Nucleic Acids Research, 1992, Vol. 20, No. 11 2657-2665
© 1992
MOLECULAR BIOLOGY |
The weak, fine-tuned binding of ubiquitous transcription factors to the II-2 enhancer contributes to its T cell-restricted activity
Institute of Virology and Immunobiology, University of WÜrzburg Versbacher Straße 7, D-87 Würzburg, Germany 1Haematology Geneva University Hospital, 25 rue Micheli-du-Crest, CH-1211 Geneva 4 2Station de Zoologie Experimentale, University of Geneva, 154 route de Malagnou, CH-1224 Chene-Bougeries, Switzerland
*To whom correspondence should be addressed
Received April 8, 1992. Accepted April 30, 1992.
The T lymphocyte-specific enhancers of the murine and human Interleukin 2 (II-2) genes harbour several binding sites for ubiquitous transcription factors. All these sites for the binding of AP-1, NF-kB or Oct-1 are noncanonical sites, i.e. they differ in one or a few base pairs from consensus sequences for the optimal binding of these factors. Although the factors bind weakly to these sites, the latter are functionally important because their mutation to non-binding sites results in a decrease of inducible activity of the II-2 enhancer. Conversion of three sites to canonical binding sites of Octamer factors, AP-1 and NF-kB results in a drastic increase in enhancer activity and the induction of the II-2 enhancer in non-T cells, such as B cell lines, murine L cells and human HeLa cells. The introduction of two or three canonical sites into the enhancer leads to a further increase of its activity. II-2 enhancer induction is also observed in B cells when the concentration of AP-1 and Oct factors increases as a result of co-transfections with FosB and Octamer expression plasmids. When II-2 enhancer constructs carrying canonical factor binding sites were injected into Xenopus oocytes the strong binding of ubiquitous factors substantially overcomes the silencing effect of negatively acting factors present in resting primary T lymphocytes. These results suggest a fine-tuned interplay between ubiquitous and lymphoid-specific factors binding to and transactivating the II-2 enhancer and show that the binding affinity of ubiquitous factors to the enhancer contributes to its cell-type specific activity. Moreover, we believe that a dramatic increase of transcriptional activity brought about by single point mutations at strategic important factor binding sites may also have relevance to the activation of nuclear oncogenes.
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