The Ets-1 and Ets-2 transcription factors activate the promoters for invasion-associated urokinase and collagenase genes in response to epidermal growth factor

Watabe, Tetsuya; Yoshida, Kôichi; Shindoh, Masanobu; Kaya, Mitsunori; Fujikawa, Keiko; Sato, Hiroshi; Seiki, Motoharu; Ishii, Seiichi; Fujinaga, Kei

doi:10.1002/(sici)1097-0215(19980703)77:1<128::aid-ijc20>3.0.co;2-9

Cited by 189 publications

(125 citation statements)

References 42 publications

(58 reference statements)

Supporting

Mentioning

120

Contrasting

Order By: Relevance

“…Magni®ca-tion=2006 regulation of uPA gene expression and enhanced cell motility are mediated at least in part by Ets1. Since the uPA gene promoter contains a binding site for Ets, and Ets1 is a major transcription factor regulating uPA gene expression, enhanced expression of uPA gene in transformed cells is largely attributed to overexpression of Ets-1 (Watabe et al, 1998;D'Orazio et al, 1997;Stacey et al, 1995). uPA is a serine protease and contributes to tumor invasion by degrading extracellular matrix components, and thus its expression is widely correlated with tumor metastasis (Testa and Quigley, 1990;Bindal et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

“…Expression of MMP-9 gene was at a very high level in parental MDCK cells and was not further stimulated by transformation with LMP1 (data not shown). However, the MMP-9 gene promoter contains a binding site for Ets in addition to AP-1 and NF-kB (Sato et al, 1992), and thus Ets1 may positively regulate MMP-9 gene expression in di erent cell lines (Watabe et al, 1998). Therefore, Ets1 may stimulate transcription of many genes associated with tumor invasion and metastasis, and would be an e ective target in preventing invasion of EBV-associated tumors.…”

Section: Discussionmentioning

confidence: 99%

“…As a gene co-expressed with PAI-1, urokinase type plasminogen activator (uPA) mRNA expression was examined by Northern hybridization, and also seen to be upregulated in transformed cells compared with parental and neo-transfected MDCK cells (Figure 4, panel uPA) (Grondaho-Hansen et al, 1993;Foekens et al, 1994). Ets1 is known to be one of the major factors regulating transcription of the uPA gene (Stacey et al, 1995;D'Orazio et al, 1997;Watabe et al, 1998), and thus ets1 mRNA expression was compared between control and LMP1-transformed MDCK cells by Northern hybridization (panel ets-1). Expression of ets1 mRNA, which was very low in parental and neotransfected MDCK cells, was also upregulated in proportion to LMP1 mRNA level in MDCK cells transformed by LMP1.…”

Section: Genes Induced By Lmp1mentioning

confidence: 99%

See 2 more Smart Citations

Transformation of Madin-Darby canine kidney (MDCK) epithelial cells by Epstein-Barr virus latent membrane protein 1 (LMP1) induces expression of Ets1 and invasive growth

et al. 2000

Self Cite

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Genes Induced By Lmp1mentioning

confidence: 99%

See 1 more Smart Citation

Transformation of Madin-Darby canine kidney (MDCK) epithelial cells by Epstein-Barr virus latent membrane protein 1 (LMP1) induces expression of Ets1 and invasive growth

et al. 2000

Self Cite

View full text Add to dashboard Cite

“…In humans, more than 20 Ets proteins have been identified. Ets1 and Ets2 are proto-oncoproteins [28,29] that are overexpressed in a variety of tumours, including breast carcinomas [30,31]. Ets2 expression has been correlated positively with mammary tumour size in mice [32].…”

Section: Introductionmentioning

confidence: 99%

Ets2 and protein kinase Cepsilon are important regulators of parathyroid hormone-related protein expression in MCF-7 breast cancer cells

Lindemann

Braig

Hauser

et al. 2003

Biochemical Journal

View full text Add to dashboard Cite

Parathyroid hormone-related protein (PTHrP) promotes the metastatic potential and proliferation of breast cancer cells, and acts anti-apoptotically. In invasive MDA-MB-231 breast cancer cells, transforming growth factor β-regulated PTHrP synthesis is mediated by an Ets1/Smad3-dependent activation of the PTHrP P3 promoter. In the present study, we studied the regulation of PTHrP expression in non-invasive, Ets1-deficient and transforming growth factor β-resistant MCF-7 cells. We found PMA to be a strong stimulator of P3-dependent PTHrP expression in MCF-7 cells. Mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinase (ERK) kinase 1 (MEK-1)/ERK1/2 inhibitor PD98059 interfered with this activity. Promoter studies revealed that the PMA effect depended on the Ets and stimulating protein-1 (Sp1)-binding sites. Of several Ets factors tested, Ets2, but not Ese-1, Elf-1 or Ets1, supported the PMA-dependent increase in promoter activity. PD98059 and a threonine to alanine mutation of the ERK1/2-responsive Ets2 phosphorylation site at position 72 inhibited the Ets2/PMA effect. Activated protein kinase C (PKC)ε could mimic PMA by stimulating the P3 promoter alone or in co-operation with Ets2 in an MEK-1/ERK1/2-dependent manner. Activated PKCα, although capable of co-operating with Ets2, failed to induce transcription from the P3 promoter on its own. The Ets2/PKCα synergistic effect was neither sensitive to PD98059 nor to Thr 72 /Ala 72 mutation. PMA neither increased the expression of Sp1 nor modulated the transcriptional activity of Sp1. However, it induced the displacement of a yet unknown factor from the Sp1-binding site, which may result in Sp1 recruitment to the promoter. Our results suggest an ERK1/2-dependent Ets2/PKCε synergism to be involved in PTHrP expression in MCF-7 breast cancer cells.

