Alx4 Binding to LEF-1 Regulates N-CAM Promoter Activity

Boras, Kata; Hamel, Paul A.

doi:10.1074/jbc.m109912200

Cited by 45 publications

(39 citation statements)

References 63 publications

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“…We demonstrated previously that the paired-like homeodomaincontaining protein, Aristaless-like 4 (Alx4), could interact with Lef1 and synergize in the regulation of the N-CAM promoter (Boras and Hamel, 2002). Consistent with this observation is the overlapping expression of Lef1 and Alx4 in embryos (Hudson et al, 1998) in the mesenchymal compartment of a number of tissues whose development depends on Lef1 (van Genderen et al, 1994).…”

Section: Introductionsupporting

confidence: 56%

Genetic interaction between Lef1 and Alx4 is required for early embryonic development

Boras-Granic¹,

Grosschedl²,

Hamel³

2006

Int. J. Dev. Biol.

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Lymphoid Enhancer Factor-1 (Lef1) facilitates the assembly of transcriptional regulatory complexes and mediates nuclear responses to Wnt signals. We determined previously that the mesenchymally restricted, paired-like homeodomain protein Aristaless-like 4 (Alx4) interacts with Lef1 and together alters promoter activity of candidate genes. In order to define their overlapping functions, mice deficient for both Lef1 and Alx4 activity (Lef1 -/-/Alx4 lstD/lstD ) were produced. Whereas embryos lacking either Lef1 or Alx4 activity remain viable up to or after birth, early embryonic lethality results when both factors were absent. No viable Lef1 -/-/Alx4 lstD/lstD embryos were recovered beyond 9.5 dpc. Between E8.5 and E10, viable Lef1 -/-/Alx4 lstD/lstD embryos were developmentally delayed 0.5 days relative to littermates of all other genotypes. Principle among the alterations seen in Lef1 -/-/Alx4 lstD/lstD animals was defective vasculature in both embryonic and extra-embryonic tissues. In the yolk sac, while the vascular network is present, it were greatly diminished and large vitelline vessels were largely absent. Platelet/endothelial cell adhesion molecule (PECAM) staining revealed that the major vessels in the head of compound mutant embryos were absent, while the other vessels were finer than those seen in normal littermates. Pools of blood and pericardial effusion were also apparent in Lef1 -/-/Alx4 lstD/lstD animals, further indicative of a defective vasculature. These data confirm genetically the interaction between Lef1 and Alx4 and further reveal unknown, overlapping roles for these transcription factors in embryonic vasculogenesis.

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Section: Introductionsupporting

confidence: 56%

Genetic interaction between Lef1 and Alx4 is required for early embryonic development

Boras-Granic¹,

Grosschedl²,

Hamel³

2006

Int. J. Dev. Biol.

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“…Three-dimensional studies show that a TAATTAAT motif similar to the one in SMS-TAAT2 could accommodate the binding of two homeodomain proteins located at opposite sides of the DNA helix (50,51). As for nonhomeodomain-related transcription factors, Alx3 can interact with basic helix-loop-helix proteins, 3 and Alx4 has been shown to establish functional interactions with LEF-1 to regulate the activity of the N-CAM promoter (52). Further studies are required to identify functionally active Alx3-interacting proteins.…”

Section: Proline-rich Domains Confer Transcriptional Transactivation mentioning

confidence: 99%

The Homeoprotein Alx3 Contains Discrete Functional Domains and Exhibits Cell-specific and Selective Monomeric Binding and Transactivation

Pérez-Villamil

Mirasierra

Vallejo

2004

Journal of Biological Chemistry

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Alx3 is a paired class aristaless-like homeoprotein expressed during embryonic development. Transcriptional transactivation by aristaless-like proteins has been associated with cooperative dimerization upon binding to artificially generated DNA consensus sequences known as P3 sites, but natural target sites in genes regulated by Alx3 are unknown. We report the cloning of a cDNA encoding the rat homolog of Alx3, and we characterize the protein domains that are important for transactivation, dimerization, and binding to DNA. Two proline-rich domains located amino-terminal to the homeodomain (Pro1 and Pro2) are necessary for Alx3-dependent transactivation, whereas another one (Pro3) located in the carboxyl terminus is dispensable but contributes to enhance the magnitude of the response. We confirmed that transcriptional activity of Alx3 from a P3 site correlates with cooperative dimerization upon binding to DNA. However, Alx3 was found to bind selectively to non-P3-related TAAT-containing sites present in the promoter of the somatostatin gene in a specific manner that depends on the nuclear protein environment. Cell-specific transactivation elicited by Alx3 from these sites could not be predicted from in vitro DNAbinding experiments by using recombinant Alx3. In addition, transactivation did not depend on cooperative dimerization upon binding to cognate somatostatin DNA sites. Our data indicate that the paradigm according to which Alx3 must act homodimerically via cooperative binding to P3-like sites is insufficient to explain the mechanism of action of this homeoprotein to regulate transcription of natural target genes. Instead, Alx3 undergoes restrictive or permissive interactions with nuclear proteins that determine its binding to and transactivation from TAAT target sites selected in a cellspecific manner.Homeodomain proteins are a large family of transcription factors that play prominent roles during embryonic development (1, 2). These proteins are characterized by the existence of a common DNA-binding structure, known as the homeodomain, that contains three ␣-helices spanning 60 amino acids.Comparison of amino acid sequences of known homeodomains from different species shows that residues in the first and third helices are highly conserved. Thus, the relative degree of sequence similarity in the DNA-binding domain defines different classes of homeodomain proteins that relate to protein homologs encoded by Drosophila melanogaster genes (3).Among the different classes of homeoproteins categorized so far, an important group with major roles in embryonic development is that of paired class proteins, characterized by the presence of a homeodomain homologous to the one encoded by the Drosophila paired gene (4). Additional conserved regions located outside the homeodomain define different subsets of paired class transcription factors.One of these subsets of paired class homeoproteins is characterized by the presence of a conserved domain located in the carboxyl-terminal region known as OAR or aristaless domain (4, 5...

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“…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 …”

Section: Covalent Modificationsmentioning

confidence: 99%

“…Another group of factors that engage in cooperative interactions are members of the homeodomain family. LEF/TCFs cooperate with Pitx2 and b-catenin to activate the LEF1 promoter (Vadlamudi et al, 2005), with Alx4 to activate the NCAM promoter (Boras and Hamel, 2002), with Cdx-1 to activate the CDX1 promoter (Beland et al, 2004), and with homeoprotein PAL-1/Caudal in C. elegans (Maduro et al, 2005). With the exception of the latter report in worms, all these interactions were detected with LEF-1; other family members were not tested, but it could be that LEF-1 is especially context-dependent because it is never expressed as an isoform with two DNA-binding domains.…”

Section: Lef/tcf Co-activatorsmentioning

confidence: 99%