression of brain and liver tumors.

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“…Several known cis-acting transcription factors have been described and most of them have been localized to a conserved region at 250 bp upstream of the proximal promoter. Potential binding sites for transcriptional regulators, such as AP-1, Myc, Oct-1, USF, v-Src, TGF-b/BMPs/Smad/Hox, Wnt/ b-catenin/APC/GSK-3b/Tcf-4, Ras/RRF, TF53, Runx2, and ETS family members, have been identified (14)(15)(16)(17)(18)(19)(20)(21).…”

Section: Introductionmentioning

confidence: 99%

Abnormal Expression of the ERG Transcription Factor in Prostate Cancer Cells Activates Osteopontin

Flajollet

Tian

Flourens

et al. 2011

Molecular Cancer Research

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Osteopontin (OPN) is an extracellular matrix glycophosphoprotein that plays a key role in the metastasis of a wide variety of cancers. The high level of OPN expression in prostate cells is associated with malignancy and reduced survival of the patient. Recent studies on prostate cancer (PCa) tissue have revealed recurrent genomic rearrangements involving the fusion of the 5 0 untranslated region of a prostate-specific androgen-responsive gene with a gene coding for transcription factors from the ETS family. The most frequently identified fusion gene is TMPRSS2:ERG, which causes ERG protein overexpression in PCa cells. ERG is a transcription factor linked to skeletogenesis. This study was designed to test whether ERG and the product of the TMPRSS2:ERG fusion gene modulate OPN gene expression in PCa cells. To characterize ERG and TMPRSS2:ERG transcriptional activity of OPN, we focused on ETS binding sites (EBS) localized in conserved regions of the promoter. Using in vitro and in vivo molecular assays, we showed that ERG increases OPN expression and binds to an EBS (nt À115 to À118) in the OPN promoter. Moreover, stable transfection of prostate tumor cell lines by TMPRSS2:ERG upregulates endogenous OPN expression. Finally, in human prostate tumor samples, detection of the TMPRSS2:ERG fusion gene was significantly associated with OPN overexpression. Taken together, these data suggest that OPN is an ERG-target gene in PCa where the abnormal expression of the transcription factor ERG, due to the TMPRSS2: ERG fusion, disturbs the expression of genes that play an important role in PCa cells and associated metastases. Mol Cancer Res; 9(7); 914-24. Ó2011 AACR.

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Cooperative cell transformation by Myc/Mil(Raf) involves induction of AP-1 and activation of genes implicated in cell motility and metastasis

Cited by 31 publications

References 64 publications

Stem cell-specific activation of an ancestral myc protooncogene with conserved basic functions in the early metazoan Hydra

Stem cell-specific activation of an ancestral myc protooncogene with conserved basic functions in the early metazoan Hydra

WS5, a direct target of oncogenic transcription factor Myc, is related to human melanoma glycoprotein genes and has oncogenic potential

Abnormal Expression of the ERG Transcription Factor in Prostate Cancer Cells Activates Osteopontin

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