Loss of the desmosomal cadherin desmoglein-2 suppresses colon cancer cell proliferation through EGFR signaling.

Desmosomal cadherins mediate cell-cell adhesion in epithelial tissues and have been known to be altered in cancer. We have previously shown that one of the two intestinal epithelial desmosomal cadherins, desmocollin-2 (Dsc2) loss promotes colonic epithelial carcinoma cell proliferation and tumor formation. In this study we show that loss of the other intestinal desmosomal cadherin, desmoglein-2 (Dsg2) that pairs with Dsc2, results in decreased epithelial cell proliferation and suppressed xenograft tumor growth in mice. Dsg2-deficient cells demonstrated a compensatory increase in Dsc2 expression, and small interfering RNA-mediated loss of Dsc2 restored proliferation in Dsg2-deficient cells. Dsg2 downregulation inhibited epidermal growth factor receptor (EGFR) signaling and cell proliferation through altered phosphorylation of EGFR and downstream extracellular signal-regulated kinase activation in parallel with inhibited EGFR receptor internalization. Additionally, we demonstrated a central role of Dsc2 in controlling EGFR signaling and cell proliferation in intestinal epithelial cells. Consistent with these findings, analyses of human colon cancers demonstrated increased Dsg2 protein expression. Taken together, these data demonstrate that partner desmosomal cadherins Dsg2 and Dsc2 play opposing roles in controlling colonic carcinoma cell proliferation through differential effects on EGFR signaling.

Protein kinase CK2 is a critical regulator of epithelial homeostasis in chronic intestinal inflammation.

The molecular mechanisms that restore intestinal epithelial homeostasis during colitis are incompletely understood. Here, we report that during intestinal inflammation, multiple inflammatory cytokines promote the activity of a master regulator of cell proliferation and apoptosis, serine/threonine kinase CK2. Enhanced mucosal CK2 protein expression and activity were observed in animal models of chronic colitis, particularly within intestinal epithelial cells (IECs). The in vitro treatment of intestinal epithelial cell lines with cytokines resulted in increased CK2 expression and nuclear translocation of its catalytic α subunit. Similarly, nuclear translocation of CK2α was a prominent feature observed in colonic crypts from individuals with ulcerative colitis and Crohn's disease. Further in vitro studies revealed that CK2 activity promotes epithelial restitution, and protects normal IECs from cytokine-induced apoptosis. These observations identify CK2 as a key regulator of homeostatic properties of the intestinal epithelium that serves to promote wound healing, in part through inhibition of apoptosis under conditions of inflammation.

IFN-γ and TNF-α-induced GBP-1 inhibits epithelial cell proliferation through suppression of ß-catenin/TCF signaling.

Proinflammatory cytokines induce guanylate-binding protein 1 (GBP-1) protein expression in intestinal epithelial tissues. GBP-1 has been described as influencing a number of cellular processes important for epithelial homeostasis, including cell proliferation. However, many questions remain as to the role of GBP-1 in intestinal mucosal homeostasis. We therefore sought to investigate the function of proinflammatory cytokine-induced GBP-1 during intestinal epithelial cell proliferation. Through the use of complementary GBP-1 overexpression and small interfering RNA-mediated knockdown studies, we now show that GBP-1 acts to inhibit pro-mitogenic ß-catenin/T cell factor (TCF) signaling. Interestingly, proinflammatory cytokine-induced GBP-1 was found to be a potent suppressor of ß-catenin protein levels and ß-catenin serine 552 phosphorylation. Neither glycogen synthase kinase 3ß nor proteasomal inhibition alleviated GBP-1-mediated suppression of cell proliferation or ß-catenin/TCF signaling, indicating a non-canonical mechanism of ß-catenin inhibition. Together, these data show that cytokine-induced GBP-1 retards cell proliferation by forming a negative feedback loop that suppresses ß-catenin/TCF signaling.

Chromatin-remodelling proteins of the pea aphid, Acyrthosiphon pisum (Harris).

Aphids display extraordinary developmental plasticity in response to environmental cues. These differential responses to environmental changes may be due in part to changes in gene expression patterns. To understand the molecular basis for aphid developmental plasticity, we attempted to identify the chromatin-remodelling machinery in the recently sequenced pea aphid genome. We find that the pea aphid possesses a complement of metazoan histone modifying enzymes with greater gene family diversity than that seen in a number of other arthropods. Several genes appear to have undergone recent duplication and divergence, potentially enabling greater combinatorial diversity among the chromatin-remodelling complexes. The abundant aphid chromatin modifying enzymes may facilitate the phenotypic plasticity necessary to maintain the complex life cycle of the aphid.

Evidence for a conserved polydnavirus gene family: ichnovirus homologs of the CsIV repeat element genes.

In Campoletis sonorensis Ichnovirus (CsIV), the repeat element genes constitute a gene family of 28 members. In the present work, we document the presence of members of this gene family in two additional ichnoviruses, Hyposoter didymator Ichnovirus (HdIV) and Tranosema rostrale Ichnovirus (TrIV). Two repeat element genes, representing at least one functional gene, were identified in TrIV, whereas HdIV was found to contain at least three such genes. In both HdIV and TrIV, the known repeat element genes are encoded on single genome segments, with hybridization studies suggesting the presence of other, related but as yet uncharacterized genes. The HdIV and TrIV repeat element genes are all transcribed in infected caterpillars, although differences exist among genes in levels and in tissue specificity of expression. A heuristic tree was generated indicating that the repeat element genes are more similar within a species of wasp than between species, with TrIV genes being more closely related to the CsIV than to the HdIV genes. These results suggest that the most significant duplication, divergence, and expansion of the repeat element genes occurred after speciation. The finding that repeat element genes form an interspecific family within the genus Ichnovirus supports the view that the proteins they encode play an important role in ichnovirus biology.

[Type I glycogenosis: extending therapy with uncooked cornstarch]. / Glykogenose Typ I: Erweiterung der Therapie mit ungekochter Maisstärke.

Normal or slightly elevated blood lactate levels and normal to slightly elevated lactate-/creatinine-ratios in 24-h-urine were found in 12 patients (0.9 to 16 years) with glycogenosis type I under conventional treatment with nocturnal gastric drip feeding with maltodextrine combined with frequent daytime feedings. Replacing the nocturnal gastric drip feeding by two doses of uncooked cornstarch suspended in water (single dose 1.4-2.0 g/kg body weight) 4 patients at the ages of 10 to 16 years obtained similar metabolic control. A 7-year old patient with glycogenosis type Ib showing an extremely low fasting tolerance attained stable blood glucose levels by eating two doses of uncooked cornstarch in the morning, so that she was able to attend school. A 2-year old patient received 2-3 g cornstarch/kg body weight every 6 h resulting in constant blood glucose levels, so that she was able to emigrate to Turkey. The therapy with uncooked cornstarch is suitable to augment the therapy of some patients with glycogenosis type I.