Wingless
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The signaling pathway mediated by Wingless-type (Wnt) proteins is highly conserved in evolution. This pivotal pathway is known to regulate cell fate decisions, cell proliferation, morphology, migration, apoptosis, differentiation and stem cell self-renewal. It currently includes the canonical or Wnt/beta-catenin pathway in which Wnt proteins bind to 'frizzled' receptors, which leads to downstream activation of gene transcription by beta-catenin. Second, the noncanonical or beta-catenin-independent pathways are now known to be mediated by three possible mechanisms: (1) the Wnt/Ca(2+) pathway, (2) the Wnt/G protein signaling pathway, and (3) the Wnt/PCP or planar cell polarity pathway. Wnt signaling is implicated at several stages of mammary gland growth and differentiation, and possibly in the involution of mammary gland following lactation. Recent evidence suggests the role of Wnt signaling in human breast cancer involves elevated levels of nuclear and/or cytoplasmic beta-catenin using immunohistochemistry, overexpression or downregulation of specific Wnt proteins, overexpression of CKII and sFRP4, downregulation of WIF-1 and sFRP1, as well as amplification of DVL-1. Further research is required to determine how Wnt signaling is involved in the development of different histological types of breast cancer and whether it promotes the viability of cancer stem cells or not. Copyright 2006 S. Karger AG, Basel.
- MeSH
- lidé MeSH
- mléčné žlázy lidské metabolismus růst a vývoj MeSH
- nádorová transformace buněk genetika metabolismus MeSH
- nádory prsu genetika metabolismus MeSH
- proteiny Wnt genetika metabolismus MeSH
- signální transdukce * fyziologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
Předmět sdělení: Ageneze zubu je nejčastější vývojovou poruchou dentice, kterou podle databáze Online Mendelian Inheritance in Man (OMIM) nacházíme přibližně u 20 % populace. Přestože se jedná o tak běžnou anomálii, její etiologie zatím není zcela objasněna. Vznik ageneze je ve většině případů podmíněn genetickou poruchou, pouze malé procento agenezí je zapříčiněno vlivem zevního prostředí. Mohou se uplatnit somatická onemocnění, jako rubeola, syfilis, spála, rachitis nebo nutriční poškození plodu během těhotenství a dětství. Chybění zubů může způsobit také ozařování kraniální oblasti v období raného vývoje organismu, poškození mateřského organismu ozářením, chemickými látkami a léky (thalidomid, cytostatika). Z místních příčin jsou nejčastější různé druhy traumat, dále nádory a osteomyelitis. Hypodoncie se může objevit jako izolovaná vývojová vada (nesyndromická hypodoncie) nebo jako symptom komplexních syndromů (syndromická hypodoncie). Dosud popsanými příčinami nesyndromické hypodoncie uvedenými v databázi OMIM jsou mutace v genech MSX1 (muscle segment homeobox gene 1), PAX9 (paired box gene 9), AXIN2 (axis inhibition protein 2), EDA (ectodysplasin A), WNT10A (Wingless-type MMTV integration site family, member 10A) a LTBP3 (latent transforming growth factor beta binding protein 3). Publikovány byly také případy, kdy byla ageneze podmíněna mutacemi v genech EDARADD (EDAR-associated death domain), NEMO (nuclear factor-kappaB essential modulator), KRT17 (keratin 17) a TGFA (transforming growth factor-alfa). Jednotlivé geny se liší jak z hlediska počtu identifikovaných mutací, tak z hlediska počtu dokumentovaných pacientů. Tyto mutace vysvětlují vznik poruchy jen u části postižených jedinců, u většiny nebyly identifikovány žádné defekty v těchto genech. Cestou pro selekci dalších genů, které zodpovídají za nesyndromické formy hypodoncie, může být identifikace genů, které zapříčiňují vznik syndromů, mezi jejichž symptomy patří hypodoncie.
