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PubMed2002

Xwnt-2 (Xwnt-2b) is maternally expressed in Xenopus oocytes and embryos.

Xwnt-2 (formerly Xwnt-2b) is a member of the Xwnt-8 class of axis-inducing Wnts. Its zygotic expression is at the prosencephalic-mesencephalic border of the early tadpole brain and above the heart primordium [Mech. Dev. 63 (1997) 199]. Here, we report that Xwnt-2 has an earlier, maternal pattern of expression. It is detected in the oocyte, egg and the developing embryo. Studies of the spatial localization of maternal Xwnt-2 show transcripts in both vegetal and animal blastomeres with enrichment in the animal hemisphere. The identification of maternal Xwnt-2 raises questions about possible roles of dorsalizing Xwnts in axial patterning of the Xenopus embryo.

Animals↗
PubMed1999

Control of transferrin receptor expression via nitric oxide-mediated modulation of iron-regulatory protein 2.

Cellular iron storage and uptake are coordinately regulated post-transcriptionally by cytoplasmic factors, iron-regulatory proteins 1 and 2 (IRP-1 and IRP-2). When iron in the intracellular transit pool is scarce, IRPs bind to iron-responsive elements (IREs) in the 5'-untranslated region of the ferritin mRNA and 3'-untranslated region of the transferrin receptor (TfR) mRNA. Such binding inhibits translation of ferritin mRNA and stabilizes the mRNA for TfR, whereas the opposite scenario develops when iron in the transit pool is plentiful. However, we (Richardson, D. R., Neumannova, V., Nagy, E., and Ponka, P. (1995) Blood 86, 3211-3219) and others reported that the binding of IRPs to IREs can also be modulated by nitric oxide (NO). In this study, we showed that a short exposure of RAW 264.7 cells (a murine macrophage cell line) to the NO(+) donor, sodium nitroprusside (SNP), caused a significant decrease in IRP-2 binding to the IREs followed by IRP-2 degradation and that these changes occurred without affecting IRP-1 binding. The SNP-mediated degradation of IRP-2 in RAW 264.7 cells could be prevented by MG-132 or lactacystin, known inhibitors of proteasome-dependent protein degradation. A SNP-mediated decrease in IRP-2 binding and levels was associated with a dramatic decrease in TfR mRNA levels and an increase in ferritin synthesis. Importantly, the proteasome inhibitor MG-132 prevented the SNP-mediated decrease in TfR mRNA levels. These observations suggest that IRP-2 can play an important role in controlling transferrin receptor expression.

Animals↗
PubMed1998

Effect of reactive oxygen species on iron regulatory protein activity.

Iron may be important in catalyzing excessive production of reactive oxygen species (ROS). Cellular iron homeostasis is regulated by iron regulatory proteins (IRPs), which bind to iron-responsive elements (IRE) of mRNAs for ferritin and transferrin receptor (TfR) modulating iron uptake and sequestration, respectively. Although iron is the main regulator of IRP activity, IRP is also influenced by other factors, including the redox state. Therefore, IRP might be sensitive to pathophysiological alterations of redox state caused by ROS. However, previous studies have produced diverging evidence on the effect of oxidative injury on IRP. Results obtained in an animal model close to a pathophysiological condition, such as ischemia reperfusion of the liver as well as in a cell-free system involving an enzymatic source of O2 and H2O2, indicate that IRP is downregulated by oxidative stress. In fact, IRP activity is inhibited at early times of post-ischemic reperfusion. Moreover, the concerted action of O2 and H2O2 produced by xanthine oxidase in a cell-free system caused a remarkable inhibition of IRP activity. IRP seems a direct target of ROS; in fact, in vivo inhibition can be prevented by the antioxidant N-acetylcysteine and by interleukin-1 receptor antagonist. In addition, modulation of iron levels of the cell-free assay did not affect the downregulation imposed by xanthine oxidase. Conceivably, downregulation of IRP activity by O2 and H2O2 may facilitate iron sequestration into ferritin, thus limiting the pro-oxidant challenge of iron.

Acetylcysteine↗
PubMed2003

How might genetic mechanisms operate in autism?

