ETS transcription factors: Possible targets for cancer therapy

Abstract

Ets family (ETS) transcription factors, characterized by an evolutionally conserved Ets domain, play important roles in cell develhe Ets family (ETS) in mammals consists of approximately 30 genes homologous to Ets-1, the first of the cellular homologues of the viral oncogene v-ets in the avian transforming retrovirus E26. The gene products of this family are transcription factors controlling various cellular functions in cooperation with other families of transcription factors and co-factors. All members have an activation or a repression domain for transcription and an evolutionarily conserved Ets domain for DNA binding. The Ets domain was shown to bind the 5′-GGAA/T-3′ core motif of DNA through its wHTH (winged helix-turn-helix) structure, as determined by NMR analysis. Which of the ETS transcription factors interacts with specific binding sequences depends on the adjacent DNA sequences and binding of transcriptional partners.ETS transcription factors are divided into several subfamilies based on homology within the Ets domain. Some subfamilies have the Ets domains at the C-terminal end, and some at the Nterminal end. Several members are expressed predominantly in certain types of tissues, and some ubiquitously. A schematic illustration of the protein structures and tissue distributions of representative ETS transcription factors is shown in Fig. 1.The target genes for ETS transcription factors include oncogenes, tumor suppressor genes, apoptosis-related genes, differentiation-related genes, angiogenesis-related genes, and invasion and metastasis-related genes.1-3) Thus, it is not surprising that the aberrant expression of ETS genes contributes to malignant transformation and tumor progression.In the first part of this review, I will briefly describe the involvement of ETS transcription factors in carcinogenesis. In the second part, I will discuss the theoretical feasibility of ETS-targeted cancer therapy. ETS transcription factors in signal transduction and apoptosisAbnormalities in signal transduction pathways are often observed in tumors. Some of the final nuclear targets of signaling pathways are ETS transcription factors.4) Several ETS transcription factors directly control the expression of the immediate-early response genes. It has been proposed that expression of the c-fos and egr-1 genes is repressed by Net (new ets factor), a member of the TCF (ternary complex factor) subfamily of ETS transcription factors, through its recruitment of HDACs (histone deacetylases) to their promoters when the Ras-MAP kinase pathway is not activated. When this pathway is activated, other members of the TCF subfamily, Elk-1 (Ets like protein-1) and Sap-1 (serum responsive factor accessory protein-1), are phosphorylated and activate gene expression in cooperation with SRF (serum responsive factor) through the recruitment of CBP/p300, HATs (histone acetyltransferases), to the promoters.5) Under these conditions, Net is also phosphorylated, and converted from a repressor to an activator.Not only the TCF subfamily but also so...

Interactions of mutant p53 with DNA: guilt by association

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Analysis of transcriptional modulation of the presenilin 1 gene promoter by ZNF237, a candidate binding partner of the Ets transcription factor ERM

“…Their specific function is unknown, however they have been associated with various cellular processes, including cell proliferation, differentiation [3,4], and tumorigenesis [22,23]. To date most identified target genes of the PEA3 group have been proteases involved in the degradation of cell matrix [6,12].…”

Ewing's sarcoma fusion protein, EWS/Fli-1 and Fli-1 protein induce PLD2 but not PLD1 gene expression by binding to an ETS domain of 5′ promoter

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