Cell Cycle Regulation by Galectin-12, a New Member of the Galectin Superfamily

Abstract

Galectins are a family of ␤-galactoside-binding animal lectins with conserved carbohydrate recognition domains (CRDs). Here we report the identification and characterization of a new galectin, galectin-12, which contains two domains that are homologous to the galectin CRD. The N-terminal domain contains all of the sequence elements predicted to form the two ␤-sheets found in other galectins, as well as conserved carbohydrate-interacting residues. The C-terminal domain shows considerable divergence from the consensus sequence, and many of these conserved residues are not present. Nevertheless, the protein has lactose binding activity, most likely due to the contribution of the Nterminal domain. The mRNA for galectin-12 contains features coding for proteins with growth-regulatory functions. These include start codons in a context that are suboptimal for translation initiation and AU-rich motifs in the 3-untranslated region, which are known to confer instability to mRNA. Galectin-12 mRNA is sparingly expressed or undetectable in many tissues and cell lines tested, but it is up-regulated in cells synchronized at the G 1 phase or the G 1 /S boundary of the cell cycle. Ectopic expression of galectin-12 in cancer cells causes cell cycle arrest at the G 1 phase and cell growth suppression. We conclude that galectin-12 is a novel regulator of cellular homeostasis.

Galectin-12 Is Required for Adipogenic Signaling and Adipocyte Differentiation

“…The cells were subsequently cultured in medium with insulin only. Cell cycle distribution during adipocyte differentiation was determined by flow cytometry of propidium iodide-stained cells fixed with ethanol as described previously (31).…”

“…We (31) and others (30) have previously cloned human galectin-12 cDNA and found that it encodes a galectin with two CRDs. The N-terminal CRD is highly homologous to those of other galectins, whereas the C-terminal CRD shows significant divergence from the consensus sequence (31).…”

“…The N-terminal CRD is highly homologous to those of other galectins, whereas the C-terminal CRD shows significant divergence from the consensus sequence (31). Its mRNA contains AU-rich motifs in the 3Ј-untranslated region, and the start codon of the major open reading frame lies in a sequence context suboptimal for translation initiation (31), suggesting vigorous post-transcriptional regulation at the levels of mRNA stability (32) and translation efficiency (33).…”

“…Its mRNA contains AU-rich motifs in the 3Ј-untranslated region, and the start codon of the major open reading frame lies in a sequence context suboptimal for translation initiation (31), suggesting vigorous post-transcriptional regulation at the levels of mRNA stability (32) and translation efficiency (33). The expression of this gene is very restricted, with high level expression only in adipocytes (30) and peripheral blood leukocytes (31). Galectin-12 is up-regulated when cells are blocked at the G 1 phase, and ectopic expression of this protein causes cell cycle arrest at the G 1 phase with concomitant cell growth suppression (31).…”

“…The expression of this gene is very restricted, with high level expression only in adipocytes (30) and peripheral blood leukocytes (31). Galectin-12 is up-regulated when cells are blocked at the G 1 phase, and ectopic expression of this protein causes cell cycle arrest at the G 1 phase with concomitant cell growth suppression (31). Its expression in adipocytes is up-regulated by insulin-sensitizing PPAR␥ agonists such as troglitazone (30) and down-regulated by agents known to impair insulin sensitivity such as isoproterenol, tumor necrosis factor-␣, and dexamethasone (34), implying a role for galectin-12 in insulin signaling and the pathogenesis of type II diabetes.…”