Wnt Catenin Signaling And Disease Pdf
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- Wnt/β-Catenin Signaling and Disease
- WNT Signaling in Disease
- Wnt signaling and human diseases: what are the therapeutic implications?
- Wnt/β-Catenin Signaling as a Molecular Target by Pathogenic Bacteria
The virulence factors from pathogenic bacteria such as Salmonella enterica sv Typhimurium, Helicobacter pylori, Mycobacterium tuberculosis, Pseudomonas aeruginosa, Citrobacter rodentium, Clostridium difficile, Bacteroides fragilis, Escherichia coli, Haemophilus parasuis, Lawsonia intracellularis, Shigella dysenteriae , and Staphylococcus epidermidis employ a variety of molecular strategies to alter the appropriate functioning of diverse signaling pathways. Such a variety of mechanisms illustrate an evolutionary co-adaptation of eukaryotic molecular signaling to a battery of soluble or structural components synthesized by pathogenic bacteria.
Wnt/β-Catenin Signaling and Disease
Wnt signaling is one of a handful of powerful signaling pathways that play crucial roles in the animal life by controlling the genetic programs of embryonic development and adult homeostasis. When disrupted, these signaling pathways cause developmental defects, or diseases, among them cancer. Canonical Wnt signaling also plays important roles in the maintenance of various embryonic or adult stem cells, and as recent findings demonstrated, in cancer stem cell types.
This has opened new opportunities to model numerous human diseases, which have been associated with deregulated Wnt signaling. That a single cell, the fertilized egg, can generate a complete animal with a wide variety of complex tissues and organs is the most remarkable process in nature. They act in parallel or in sequence in order to regulate crucial aspects of development and morphogenesis including cellular proliferation, differentiation, cell migration, and apoptosis.
Deregulation of these signaling cascades may lead to severe developmental perturbations and lethality. In adult organisms, the same pathways play crucial roles in the maintenance of tissue homeostasis and control stem cell functions. Their dysfunction may lead to pathological conditions such as cancer for review, see Hunter ; Polakis ; Chari and McDonnell ; Dreesen and Brivanlou Almost three decades of interdisciplinary research have revealed the physiological function of these pathways in a spectrum of model organisms including hydra, worms, flies, fish, frogs, mice, and humans.
Mice have proven to be a particularly powerful model to study molecular mechanisms of development and disease. This is due to the close evolutionary relationship of rodents and humans, similarities in physiological and pathophysiological mechanisms in mice and man, and the large repertoire of genetic techniques available to assess gene functions in mice. Wnt signaling is an ancient and highly conserved pathway for review, see Logan and Nusse ; Clevers ; Klaus and Birchmeier The molecular components of Wnt signaling and the mechanisms of Wnt signal transduction have been elucidated through genetic and biochemical experiments in various model organisms and in cultured cells.
In , Nusse and Varmus identified the proto-oncogene int-1 integration-1 as a preferential site for proviral integration of the mouse mammary tumor virus MMTV in a mouse model of mammary cancer Nusse and Varmus Int-1 turned out to be the mammalian homolog of the genetically characterized segment polarity gene in Drosophila , wingless wg Nusslein-Volhard and Wieschaus ; Cabrera et al.
Xenopus oocytes provided an additional, widely used assay to study components of the Wnt signaling system. The injection of Xenopus oocytes with RNA that encodes components regulating the Wnt pathway in a positive manner—e. Our current knowledge of the molecular components of the Wnt signaling cascade is summarized in Figure 1. The signal is initiated by Wnt ligands there are 19 Wnt genes in the human genome.
The secretion and post-translational modifications of Wnt ligands are accomplished by the retromer complex and accompanying molecules, such as porcupine and Wntless Wls for review, see Coudreuse and Korswagen ; Hausmann et al. Scheme of the Wnt signaling pathway. The Wnt glycoproteins are produced by the neighboring cells and secreted in a process that involves many components, such as a multiprotein retromer complex, and the multispanning transmembrane protein Wntless Wls.
The secreted Wnt ligands bind to the receptors of the seven-membrane-spanning Frizzled family and single-spanning LRP family. Secreted factors like secreted Frizzled-related proteins sFRPs bind to Wnts and block the interaction with Frizzled receptors.