show abstract

“…5-7 Ets-1 plays an important role in cancer progression due to its ability to activate transcription of metastasis-, angiogenesis-and invasion-associated genes. [8][9][10][11][12] In a limited study on 10 melanomas and 24 benign melanocytic lesions, Keehn et al 13 recently reported expression of the Ets-1 in melanocytic lesions and suggested that Ets-1 expression might be an important pathogenic mechanism and predictor of aggressive biologic behavior of cutaneous melanoma. …”

mentioning

confidence: 99%

Ets-1 transcription factor is widely expressed in benign and malignant melanocytes and its expression has no significant association with prognosis

et al. 2004

View full text Add to dashboard Cite

Ets-1 transcription factor has been associated with tumor progression in various carcinomas, but its expression in malignant melanoma was only recently described. The study was conducted in two steps: exploratory and confirmatory. In the first step, we studied 69 primary melanomas, 28 metastatic melanomas, 10 usual intradermal nevi and 13 various melanocytic skin lesions. In the second step, an additional group of 98 patients with follow-up of up to 200 months was also evaluated. Immunohistochemical analysis of formalinfixed/paraffin-embedded tissues was performed using 1G11 antibody and polymer conjugate for visualization. While Ets-1 was variably expressed in 83% primary melanomas in exploratory and 69% in the confirmatory group, the expression of Ets-1 was also found in normal benign melanocytes and all nevi. Analysis of the exploratory group revealed lower expression of Ets-1 in primary melanomas than in common nevi (P ¼ 0.048, Mann-Whitney U-test) and metastatic melanomas expressed significantly less Ets-1 than primary melanomas (P ¼ 0.015, Mann-Whitney U-test). There was a negative correlation between Ets-1 expression and the largest dimension of the primary tumors (r ¼ 0.23, P ¼ 0.034, Spearman's correlation rank test), but no correlation with the depth of tumor invasion (Breslow thickness) or the presence of ulceration was found. Analyses of the confirmatory group revealed no association between Ets-1 expression with disease-specific survival or time to treatment failure. However, a statistical trend was found for worse outcome for those primary melanomas that had strong expression (H-score 4100) of Ets-1 (P ¼ 0.054). Ets-1 is expressed in benign melanocytes probably due to their neural crest origin. We conclude that Ets-1 expression cannot be used to differentiate between benign and malignant melanocytic lesions and it has no definite association with clinical outcome. At the same time, its role in tumor progression in some cases of malignant melanoma cannot be entirely excluded. Keywords: Ets-1; malignant melanoma; survival; neural crest Malignant melanoma originates from melanocytes derived from the neural crest. 1 It is the most deadly form of skin cancer, whose incidence is rapidly increasing worldwide. 2 To date the most reliable prognostic marker of malignant melanoma is the vertical thickness (Breslow thickness) of the primary tumor. 3,4 Although progression of malignant melanoma occurs through a series of well-defined steps, the knowledge of genetic and phenotypic background for the disease is still rather scarce. The proto-oncogene ETS-1 belongs to the ETS family of transcription factors that also include, among others, ets-2, elf-1, fli-1 and PU-1. 5-7 Ets-1 plays an important role in cancer progression due to its ability to activate transcription of metastasis-, angiogenesis-and invasion-associated genes. [8][9][10][11][12] In a limited study on 10 melanomas and 24 benign melanocytic lesions, Keehn et al 13 recently reported expression of the Ets-1 in melanocytic lesions and suggested that E...

show abstract

The Ets-1 and Ets-2 transcription factors activate the promoters for invasion-associated urokinase and collagenase genes in response to epidermal growth factor

Cited by 189 publications

References 42 publications

Transformation of Madin-Darby canine kidney (MDCK) epithelial cells by Epstein-Barr virus latent membrane protein 1 (LMP1) induces expression of Ets1 and invasive growth

Transformation of Madin-Darby canine kidney (MDCK) epithelial cells by Epstein-Barr virus latent membrane protein 1 (LMP1) induces expression of Ets1 and invasive growth

Ets2 and protein kinase Cepsilon are important regulators of parathyroid hormone-related protein expression in MCF-7 breast cancer cells

Ets-1 transcription factor is widely expressed in benign and malignant melanocytes and its expression has no significant association with prognosis

Contact Info

Product

Resources

About