Twin and family studies provide strong evidence that autism has a largely genetic aetiology. The pattern of familial aggregation suggests that in individual families, a small number of genes act together to cause the phenotype. However, it is unlikely that the same genes act in all families. Thus, the total number of genes involved could be large. One key to finding genes for disorders with considerable locus heterogeneity is to detect genetically more homogeneous subsamples. There exist several traits in families who have a child with autism--biochemical, physical, or behavioural--that are likely to reflect underlying genetic heterogeneity and can thus be used to divide families into more homogeneous subsets. These traits (1) show variation in autism samples; (2) are found in non-autistic family members more often than controls; (3) aggregate in particular autism families; and (4) result in increased signals when used in linkage analysis to define 'affected'.

Animals↗
PubMed1997

Xwnt-2b is a novel axis-inducing Xenopus Wnt, which is expressed in embryonic brain.

Xwnt-2b is a novel member of the Wnt gene family and is 73-74% similar to human and mouse Wnt-2 proteins. Starting from stage 15, Xwnt-2b transcripts are localized to a non-contiguous stripe in the anterior neural plate of the Xenopus embryo. In the tailbud, Xwnt-2b is expressed along the dorsoanterior side of the prosencephalon-mesencephalon boundary. At the tadpole stages, the brain-specific expression fades, but the total amount of Xwnt-2b mRNA does not decline due to activation of its expression in non-brain areas. Microinjection of Xwnt-2b mRNA into a ventral blastomere of 4-8-cell embryos results in the formation of complete secondary body axes. These results suggest that Xwnt-2b is a member of the axis-inducing Wnts and that it is involved in brain development and in later organogenesis.

Amino Acid Sequence↗
PubMed2000

Wnt/beta-catenin signaling induces the expression and activity of betaTrCP ubiquitin ligase receptor.

Beta-transducing repeat-containing protein (betaTrCP) targets the ubiquitination and subsequent degradation of both beta-catenin and IkappaB, thereby playing an important role in beta-catenin/Tcf and NF-kappaB-dependent signaling. Here evidence is presented that beta-catenin/Tcf signaling elevates the expression of betaTrCP mRNA and protein in a Tcf-dependent manner, which does not require betaTrCP transcription. Induction of betaTrCP expression by the beta-catenin/Tcf pathway results in an accelerated degradation of the wild-type beta-catenin, suggesting that the negative feedback loop regulation may control the beta-catenin/Tcf pathway. This signaling also upregulated NF-kappaB transactivation without affecting the activity of IkappaB kinase, thereby establishing that the maintenance of the betaTrCP level is important for coordination between beta-catenin/Tcf and NF-kappaB signaling.

Cytoskeletal Proteins↗
PubMed1999

Identification of RNA-binding surfaces in iron regulatory protein-1.

Post-transcriptional regulation of mRNA translation and stability in iron metabolism involves the interaction between the trans-acting cytoplasmic iron regulatory proteins (IRP-1 and IRP-2) and cis-acting iron-responsive elements (IREs) in mRNA 5'- or 3'-untranslated regions. IRP-1 can adopt two conformations: one with a [4Fe-4S]-cluster, unable to bind IREs, which functions as a cytoplasmic aconitase; one lacking this cluster, which accumulates in iron-deprived cells and binds mRNA firmly. We investigated which surfaces of IRP-1 interact with IREs. Surface areas were predicted on the basis of the crystallized porcine mitochondrial aconitase structure. We selected nine sequences absent or different in mitochondrial and Escherichia coli aconitases, both being devoid of RNA-binding properties. Mutations in two regions of domain 4 of IRP-1 lowered the affinity for a wild-type IRE up to 7-fold in vitro, whereas the aconitase activity, a control for structural integrity, was not affected. Scatchard plot analysis with mutant IREs indicated that domain 4 is involved in the binding specificity. This conclusion was confirmed with hybrid proteins in which IRP-1 surface loops were grafted into IRP-2. The results indicate that arginines 728 and 732 contact the IRE bulge, whereas region 685-689 is necessary for recognition of the IRE loop.

Aconitate Hydratase↗
PubMed1998

Dietary iron intake rapidly influences iron regulatory proteins, ferritin subunits and mitochondrial aconitase in rat liver.

