Aberrant expression of ETS1 and ETS2 proteins in cancer

Abstract

The ETS transcription factors regulate expression of genes involved in normal cell development, proliferation, differentiation, angiogenesis, and apoptosis, consisting of 28 family members in humans. Dysregulation of these transcription factors facilitates cell proliferation in cancers, and several members participate in invasion and metastasis by activating gene transcription. ETS1 and ETS2 are the founding members of the ETS family and regulate transcription by binding to ETS sequences. They are both involved in oncogenesis and tumor suppression depending on the biological situations used. The essential roles of ETS proteins in human telomere maintenance have been suggested, which have been linked to creation of new Ets binding sites. Recently, preferential binding of ETS2 to gain-of-function mutant p53 and ETS1 to wild type p53 (WTp53) has been suggested, raising the tumor promoting role for the former and tumor suppressive role for the latter. The oncogenic and tumor suppressive functions of ETS1 and 2 proteins have been discussed.

Keywords: ETS1; ETS2; cancer; expression; mutant p53; telomerase.

Figure 1

The structure of ETS proteins. A. The structure of AMV v-Myb and E26 retrovirus. R1, R2, and R3 are Myb-like repeats. The E26 virus consists with Gag, Myb, and Ets-like regions (–, –54). B. The structure of ETS proteins reviewed in this article. The domain structures for ETS1, ETS2, Fli1, and ERG are shown. The ETS domain that is essential for DNA-binding is shown in dark box. The DNA-binding by the ternary complex factor (TCF) subfamily of ETS-domain transcription factors (4) is tightly regulated by intramolecular and intermolecular interactions. The helix-loop-helix (HLH) -containing Id proteins (138) are trans-acting negative regulators of DNA binding by the TCFs. Inhibition is mediated by direct interactions of the Ids with the ETS DNA-binding domain of the TCFs. PNT: pointed domain, TAD: transactivation domain, ID: Id-interaction domain.

Figure 2

Oncogenic and tumor suppressive activities of ETS proteins. Both mitogenic signals stemming from growth factors and stress signals stimulate the RAS-RAF-MEK-ERK pathway to activate the ETS transcription factors. ETS proteins show oncogenic or tumor suppressive activities by increased nuclear transport (178, 179), enhanced DNA binding of nuclear proteins (180, 181), recruitment of co-repressors (182, 183), and gene transactivation (184, 185) involved in cell proliferation, apoptosis, angiogenesis. Mutation of hTERT promoter created novel ETS binding sites, which contributes increased telomerase activity in cancer cells. Mutant p53 which is overexpressed in half of human cancer cells, bind to ETS2 to stabilize the protein and reveal its oncogenic activity.

Figure 3

The human TERT promoter (, –145). The proximal promoter has both WT1 (black arrows) and E2F1 (red arrows) -binding sites for regulation. In addition, E2F-binding sites are clustered at 600 – 1100 base pairs from the transcription initiating G. The hTERT promoter is often mutated to create new ETS sits for transcription factor-binding, which contributes increased telomerase activity in tumor cells.