HIC1 attenuates Wnt signaling by recruitment of TCF-4 and β-catenin to the nuclear bodies

Abstract

The hypermethylated in cancer 1 (HIC1) gene is epigenetically inactivated in cancer, and in addition, the haploinsufficiency of HIC1 is linked to the development of human Miller-Dieker syndrome. HIC1 encodes a zinc-finger transcription factor that acts as a transcriptional repressor. Additionally, the HIC1 protein oligomerizes via the N-terminal BTB/POZ domain and forms discrete nuclear structures known as HIC1 bodies. Here, we provide evidence that HIC1 antagonizes the TCF/b-catenin-mediated transcription in Wnt-stimulated cells. This appears to be due to the ability of HIC1 to associate with TCF-4 and to recruit TCF-4 and b-catenin to the HIC1 bodies. As a result of the recruitment, both proteins are prevented from association with the TCF-binding elements of the Wnt-responsive genes. These data indicate that the intracellular amounts of HIC1 protein can modulate the level of the transcriptional stimulation of the genes regulated by canonical Wnt/b-catenin signaling.

The transcriptional repressor HIC1 regulates intestinal immune homeostasis

“…HIC1 has been shown to interact with and inhibit DNA binding of transcription factors such as T-cell factor-4, b-catenin, and STAT3. [38][39][40] As HIC1-deficient T H 17 cells produce heightened levels of the STAT3 target gene IL-17A, 41 we hypothesized that increased STAT3 activity was associated with HIC1 deficiency. We first examined the levels of IL-6-induced active phosphorylated STAT3 in HIC1-sufficient and -deficient T H 17 cells by flow cytometry.…”

Diversity of LEF/TCF action in development and disease

“…HIC1 (in an unusual convergence of nomenclature, three proteins discussed in this review, HIC1, HIC5 and HIC, are three completely different proteins; a BTB/POZ protein, LIM domain protein and I-mfa protein, respectively) is the Kaisorelated BTB/POZ family member that binds directly to CtBP (mentioned above in LEF/TCF co-repressors). But instead of acting as a Kaiso-like repressor, HIC1 apparently antagonizes TCF-4 through sequestration to novel dot structures in the nucleus (Deltour et al, 2002;van Roy and McCrea, 2005;Valenta et al, 2006). CtBP is important for this effect as a mutant HIC1 missing its CtBP-binding motif cannot redirect TCF-4 to nuclear dots despite an intact HIC1/TCF-4 interaction (Valenta et al, 2006).…”

“…Also, deletion of these motifs or mutation by amino-acid substitution has consequences. For example, loss of the two motifs from the E-tail of a xLEF/xTCF-3 chimera relieves repressive activity in Siamois reporter assays in Xenopus (albeit, not in the context of full-length xTCF-3), and loss of the two motifs from the E-tail of TCF-4 disrupts its colocalization in nuclear dots with the BTB/POZ antagonist HIC1 (see below in LEF/TCF antagonists) and CtBP (Valenta et al, 2006). Interestingly, HIC1 and CtBP directly interact in vitro and in vivo and HIC1 and TCF-4 also interact directly (Deltour et al, 2002;Stankovic-Valentin et al, 2006).…”

“…Phosphorylation is another modification with negative consequences. Casein kinase 1 phosphorylation of LEF-1 on a serine in the b-catenin-binding domain (Behrens et al, 1996;Brunner et al, 1997;Daniels & Weis, 2005;Graham et al, 2000;Huber et al, 1996;Molenaar et al, 1996;van de Wetering et al, 1997) -catenin (Kolligs et al, 2000;Miravet et al, 2002) YCTTTGWW~1 0 -9 M; (Giese et al, 1991;Love et al, 1995;van Beest et al, 2000;van de Wetering et al, 1997;Waterman et al, 1991) Double-strand DNA Atcha et al, 2006, submitted Importin alpha (Prieve et al, 1996;Prieve et al, 1998) SMADs (Nishita et al, 2000) Cdx1 (Beland et al, 2004) Alx4 (Boras & Hamel, 2002) Pitx2 (Vadlamudi et al, 2005) Ets (Carlsson et al, 1993;Giese et al, 1995;Sheridan et al, 1995) MITF LEF-1 only; Aly LEF-1; (Bruhn et al, 1997) p300 (Hecht & Stemmler, 2003) Groucho/TLE (Brantjes et al, 2001;Daniels & Weis, 2005;Levanon et al, 1998;Roose et al, 1998) CtBP PLSLSxK, PLSLVTK (TCF3, TCF4) (Brannon et al, 1999;Valenta et al, 2003) Kaiso (Park et al, 2005) Runx2 (Kahler & Westendorf, 2003) HIC5 (Ghogomu et al, 2006) HIC1 (Deltour et al, 2002;Valenta et al, 2006) I-mfa, HIC …”

“…But instead of acting as a Kaiso-like repressor, HIC1 apparently antagonizes TCF-4 through sequestration to novel dot structures in the nucleus (Deltour et al, 2002;van Roy and McCrea, 2005;Valenta et al, 2006). CtBP is important for this effect as a mutant HIC1 missing its CtBP-binding motif cannot redirect TCF-4 to nuclear dots despite an intact HIC1/TCF-4 interaction (Valenta et al, 2006). Likewise, the CtBP-binding motifs in the TCF-4 E tail are important for co-localization with HIC1 even though a direct interaction between CtBP and wild-type TCF-4 cannot be detected.…”