Trends in Biochemical Sciences
Ets transcription factors: nuclear effectors of the Ras–MAP-kinase signaling pathway
Section snippets
Ets–AP-1 composite sites: prototypical Ras-responsive elements
Shortly after the discovery of the Ets-1–AP-1 composite element as a functional RRE in the polyomavirus enhancer, a number of similar elements were identified in regulatory regions of cellular genes. The latter include the promoters of the matrix metalloproteinases (e.g. stromelysin), heparin-binding epidermal growth factor, the tumor suppressor maspin, keratin 18, macrophage scavenger receptor and granulocyte-macrophage colony-stimulating factor (GM-CSF) genes1, 2. In Drosophila melanogaster,
The serum-response element: a multifunctional Ras-responsive element
Serum-response elements (SREs) are present in the promoters of many immediate early genes (e.g. c-fos, egr-1, egr-2, nur77, pip92, β-actin, vinculin and jun-B)[1]and function as RREs that mediate responses to many extracellular stimuli (Fig. 2). The c-fos SRE is continuously occupied in vivo by SRF, and Ets proteins of the TCF subfamily10, 11. An SRF dimer binds with high affinity to the sequence CC(A/T)6GG within the SRE. On most SREs, SRF functions by recruiting the TCFs, which bind
Complexity of the ternary complex factors
A growing complexity is being unveiled, both in the properties and forms of the classical TCFs, and in the identification of new, related proteins. The original TCFs, Elk-1, Sap-1a and Net (also termed ERP or Sap-2), have similar properties because of their common domain structure (Fig. 3). Each comprises three functionally important domains: the A or ETS domain, which binds to the 5′-CAGGA motif of the SRE; the B domain, which interacts directly with SRF; and the C domain, which activates
Serum-response element sequences and recognition by ternary-complex factors
Variations in the nucleotide sequence, spacing of factor-recognition sequences, and the topology of an SRE contribute to its specificity. On the prototypical c-fos SRE, SRF binds with high affinity and recruits TCFs that, in the absence of SRF, bind poorly. In contrast, the promoters of the pip92 and nur77 genes contain SREs that facilitate high-affinity binding by Elk-1, which then recruits SRF to a suboptimal binding site[19]. Interestingly, the sequence and spacing of the SRF- and
Selectivity of distinct MAP kinases for ternary complex factors
The TCFs mediate signaling by three types of MAPKs: ERK, JNK and p38/RK (Fig. 4). The specificity of these kinases is, in part, a function of their preference for individual TCFs. Elk-1 is an efficient substrate for all three classes of MAPK, which suggests that it is a point of convergence for the MAPK cascades, while Sap-1 is activated preferentially by ERK and p3823, 24, 25, 26, 27. In contrast to Elk-1 and Sap-1a, Net is not activated by expression of oncogenic Raf.
The regulation of TCFs
Interactions between Ets-1 and Pit-1: a tissue-specific Ras-responsive element
The versatility of Ets factors as nuclear effectors of signaling pathways in different contexts is further illustrated by RREs that mediate the recruitment of Ets factors by a dedicated tissue-specific factor: for example, Pit-1. Pit-1 is a POU-homeodomain protein that governs the ontogeny of the somatotroph, lactotroph and thyrotroph pituitary-cell lineages[29]. Pit-1 is required for the pituitary-specific expression of the rat prolactin (PRL), growth hormone (GH) and thyrotropin (TSHβ) genes,
Conclusions
Important conclusions have emerged from the studies of Ets-1 and the TCFs described here. The control of highly diverse sets of genes by Ets proteins involves their regulation at four different levels. First, the differential expression of individual Ets proteins in different cell types dictates their availability for regulating sets of target genes. Second, individual Ets proteins (e.g. Elk-1 and Sap1a) exhibit different nucleotide-sequence specificities, which are important for the selection
Acknowledgements
We thank Rebecca Tucker and Sauveur-Michel Maira for their helpful comments. Owing to TiBS policy of short reference lists, we have not cited original work that is already discussed in recent reviews. A. G-H., B. W. and J. H. thank the CNRS, NSF and NIH for joint funding. B. W. also thanks the following funding agencies: the Institut National de la Santé et de la Recherche Médicale, the Centre Hospitalier Universitaire Régional, the Association pour la Recherche sur le Cancer, the Fondation
References (33)
- et al.
Curr. Opin. Genet. Dev.
(1997) - et al.
Cell
(1994) - et al.
Cell
(1995) - et al.
FEBS Lett.
(1996) J. Biol. Chem.
(1996)- Wasylyk, B. and Nordheim, A. (1997) in Transcription Factors in Eukaryotes (Papavassiliou, A. G., ed.), pp. 251–284, R....
- Graves, B. J. and Petersen, J. M. in Advances in Cancer Research (Vande Woude, G. and Klein, G., eds), in...
Mol. Cell. Biol.
(1996)- et al.
Oncogene
(1997) Nature
(1994)
Mol. Cell. Biol.
Nature
Nucleic Acids Res.
Mol. Cell. Biol.
EMBO J.
EMBO J.
Cited by (451)
Transport and gradient formation of Wnt and Fgf in the early zebrafish gastrula
2024, Current Topics in Developmental BiologyPituitary Development
2022, The PituitaryCharacterization and analysis of transcriptome complexity using SMRT-Seq combined with RNA-Seq for a better understanding of Acanthogobius ommaturus in response to temperature stress
2021, International Journal of Biological Macromolecules