Background: Tooth agenesis represents the most common anomaly of dental development, which according to Online Mendelian Inheritance in Man (OMIM) database, affects approximately 20% of the population. Although the anomaly is so common, the ethiology is still undisclosed. In most cases the agenesis is caused by genetic disorder, only a few develop due to external factors. Some of the external factors are rubeolla, syphilis, vitamin D deficiency or nutritional damage during pregnancy and early childhood. Other harmful factors are radiation therapy in orofacial area in early stages of the development of the patient, harms the mother caused by radiation, chemical substances or drugs (e.g. thalidomide, cytostatics). Local factors include various types of injuries, tumors and osteomyelitis. Hypodontia can occur as an isolated condition (non-syndromic hypodontia) or can be associated with a systemic condition or syndrome (syndromic hypodontia). Despite the fact that, tooth agenesis is so common, little is known about the genetic defects responsible for this complex condition. To date, the genes associated with the non-syndromic form of tooth agenesis, listed in OMIM, are MSX1 (muscle segment homeobox gene 1), PAX9 (paired box gene 9), AXIN2 (axis inhibition protein 2), EDA (ectodysplasin A), WNT10A (Wingless-type MMTV integration site family, member 10A) and LTBP3 (latent transforming growth factor beta binding protein 3). Cases with selective tooth agenesis caused by mutation in genes EDARADD (EDAR-associated death domain), NEMO (nuclear factor-kappaB essential modulator), KRT17 (keratin 17) and TGFA (transforming growth factor-alfa), were also published. All these genes vary both in terms of number of identified mutations and in terms of number of documented patients. These mutations explain the formation of tooth agenesis in only a part of affected individuals. Most patients have no defects in these genes. To select other genes, that are responsible for non-syndromic forms of hypodontia, the identification of genes that cause syndroms with symptoms of hypodontia, seems as reasonable direction of further research.
- Klíčová slova
- hypodoncie, TGFA, KRT17, NEMO, EDARADD, LTBP3, WNT10A, EDA, AXIN2, PAX9, MSX1,
- MeSH
- anodoncie * etiologie genetika MeSH
- axin protein genetika MeSH
- ektodysplasiny genetika MeSH
- kinasa I-kappa B genetika MeSH
- lidé MeSH
- mutace * MeSH
- odontogeneze genetika MeSH
- protein Edaradd genetika MeSH
- proteiny vázající latentní TGF-beta genetika MeSH
- proteiny Wnt genetika MeSH
- transkripční faktor MSX1 genetika MeSH
- transkripční faktor PAX9 genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Malignant gliomas are among the most severe types of cancer, and the most common primary brain tumors. Treatment options are limited and the prognosis is poor. WNT-5A, a member of the WNT family of lipoglycoproteins, plays a role in oncogenesis and tumor progression in various cancers, whereas the role of WNT-5A in glioma remains obscure. Based on the role of WNT-5A as an oncogene, its potential to regulate microglia cells and the glioma-promoting capacities of microglia cells, we hypothesize that WNT-5A has a role in regulation of immune functions in glioma. We investigated WNT-5A expression by in silico analysis of the cancer genome atlas (TCGA) transcript profiling of human glioblastoma samples and immunohistochemistry experiments of human glioma tissue microarrays (TMA). Our results reveal higher WNT-5A protein levels and mRNA expression in a subgroup of gliomas (WNT-5A(high)) compared to non-malignant control brain tissue. Furthermore, we show a significant correlation between WNT-5A in the tumor and presence of major histocompatibility complex Class II-positive microglia/monocytes. Our data pinpoint a positive correlation between WNT-5A and a proinflammatory signature in glioma. We identify increased presence of microglia/monocytes as an important aspect in the inflammatory transformation suggesting a novel role for WNT-5A in human glioma.
