Ets-1

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Gene: maps to 11q23. It consists of eight exons spanning over 60 kb. DNA sequence analysis indicated a high G + C content in the promoter region and the absence of either a 'TATA' box or a 'CAAT' box. Six consensus recognition sequences for the transcription factor SP1, two AP1 consensus sequences and one consensus AP2 recognition sequence were identified, as well as two GC elements with dyad symmetry. 5' boundary for maximum promoter activity was locared at 486 bp upstream of the first initiation site (Jorcyk C.l. et al., 1991).
mRNA: size: 6.8 kb.
Protein: Ets-1 is member of a multigene (>30) family of transcriptional regulators involved in early embryonic development and late tissue maturation, directing stage-specific and tissue-restricted programs of target gene expression. Identifiable primarily by their 85 amino acid ETS DNA-binding domain and dispersed across all metazoan lineages into distinct subfamilies, Ets genes also produce malignancies in humans and other vertebrates when overexpressed or rearranged into chimeras retaining the ETS domain, suggesting that their oncogenic potential is determined by the program of target genes they regulate.

Cell lines:
- EGF stimulates the motile and invasive activities specifically in the ErbB-2-overexpressing SK-BR-3 cells. EGF also induces expression by these cells of extracellular matrix-degrading proteases including type I collagenase/MMP-1, 92 kDa type IV collagenase/MMP-9, uPA and uPAR. EGF also transiently stimulates expression of the transcription factors Ets-1 and Ets-2. Reporter transfection assays revealed the activation of uPA and MMP-9 collagenase promoters by EGF and the requirement of each of the Ets and AP-1 transcription factor binding sites for an EGF response. Most notably, transfections with the Ets-1 and Ets-2 expression vectors potentiated uPA and MMP-9 promoter activation in response to EGF. Ets-1 and Ets-2 were highly expressed in invasive breast tumor cell lines. Thus, Ets-1 and Ets-2 could provide the link connecting EGF stimuli with activation of uPA and 92 kDa type IV collagenase promoters and may contribute to invasion phenotypes (Watabe T. et al., 1998).

- The expression of c-ets-1 was compared with invasiveness in vitro and expression of vimentin, E-cadherin, uPA, MMP-1 and MMP-3 in a panel of human breast cancer cell lines. An association was found between c-ets-1 expression and the invasive, EMT-derived phenotype, which is typified by the expression of vimentin and the lack of E-cadherin. However, no clear quantitative or qualitative relationship between the expression of c-ets-1 and the three proteinases known to be regulated by c-ets-1, except that when they were expressed, it was only in the invasive c-ets-1-positive lines. uPA mRNAs were found in three of the four vimentin-positive lines, MMP-1 in two of the four, and MMP-3 could not be detected in any of the cell lines. Intriguingly, MDA-MB-435 cells, which exhibit the highest metastatic potential of these cell lines in nude mice, expressed vimentin and c-ets-1, but lacked expression of these three proteinases, at least under the culture conditions employed (Gilles C. et al., 1997).

Tumors:
- In a population of 297 mammary tumors, ETS-1 was rarely amplified and always independently from proto-oncogenes mapping to 11q13 (BCL-1, HST, INT-2, and SEA) (Theillet C. et al., 1990).

Gilles C. et al. (1997) Expression of c-ets-1 mRNA is associated with an invasive, EMT-derived phenotype in breast carcinoma cell lines. Clin. Exp. Metastasis 15, 519-526.
Jorcyk C.L. et al. (1991) The human ETS1 gene: genomic structure, promoter characterization and alternative splicing. Oncogene 6, 523-532.
Sacchi N. et al. (1986) Hu-ets-1 and Hu-ets-2 genes are transposed in acute leukemias with (4;11) and (8;21) translocations. Science 231, 379-382.
Theillet C. et al. (1990) BCL-1 participates in the 11q13 amplification found in breast cancer. Oncogene 5, 147-149.
Watabe T. et al. (1998) The Ets-1 and Ets-2 transcription factors activate the promoters for invasion-associated urokinase and collagenase genes in response to epidermal growth factor. Int. J. Cancer 77, 128-137.