HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 283, Issue 21, 14345-14354, May 23, 2008

This Article Free via Author's Choice: AC AC Full Text Full Text (PDF) Supplemental Data AC All Versions of this Article: 283/21/14345    most recent M800299200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Shimokawa, T. Articles by Zaphiropoulos, P. G. PubMed PubMed Citation Articles by Shimokawa, T. Articles by Zaphiropoulos, P. G. Social Bookmarking                      What's this?

Novel Human Glioma-associated Oncogene 1 (GLI1) Splice Variants Reveal Distinct Mechanisms in the Terminal Transduction of the Hedgehog Signal^*

From the Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge SE-14157, Sweden

Hedgehog (HH) signaling is one of the key pathways with major significance for embryogenesis, tumorigenesis, and stem cell maintenance. Glioma-associated oncogene 1 (GLI1) is a transcription factor that acts as the terminal signaling effector but also represents a pathway target gene. Here we report the identification and functional properties of novel GLI1 splice variants generated by skipping exons 2 and 3 and encoding an N-terminal truncated GLI1 protein (GLI1N). Analysis of the GLI1N mRNAs in adult human tissues revealed comparable expression levels to the full-length GLI1 (GLI1FL), whereas in tumor cell lines a generally lower and more variable expression pattern was observed. Furthermore, GLI1N is up-regulated by HH signaling to the same extent as GLI1FL but has a weaker capacity to activate transcription. However, in specific cellular contexts GLI1N may be more potent than GLI1FL in activating endogenous gene expression. Moreover, the dual-specificity tyrosine phosphorylation-regulated kinase 1 (Dyrk1) potentiates the transcriptional activity of GLI1FL but not GLI1N. Interestingly, GLI1FL, in contrast to GLI1N, is localized solely at the nucleus, in line with its increased transcriptional capacity. The negative regulator of the pathway, Suppressor of Fused (SUFU), elicits a cytoplasmic retention of the GLI1 isoforms, which is more pronounced for GLI1FL, as this contains an N-terminal SUFU binding domain. Collectively, our findings reveal that the activation mechanism of the terminal transducer of the pathway, GLI1, is mediated not only by GLI1FL but also by the GLI1N variant.

Received for publication, January 11, 2008 , and in revised form, March 21, 2008.

Author's Choice—Final version full access.

^* This work was supported in part by the Swedish Cancer Fund, the Swedish Research Council, and the Magnus Bergvalls and Anders Otto Swärds/Ulrika Eklunds foundations. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1 and Figs. S1–S7.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AB239136 [GenBank] (GLI1 E1–4) and AB239328 [GenBank] (GLI1 E1A-4).

² These authors contributed equally to this work.

Author's Choice

Creative Commons Attribution Non-Commercial License applies to Author Choice Articles

¹ Supported by a Marie Curie International Incoming Fellowship. To whom correspondence may be addressed. E-mail: tash{at}biosci.ki.se. ³ To whom correspondence may be addressed: Tel.: 46-8-6089151; Fax: 46-8-6081501; E-mail: peza{at}cnt.ki.se.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?