- MeSH
- čipová analýza tkání MeSH
- gliom metabolismus patologie MeSH
- lidé MeSH
- mikroglie metabolismus patologie MeSH
- monocyty metabolismus patologie MeSH
- proteiny Wnt biosyntéza genetika metabolismus MeSH
- protoonkogenní proteiny biosyntéza genetika metabolismus MeSH
- výpočetní biologie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
OBJECTIVES: The aim of this study was the analysis of WNT10A variants in seven families of probands with various forms of tooth agenesis and self-reported family history of cancer. MATERIALS AND METHODS: We enrolled 60 young subjects (aged 13 to 17) from the Czech Republic with various forms of tooth agenesis. Dental phenotypes were assessed using Planmeca ProMax 3D (Planmeca Oy, Finland) with Planmeca Romexis software (version 2.9.2) together with oral examinations. After screening PAX9, MSX1, EDA, EDAR, AXIN2 and WNT10A genes on the Illumina MiSeq platform (Illumina, USA), we further analyzed the evolutionarily highly conserved WNT10A gene by capillary sequencing in the seven families. RESULTS: All the detected variants were heterozygous or compound heterozygous with various levels of phenotypic expression. The most severe phenotype (oligodontia) was found in a proband who was compound heterozygous for the previously identified WNT10A variant p.Phe228Ile and a newly discovered c.748G > A variant (p.Gly250Arg) of WNT10A. The newly identified variant causes substitution of hydrophobic glycine for hydrophilic arginine. CONCLUSIONS: We suggest that the amino acid changes in otherwise highly conserved sequences significantly affect the dental phenotype. No relationship between the presence of WNT10A variants and a risk of cancer has been found. CLINICAL RELEVANCE: Screening of PAX9, MSX1, EDA, EDAR, AXIN2 and WNT10A genes in hope to elucidate the pattern of inheritance in families.
Background. The Wnt signaling pathway is crucial for cell fate decisions, stem cell renewal, regulation of cell proliferation and differentiation. Deregulated Wnt signaling is also implicated in a number of hereditary and degenerative diseases and cancer. Methods and results. This review highlights the role of the Wnt pathway in the regulation of stem/progenitor cell renewal and prostate gland development and how this signaling is altered in prostate cancer. Recent evidence suggests that Wnt signaling regulates androgen activity in prostate cancer cells, enhances androgen receptor expression and promotes the growth of prostate cancer even after androgen ablation therapy. There is also strong evidence that Wnt signaling is enhanced in androgen-ablation resistant tumors and bone metastases. Conclusions. Further study of the modulators of this pathway will be of therapeutic relevance as inhibition of Wnt signaling may have the potential to reduce the self-renewal and aggressive behaviour of prostate cancer while Wnt signaling activation might enhance stem cell activity when tissue regeneration is required.
The last years of cancer research have established the concept of cancer stem cells (CSCs) as a subpopulation of cells within a tumor entirely responsible for tumorigenesis. This has aroused expectations that targeting cancer stem cells would allow effective tumor eradication. This review aims to summarize the relevant achievements in the field and to highlight the complex mechanisms that are involved in regulating CSC function. RECENT FINDINGS: A growing number of studies have identified CSCs in a variety of human tumor types. The focus of attention is now moving to discover molecular signals which are essential to sustain CSC. We summarize recent results on intrinsic and extrinsic signaling pathways such as Wnt signals, which control stem cell self-renewal and highlight the role of the microenvironment or niche in this process. SUMMARY: The discovery of cancer stem cells points into new directions to gain better understanding of cancer biology. This is expected to alter the design of clinical research programs and to improve the way we assess the efficacy of novel anticancer drugs. Several conclusions and predictions derived from this concept hold great promise to speed up the process of discovering effective targets for clinical application.