Iron regulatory protein 1 (IRP1) and IRP2 are cytoplasmic RNA binding proteins that are central regulators of mammalian iron homeostasis. We investigated the time-dependent effect of dietary iron deficiency on liver IRP activity in relation to the abundance of ferritin and the iron-sulfur protein mitochondrial aconitase (m-acon), which are targets of IRP action. Rats were fed a diet containing 2 or 34 mg iron/kg diet for 1-28 d. Liver IRP activity increased rapidly in rats fed the iron-deficient diet with IRP1 stimulated by d 1 and IRP2 by d 2. The maximal activation of IRP2 was five-fold (d 7) and three-fold (d 4) for IRP1. By d 4, liver ferritin subunits were undetectable and m-acon abundance eventually fell by 50% (P < 0.05) in iron-deficient rats. m-Acon abundance declined most rapidly from d 1 to 11 and in a manner that was suggestive of a cause and effect type of relationship between IRP activity and m-acon abundance. In liver, iron deficiency did not decrease the activity of cytosolic aconitase, catalase or complex I of the electron transport chain nor was there an effect on the maximal rate of mitochondrial oxygen consumption with the use of malate and pyruvate as substrates. Thus, the decline in m-acon abundance in iron deficiency is not reflective of a global decrease in liver iron-sulfur proteins nor does it appear to limit ATP production. Our results suggest a novel role for m-acon in cellular iron metabolism. We conclude that, in liver, iron deficiency preferentially affects the activities of IRPs and the targets of IRP action.

Aconitate Hydratase↗
PubMed1997

Mammary gland development is mediated by both stromal and epithelial progesterone receptors.

A combination of a knockout mouse model, tissue transplantation, and gene expression analysis has been used to investigate the role of steroid hormones in mammary gland development. Mouse mammary gland development was examined in progesterone receptor knockout (PRKO) mice using reciprocal transplantation experiments to investigate the effects of the stromal and epithelial PRs on ductal and lobuloalveolar development. The absence of PR in transplanted donor epithelium, but not in recipient stroma, prevented normal lobuloalveolar development in response to estrogen (E) and progesterone (P) treatment. Conversely, the presence of PR in the transplanted donor epithelium, but not in the recipient stroma, revealed that PR in the stroma may be necessary for ductal development. Members of the Wnt growth factor family, Wnt-2 and Wnt-5B, were employed as molecular markers of steroid hormone action in the mammary gland stroma and epithelium, respectively, to investigate the systemic effects of E and P. Hormonal treatment of intact, ovariectomized, and PR-/- mice and mice after transplantation of PR-/- epithelium into wild type (PR+/+) stroma demonstrated that these two locally acting growth factors are regulated by independent mechanisms. Wnt-2 is acutely repressed by E alone, while Wnt-5B gene expression is induced only after chronic treatment with both E and P. Wnt 5B appears to be one of the few molecular markers of P action in the mammary epithelium. This study suggests that the regulation of mammary gland development by steroid hormones is mediated by distinct effects of the stromal and epithelial PR and differential growth factor expression.

Animals↗
PubMed1993

Analysis of genetic alterations related to the development and progression of breast carcinoma.

To study genetic alterations related to the development and/or progression of breast carcinoma, we examined amplification of the ERBB2, INT2, and MYC genes, as well as loss of heterozygosity (LOH) at loci on 11p, 16q, 17p (D17S5 and TP53), 17q (D17S74 and NME1), and 18q by restriction fragment length polymorphism analysis. The subjects were 26 patients with small breast carcinomas (< or = 2 cm) and 88 patients with larger breast carcinomas (2 to < 5 cm). All patients were free of distant metastasis. As tumor diameter increased, the frequency of oncogene amplification and LOH at all loci except D17S5 increased. However, there was no relationship between tumor diameter and amplification of specific oncogenes or allelic loss at specific loci. LOH at D17S5 was detected in 40% of small breast carcinomas (< or = 2 cm) and 43% of larger breast carcinomas (2 to < 5 cm). There was a significant correlation of LOH at D17S5 with INT2 amplification or with LOH on 11p, 16q, and 18q. These findings suggest that LOH at D17S5 may be involved in the early stage of breast carcinoma development, while INT2 amplification and LOH at 11p, 16q, and 18q appear to be genetic alterations that occur with tumor progression. In addition, as lymph node metastases were significantly related to amplification of the ERBB2 and MYC genes, and LOH of the NME1 gene, these genetic alterations may play a role in the mechanism of lymph node metastases.

