HIC-5 Is a Novel Repressor of Lymphoid Enhancer Factor/T-cell Factor-driven Transcription

Abstract

Activation of Wnt/␤-catenin target genes is regulated by a heterodimer of ␤-catenin and the high mobility group box transcription factors of the lymphoid enhancer factor (LEF)/T-cell factor (TCF) family. In vertebrates, four LEF/TCF family members have been identified. They all contain a conserved ␤-catenin-binding motif at the N terminus and a highly conserved high mobility group box for DNA binding. The core sequence between these motifs is less conserved and contributes to the specific properties of the individual family members. To identify interacting proteins that allocate specific functions to the individual LEF/TCF transcription factors, we performed a yeast two-hybrid screen using the less conserved core sequence as bait. We isolated the murine LIM protein HIC-5 (hydrogen peroxide-induced clone 5; also termed ARA-55 (androgen receptor activator of 55 kDa)) and cloned the highly conserved Xenopus homolog. In addition, we report that the LIM domain-containing C-terminal half of HIC-5 binds to a conserved alternatively spliced exon in LEF/TCF transcription factors. Our functional analyses revealed that HIC-5 acts as negative regulator of a subset of LEF/TCF family members, which have been characterized as activators in reporter gene analyses and in the Xenopus axis induction assay. In addition, we observed a repressive interference of LEF/TCF family members with HIC-5-mediated activation of glucocorticoid-driven transcription, which again could be allocated to specific LEF/TCF subtypes. With the characterization of HIC-5 as a binding partner of the alternatively spliced exon in LEF/ TCF transcription factors, we identified a novel molecular mechanism in the dialog of steroid and canonical Wnt signaling that is LEF/TCF subtype-dependent.

SLK-mediated phosphorylation of paxillin is required for focal adhesion turnover and cell migration

“…Interestingly, preliminary analyses of a tissue microarray [127] of breast cancer appear to mirror these findings, showing phospho-S250 immuno-reactivity to positively correlate with breast cancer invasiveness ( Figure 5.6 (B)). Additionally, these TMA results would suggest that the phospho-S250 immuno-reactivity is also not solely dependent on Her2 status.…”

“…Paraffin-embedded human tissues (HuFPT130) and tissue microarrays (BRC961) [127] were purchased from US Biomax (Rockville, Maryland, USA). Tissues were processed as described by Luise and Nuciforo (2006) [128].…”

Expression of the AmphiTcf gene in amphioxus: Insights into the evolution of the TCF/LEF gene family during vertebrate evolution

“…In addition AmphiTcf includes a CRARF domain (amino acids 392-396) comparable to those of all known TCF/LEF proteins of invertebrates as well as Tcf1 and Tcf4 of vertebrates; this motif evidently both binds DNA and transactivates (Hecht and Stemmler, 2003). There is also a putative Groucho (Grg) binding domain (amino acids 212-241; exon VI), which is structurally similar to the Grg binding/ HIC-5 interaction site known for several splice variants of vertebrate TCF/LEF family members (Ghogomu et al, 2006). In contrast, AmphiTcf lacked counterparts for following motifs: the CAD domain of vertebrate Lef1, the CtBP domain of vertebrate Tcf3 and Tcf4, and the LVPQ and SXXSS domains of vertebrate Tcf3 (van Noort and Clevers, 2002;Liu et al, 2005).…”

Controlled levels of canonical Wnt signaling are required for neural crest migration

“…In the absence of Wnt signal Lef/Tcf acts as transcriptional repressors of Wnt target genes by forming a complex with several corepressors including myeloid translocation gene related-1 (Mtgr1) (Moore et al, 2008), corepressor of Pan (Coop) (Song et al, 2010), hydrogen peroxide-inducible clone (HIC5) (Ghogomu et al, 2006;Li et al, 2011) and the most intensively studied Groucho/transducin-like enhancer of split (Gro/TLE) repressor family Chen and Courey, 2000). Upon translocation of β-catenin to nucleus Lef/Tcf factors become converted into transcriptional activators and perform expression of the target genes (Daniels and Weis, 2005).…”