Frizzleds (FZDs) are unconventional G protein-coupled receptors that belong to the class Frizzled. They are bound and activated by the Wingless/Int-1 lipoglycoprotein (WNT) family of secreted lipoglycoproteins. To date, mechanisms of signal initiation and FZD-G protein coupling remain poorly understood. Previously, we showed that FZD6 assembles with Gαi1/Gαq (but not with Gαs, Gαo and Ga12/13), and that these inactive-state complexes are dissociated by WNTs and regulated by the phosphoprotein Dishevelled (DVL). Here, we investigated the inactive-state assembly of heterotrimeric G proteins with FZD4, a receptor important in retinal vascular development and frequently mutated in Norrie disease or familial exudative vitreoretinopathy. Live-cell imaging experiments using fluorescence recovery after photobleaching show that human FZD4 assembles-in a DVL-independent manner-with Gα12/13 but not representatives of other heterotrimeric G protein subfamilies, such as Gαi1, Gαo, Gαs, and Gαq The FZD4-G protein complex dissociates upon stimulation with WNT-3A, WNT-5A, WNT-7A, and WNT-10B. In addition, WNT-induced dynamic mass redistribution changes in untransfected and, even more so, in FZD4 green fluorescent protein-transfected cells depend on Gα12/13 Furthermore, expression of FZD4 and Gα12 or Gα13 in human embryonic kidney 293 cells induces WNT-dependent membrane recruitment of p115-RHOGEF (RHO guanine nucleotide exchange factor, molecular weight 115 kDa), a direct target of Gα12/13 signaling, underlining the functionality of an FZD4-Gα12/13-RHO signaling axis. In summary, Gα12/13-mediated WNT/FZD4 signaling through p115-RHOGEF offers an intriguing and previously unappreciated mechanistic link of FZD4 signaling to cytoskeletal rearrangements and RHO signaling with implications for the regulation of angiogenesis during embryonic and tumor development.
- MeSH
- faktory zaměňující Rho guanin nukleotidy metabolismus MeSH
- FRAP MeSH
- frizzled receptory chemie metabolismus MeSH
- HEK293 buňky MeSH
- lidé MeSH
- protein dishevelled metabolismus MeSH
- proteinové domény MeSH
- proteiny vázající GTP - alfa-podjednotky G12-G13 metabolismus MeSH
- proteiny Wnt farmakologie MeSH
- rezonanční přenos fluorescenční energie MeSH
- signální transdukce účinky léků MeSH
- vazba proteinů účinky léků MeSH
- zelené fluorescenční proteiny metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Genetic predisposition affects the penetrance of tumor-initiating mutations, such as APC mutations that stabilize β-catenin and cause intestinal tumors in mice and humans. However, the mechanisms involved in genetically predisposed penetrance are not well understood. Here, we analyzed tumor multiplicity and gene expression in tumor-prone ApcMin/+ mice on highly variant C57BL/6J (B6) and PWD/Ph (PWD) genetic backgrounds. (B6 × PWD) F1 APCMin offspring mice were largely free of intestinal adenoma, and several chromosome substitution (consomic) strains carrying single PWD chromosomes on the B6 genetic background displayed reduced adenoma numbers. Multiple dosage-dependent modifier loci on PWD chromosome 5 each contributed to tumor suppression. Activation of β-catenin-driven and stem cell-specific gene expression in the presence of ApcMin or following APC loss remained moderate in intestines carrying PWD chromosome 5, suggesting that PWD variants restrict adenoma initiation by controlling stem cell homeostasis. Gene expression of modifier candidates and DNA methylation on chromosome 5 were predominantly cis controlled and largely reflected parental patterns, providing a genetic basis for inheritance of tumor susceptibility. Human SNP variants of several modifier candidates were depleted in colorectal cancer genomes, suggesting that similar mechanisms may also affect the penetrance of cancer driver mutations in humans. Overall, our analysis highlights the strong impact that multiple genetic variants acting in networks can exert on tumor development. SIGNIFICANCE: These findings in mice show that, in addition to accidental mutations, cancer risk is determined by networks of individual gene variants.