Breast Neoplasms↗
PubMed2005

Morphogens in motion: growth control of the neural tube.

The entire vertebrate nervous system develops from a simple epithelial sheet, the neural plate which, along development, acquires the large number and wide variety of neuronal cell types required for the construction of a functional mature nervous system. These include processes of growth and pattern formation of the neural tube that are achieved through complicated and tightly regulated genetic interactions. Pattern formation, particularly in the vertebrate central nervous system, is one of the best examples of a morphogen-type of function. Cell cycle progression, however, is generally accepted to be dependent on cell-intrinsic factors. Recent studies have demonstrated that proliferation of neural precursors is also somehow controlled by secreted signaling molecules, well-known by their role as morphogens, such as fibroblast growth factor (FGF), vertebrate orthologs of the Drosophila wingless (Wnt), hedgehog (Hh), and transforming growth factor beta (TGF-beta) families, that in turn regulate the activity of factors controlling cell cycle progression. In this review we will summarize the experimental data that support the idea that classical morphogens can be reused to regulate proliferation of neural precursors.

Animals↗
PubMed2002

Direct flight muscles in Drosophila develop from cells with characteristics of founders and depend on DWnt-2 for their correct patterning.

The direct flight muscles (DFMs) of Drosophila allow for the fine control of wing position necessary for flight. In DWnt-2 mutant flies, certain DFMs are either missing or fail to attach to the correct epithelial sites. Using a temperature-sensitive allele, we show that DWnt-2 activity is required only during pupation for correct DFM patterning. DWnt-2 is expressed in the epithelium of the wing hinge primordium during pupation. This expression is in the vicinity of the developing DFMs, as revealed by expression of the muscle founder cell-specific gene dumbfounded in DFM precursors. The observation that a gene necessary for embryonic founder cell function is expressed in the DFM precursors suggests that these cells may have a similar founder cell role. Although the expression pattern of DWnt-2 suggests that it could influence epithelial cells to differentiate into attachment sites for muscle, the expression of stripe, a transcription factor necessary for epithelial cells to adopt an attachment cell fate, is unaltered in the mutant. Ectopic expression of DWnt-2 in the wing hinge during pupation can also create defects in muscle patterning without alterations in stripe expression. We conclude that DWnt-2 promotes the correct patterning of DFMs through a mechanism that is independent of the attachment site differentiation initiated by stripe.

Animals↗
PubMed2004

Inhibition of Wnt-2-mediated signaling induces programmed cell death in non-small-cell lung cancer cells.

In this report, we have demonstrated that Wnt-2 protein is overexpressed in freshly resected human non-small-cell lung cancer (NSCLC) tissues. We have also developed a monoclonal antibody against the N-terminus of human Wnt-2 protein. This monoclonal antibody induces apoptosis in human NSCLC cell lines that overexpress Wnt-2 protein. Incubation of this antibody with normal human airway cells lacking Wnt-2 expression does not induce apoptosis. Wnt-2 signaling blockade by the anti-Wnt-2 antibody is confirmed by downregulation of cytosolic beta-catenin and reduction in TCF-dependent transcriptional activity (TOPFLASH assay). In addition, Wnt-2-specific small interfering RNA (siRNA) treatment in the NSCLC cell line A549 also downregulated cytosolic beta-catenin and induced apoptosis. Moreover, downregulation of an inhibitor of apoptosis family protein, Survivin, was noticed both in the Wnt-2 antibody- and siRNA-treated NSCLC cells, suggesting that inhibition of Wnt-2-mediated signaling induces apoptosis through inactivating Survinin.

Antibodies, Monoclonal↗
PubMed2003

[Wnt/Frizzled signaling pathway in renal carcinoma].

OBJECTIVE: To investigate the transduction of Wnt/Frizzled signaling pathway, especially the function of T cell factor 4 (TCF(4)), in renal carcinoma. METHODS: A renal carcinoma yeast two hybrid library and a human TCF(4) yeast two hybrid expression vector were constructed. Proteins interacting with the bait protein human TCF(4) were obtained from the renal carcinoma yeast two hybrid library by reverse yeast two hybrid system. RESULTS: 67 positive clones interacting with the bait protein TCF(4) were obtained by reverse yeast two hybrid system, including 18 beta-catenin clones, 24 TCF(4) clones and 25 unknown clones. CONCLUSION: Wnt/Frizzled signaling pathway exists in renal carcinoma. TCF(4), its important signal factor, interacts with beta-catenin and forms homodimer or homocopolymer by itself, thus displaying its constitutive transcriptional activity.