Dickkopf antagonizes Wnt signaling by blocking LRP receptors. The three pathways branch at the level of Dishevelled Dsh protein. In the noncanonical Jun kinase pathway, Dsh via Daam1, is connected to downstream effectors, such as Rho, and regulates cytoskeletal organization and cell polarity. In line with the initial discovery of Wnt1 in mouse mammary neoplasias, the constitutive activation of Wnt signaling causes tumor formation and progression in humans.
Gain-of-function mutations of activators of the Wnt pathway can have oncogenic activity, whereas loss-of-function mutations of inhibitors of Wnt signaling can lead to a loss of tumor suppressor activity. Over nearly two decades, gene targeting techniques have provided ever deeper insights into Wnt activity and functions. In mice, these methods are based on homologous recombination in embryonic stem cells and allow the introduction of mutations into any gene work for which Mario R.
Capecchi, Martin J. These mutant embryonic stem cells are then used to produce mice that carry the mutant allele. During the s, knockout mice carrying targeted mutations in genes encoding newly identified members of the Wnt family of ligands were generated Stark et al. These studies revealed an important role of Wnt genes in development of additional tissues including the mesoderm, kidney, and extremities.
The fact that compound mutations of these genes often exhibited stronger and earlier phenotypes than the single mutations suggested a functional redundancy between the different Wnt genes Ikeya et al. Such mutant embryos failed to form an A—P axis at embryonic day 6 E6 and did not generate mesoderm at E7. We should also mention that the use of the various Wnt reporter mice generated by several groups was an important help to the field, and those mice were used extensively to monitor endogenous Wnt signaling activity DasGupta and Fuchs ; Cheon et al.
The ability to mutate genes in the mouse in a temporal and tissue-specific manner by conditional gene mutation, techniques developed by Klaus Rajewsky and collaborators Gu et al. This strategy relies on the introduction of recombinase recognition sites LoxP or Frt that flank the target gene or parts of it. These recognition sites are, for instance, inserted into intronic sequences of a gene in such a way that in the absence of the recombinase Cre or Flp , the normal gene function is not altered.
Transient expression of cre recombinase results in excision of the neo resistance cassette. Subsequently, tissue-specific cre expression leads to excision of the floxed exons, frameshift mutations, and production of a null-allele see in c , cf. Tissue-specific cre expression leads to excision of exon 3 and in-frame splicing on exons 2 and 4, thus resulting in expression of a protein that escapes the degradation.
The epidermis forms the outermost layer of the mammalian skin. Progenitor cells in the basal layer of the epidermis constantly proliferate, ensuring the renewal of the epithelium. In addition to these epidermal progenitors, the bulge attached to the hair follicles is a niche for skin stem cells.
These are able to contribute to all epithelial cell types of the skin appendages; e. After wounding, bulge stem cells contribute in addition to the newly formed epidermal epithelium for review, see Paus and Foitzik ; Blanpain and Fuchs Several Wnt genes are expressed in the skin Wang and Shackleford ; Saitoh et al.
In addition, gene ablation had demonstrated an essential role of Lef1 in formation of hair, whiskers, and other epidermal appendages van Genderen et al.
Conversely, one-third of human sebaceous gland tumors carry inactivating mutations of Lef1, indicating that Wnt signaling activity needs to be repressed for proper sebaceous gland development Takeda et al. The epidermis develops correctly, but the skin of the mutant mice becomes naked. Instead of hair, unusual cyst-like structures appeared in the skin of these mice Fig. Moreover, transgenic expression of dominant-negative Lef1 also resulted in the formation of cysts instead of hair Merrill et al.
A similar phenotype—i. Finally, Wnt signals have also been found to be essential for de novo hair follicle formation after wounding Ito et al. Such animals display densely packed hair follicles with little or no interfollicular epidermis Fig. In such cells, proliferation, cell cycle progression, and expression of CyclinD1 were similar to the processes in control cells. More recently, interactions between Wnt and Bmp signaling have been described as essential in the control of the skin stem cell niche Zhang et al.
The conditional ablation of Bmp receptor 1a BmpR1a resulted in increased canonical Wnt signaling, stem cell overproliferation and expansion of the bulge, and loss of quiescent cells. Oscillating expression of Bmps in normal skin regulate oscillations in Wnt signaling in cases such as when Bmp levels in the dermis are high, Wnt signaling activity is low and vice versa Plikus et al.
