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Papers In Press, published online ahead of print May 25, 2001
Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, Cincinnati, OH 45267-0524
Corresponding Author: jerry.lingrel{at}uc.edu
Lung Krüppel-like factor (LKLF/KLF2), a member of the Krüppel-like factor family of transcription factors, is predominately expressed in the lungs, with low levels of expression in other organs such as heart, spleen, skeletal muscle and testis. LKLF is essential during pulmonary development, single-positive T cell development, and is indispensable during mouse embryogenesis. In this study, we performed a series of experiments to define the activation domain of LKLF as a means to further advance the understanding of the molecular mechanisms underlying transcriptional regulation by this transcription factor. Using deletion analysis, it is shown that LKLF contains a transcriptional activation domain as well as a strong autoinhibitory subdomain. The inhibitory subdomain is able to independently suppress transcriptional activation of other strong activators such as VP16. This occurs either when the inhibitory domain is fused directly to VP16 or when the inhibitory domain is independently bound to DNA by GAL4 DBD independent of the VP16 activator. Overexpression of the LKLF autoinhibitory domain alone potentiates transactivation by wild type LKLF, suggesting the inhibitory domain binds a cofactor that prevents LKLF from transactivating. A yeast-two hybrid screen identified WWP1, an E3 ubiquitin ligase, that binds specifically to the LKLF inhibitory domain but not to other transcription factors. In mammalian cells, WWP1 functions as a cofactor by not only binding LKLF, but WWP1 suppress transactivation by LKLF. These data demonstrate that LKLF contains multiple domains that either potentiate or inhibit the ability of this factor to function as an activator of transcription, moreover, regulation of LKLF transactivation is attenuated by an E3 ubiquitin ligase, WWP1.
J. Biol. Chem, 10.1074/jbc.M103670200
Submitted on April 24, 2001
Revised on May 25, 2001
Accepted on May 25, 2001
Lung Krüppel-like factor contains an autoinhibitory domain that regulates its transcriptional activation by binding WWP1, an E3 Ubiquitin ligase
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