- MeSH
- beta-katenin genetika metabolismus MeSH
- genetická predispozice k nemoci MeSH
- geny APC * MeSH
- kolorektální nádory genetika patologie prevence a kontrola MeSH
- mutace * MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- nádorová transformace buněk genetika metabolismus patologie MeSH
- proteiny Wnt genetika metabolismus MeSH
- střeva patologie MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Sonic hedgehog (Shh) and Wnt-7a are morphogens involved in embryonic as well as ongoing adult neurogenesis. Their effects on the differentiation and membrane properties of neonatal neural stem/progenitor cells (NS/PCs) were studied in vitro using NS/PCs transduced with either Shh or Wnt-7a. Eight days after the onset of in vitro differentiation the cells were analyzed for the expression of neuronal and glial markers using immunocytochemical and Western blot analysis, and their membrane properties were characterized using the patch-clamp technique. Our results showed that both Shh and Wnt-7a increased the numbers of cells expressing neuronal markers; however, quantitative immunocytochemical analysis showed that only Wnt-7a enhanced the outgrowth and the development of processes in these cells. In addition, Wnt-7a markedly suppressed gliogenesis. The electrophysiological analysis revealed that Wnt-7a increased, while Shh decreased the incidence of cells displaying a neuron-like current pattern, represented by outwardly rectifying K(+) currents and tetrodotoxin-sensitive Na(+) currents. Additionally, Wnt-7a increased cell proliferation only at the early stages of differentiation, while Shh promoted proliferation within the entire course of differentiation. Thus we can conclude that Shh and Wnt-7a interfere differently with the process of neuronal differentiation and that they promote distinct stages of neuronal differentiation in neonatal NS/PCs.
- MeSH
- buněčná diferenciace genetika MeSH
- kmenové buňky cytologie metabolismus MeSH
- kultivované buňky MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- nervové kmenové buňky cytologie metabolismus MeSH
- neurogeneze genetika MeSH
- novorozená zvířata MeSH
- proteiny hedgehog genetika fyziologie MeSH
- proteiny Wnt genetika fyziologie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
The seven-transmembrane-spanning receptors of the FZD1-10 class are bound and activated by the WNT family of lipoglycoproteins, thereby inducing a complex network of signaling pathways. However, the specificity of the interaction between mammalian WNT and FZD proteins and the subsequent signaling cascade downstream of the different WNT-FZD pairs have not been systematically addressed to date. In this study, we determined the binding affinities of various WNTs for different members of the FZD family by using bio-layer interferometry and characterized their functional selectivity in a cell system. Using purified WNTs, we show that different FZD cysteine-rich domains prefer to bind to distinct WNTs with fast on-rates and slow off-rates. In a 32D cell-based system engineered to overexpress FZD2, FZD4, or FZD5, we found that WNT-3A (but not WNT-4, -5A, or -9B) activated the WNT-β-catenin pathway through FZD2/4/5 as measured by phosphorylation of LRP6 and β-catenin stabilization. Surprisingly, different WNT-FZD pairs showed differential effects on phosphorylation of DVL2 and DVL3, revealing a previously unappreciated DVL isoform selectivity by different WNT-FZD pairs in 32D cells. In summary, we present extensive mapping of WNT-FZD cysteine-rich domain interactions complemented by analysis of WNT-FZD pair functionality in a unique cell system expressing individual FZD isoforms. Differential WNT-FZD binding and selective functional readouts suggest that endogenous WNT ligands evolved with an intrinsic natural bias toward different downstream signaling pathways, a phenomenon that could be of great importance in the design of FZD-targeting drugs.
- MeSH
- beta-katenin metabolismus MeSH
- buněčné linie MeSH
- fosforylace MeSH
- frizzled receptory metabolismus MeSH
- mapování interakce mezi proteiny MeSH
- mapy interakcí proteinů * MeSH
- myši MeSH
- protein - isoformy metabolismus MeSH
- proteiny Wnt metabolismus MeSH
- signální dráha Wnt * MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Intramural MeSH