Adenocarcinoma, Clear Cell↗
PubMed2004

Progression of pregnancy-dependent mouse mammary tumors after long dormancy periods. Involvement of Wnt pathway activation.

Mouse mammary tumor virus (LA) induces pregnancy-dependent mammary tumors that progress toward autonomy. Here we show that in virgin females, pregnancy-dependent tumor transplants are able to remain dormant for up to 300 days. During that period, these tumors synthesize DNA, express high levels of estrogen and progesterone receptors (ER+PR+) and are able to resume growth after hormone stimulation. Surprisingly, in a subsequent transplant generation, all these tumors are fully able to grow in virgin females, they express low levels of ER and PR (ER-PR-) and have a monoclonal origin; i.e., show all of the features we have described previously in pregnancy-independent tumors. Histologically, mouse mammary tumor virus (LA)-induced tumors are morphologically similar to genetically engineered mouse (GEM) mammary tumors that overexpress genes belonging to the Wnt pathway. Interestingly, in the virus-induced neoplasias, pregnancy-independent passages arising after a dormant phase usually display a lower level of glandular differentiation together with epithelial cell trans-differentiation, a specific feature associated to Wnt pathway activation. In addition, dormancy can lead to the specific selection of Int2/Fgf3 mutated and overexpressing cells. Therefore, our results indicate that during hormone-dependent tumor dormancy, relevant changes in cell population occur, allowing rapid progression after changes in the animal internal milieu.

Animals↗
PubMed1992

Growth and developmental regulation of wnt-2 (irp) gene in mesenchymal cells of fetal lung.

The wnt gene family encodes a group of proteins implicated as intercellular signaling molecules in vertebrate development. Because many wnt genes are also expressed in the lung, we have examined whether the wnt family member wnt-2 (irp) plays a role in lung development. We have cloned rat wnt-2 and found that this cDNA detects multiple mRNAs expressed at high levels in fetal rat lung. Much lower levels were found in adult rat lung and other tissues, including, surprisingly, the mammary gland. The wnt-2 mRNA was also detected in human fetal lung fibroblast cell lines, where the mRNA levels were dramatically regulated by growth state as well as growth factor stimulation. In situ hybridization showed that, in fetal rat lung, wnt-2 mRNA expression is restricted to the mesenchyme; levels in the developing epithelium were indistinguishable from background. Based on the known properties of other wnt proteins, our data lead us to propose that wnt-2 may play a role in lung development by mediating intercellular interaction(s) between mesenchyme and epithelium.

Amino Acid Sequence↗
PubMed2004

An anti-Wnt-2 monoclonal antibody induces apoptosis in malignant melanoma cells and inhibits tumor growth.

Activation of the Wnt/beta-catenin signaling pathway has been associated with human cancers. To test whether Wnt-2 signal is a survival factor in human melanoma cells and thus represents a potential therapeutic target, we investigated the effects of inhibition of Wnt-2 signaling in human melanoma cell lines. We have developed a novel monoclonal antibody against the NH(2) terminus of the human Wnt-2 ligand that induces apoptosis in human melanoma cells overexpressing Wnt-2. Whereas incubation of this antibody with normal cells lacking Wnt-2 expression does not induce apoptosis, Wnt-2 signaling blockade by the ligand-binding antibody is confirmed by down-regulation of Dishevelled and beta-catenin. Wnt-2 small interfering RNA treatment in these cells yielded similar apoptotic effects and downstream changes. Down-regulation of an inhibitor of apoptosis family protein, survivin, was observed in both the Wnt-2 antibody-treated and small interfering RNA-treated melanoma cell lines, suggesting that the antibody induces apoptosis by inactivating survivin. In an in vivo study, this monoclonal anti-Wnt-2 antibody suppresses tumor growth in a xenograft model. These findings suggest that the anti-Wnt-2 monoclonal antibody may be useful for the treatment of patients with malignant melanoma.

Adaptor Proteins, Signal Transducing↗