Nucleic Acids Research Advance Access published online on February 7, 2008
Nucleic Acids Research, doi:10.1093/nar/gkn009
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Molecular Biology |
Functional analysis of the zinc finger and activation domains of Glis3 and mutant Glis3(NDH1)
Cell Biology Section, LRB, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA
*To whom correspondence should be addressed. Tel: 919 541 2768; Fax: 919 541 4133; Email: jetten{at}niehs.nih.gov
Received November 16, 2007. Revised December 21, 2007. Accepted January 8, 2008.
The Krüppel-like zinc finger protein Gli-similar 3 (Glis3) plays a critical role in pancreatic development and has been implicated in a syndrome with neonatal diabetes and hypothyroidism (NDH). In this study, we examine three steps critical in the mechanism of the transcriptional regulation by Glis3: its translocation to the nucleus, DNA binding and transcriptional activity. We demonstrate that the putative bipartite nuclear localization signal is not required, but the tetrahedral configuration of the fourth zinc finger is essential for the nuclear localization of Glis3. We identify (G/C)TGGGGGGT(A/C) as the consensus sequence of the optimal, high-affinity Glis3 DNA-binding site (Glis-BS). All five zinc finger motifs are critical for efficient binding of Glis3 to Glis-BS. We show that Glis3 functions as a potent inducer of (Glis-BS)-dependent transcription and contains a transactivation function at its C-terminus. A mutation in Glis3 observed in NDH1 patients results in a frameshift mutation and a C-terminal truncated Glis3. We demonstrate that this truncation does not effect the nuclear localization but results in the loss of Glis3 transactivating activity. The loss in Glis3 transactivating function may be responsible for the abnormalities observed in NDH1.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors
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