The oscillations of Bmp and Wnt signaling ensure periodic activation of the bulge stem cells and allow the coordinated hair differentiation during the hair cycle. This demonstrated an essential role of canonical Wnt signals in the specification of the dermis Table 1. Canonical Wnt signals are required in the epithelium at several steps during the formation of teeth, first at an early stage for proper tooth bud development, and at later stages for patterning of the molar cusp and for establishment of molar polarity Liu et al.
It remains to be determined whether a stem cell population exists in the tooth germs of the dental epithelium and if so, what role Wnt signaling plays in such cells. Canonical Wnt signaling is not only required in the epithelium, but also in the mesenchyme of skin and its appendages, as demonstrated by the analysis of Lef1 mutant and Dkk1-transgenic mice van Genderen et al. This fits given the fact that epithelial—mesenchymal interactions are known to govern hair and tooth development.
Cancer stem cells and normal stem cells share many characteristics, like the capacity for self-renewal and differentiation and their dependence on a particular micro-environment, the cancer stem cell niche for review, see Passegue and Weissman ; Wilson and Trumpp ; Fodde and Brabletz ; Sneddon and Werb Malanchi et al.
These cancer stem cells can be isolated by cell sorting based on the presence of the stem cell marker CD34 and absence of other markers. Secondary tumors that formed after transplantation resembled the parental tumors.
Thus, canonical Wnt signals are required in normal skin to instruct bulge stem cells toward the hair cell fate, whereas in epidermal tumors, they control the maintenance of skin cancer stem cells. It may be possible to exploit this differential response of normal and cancer stem cells in therapies. Wnt signaling plays a crucial role during development of the gastrointestinal tract, in particular, in endoderm specification and gut tube patterning, as well as in intestinal stem cell maintenance Lickert et al.
During development, the gastrointestinal tract forms from the embryonic gut tube. This structure, which is of endodermal origin, undergoes a series of morphogenic changes and patterning events along its A—P and dorsal—ventral D—V axes that give rise to major organs such as the esophagus, stomach, and intestine small intestine, colon , as well as to associated organs including the liver, pancreas, and thyroid Wells and Melton ; Gregorieff and Clevers The absorptive epithelium of the small intestine is ordered into villi and crypts of Lieberkuehn; in contrast, colon epithelium consists of crypts only.
Intestinal crypts are stem cell niches that ensure the self-renewing capacity of the intestine through maintenance of intestinal stem cells and proliferation of transit amplifying cells, which give rise to all differentiated cell types, that is, enterocytes, enteroendocrine and goblet cells of the villi, and to the Paneth cells, which reside at the bottom of the crypts. Activated Wnt signaling is required in the posterior part of the gut tube for intestinal lineage specification, whereas in the anterior part, stomach and esophagus formation require Wnt repression Gregorieff et al.
In the adult intestine, canonical Wnt activity is restricted to the proliferative compartment of crypts only. This demonstrated that downstream from canonical Wnt signaling, the Tcf4-driven genetic program is essential to maintain the crypt stem cells of the small intestine.
As in the skin, defects in Wnt signaling in the intestine can lead to cancer. Numerous polyps in the small intestine up to per mouse were found in all mice at a young age. The mutant mice developed well-separated polyps at the crypt intervillus region — per mouse Harada et al. In both models, polyps were composed uniquely of enterocytes.
The conditional ablation of c-myc using an inducible Cyp promoter-driven cre normalized the tissue; i. Mutant embryos showed reduced stomach size and highly disorganized glandular morphology. The esophagus displayed inverted positioning of squamous and cuboidal epithelial cell types along the D—V axis. The esophagus epithelium showed abnormal mucin secretion, which is normally produced by the stomach, indicating posteriorization of the gut tube Kim et al. These data are consistent with the general role of Wnt signaling in the establishment of A—P and D—V polarity of the gut tube.
Development of the pancreas starts with two epithelial invaginations of the posterior foregut endoderm, which expand and invade the surrounding mesenchyme. There they branch and differentiate to form two lobes of the mature pancreas for review, see Wells and Melton Gut rotation brings these dorsal and ventral lobes to a close proximity, where they undergo partial fusion. The mature pancreas consists of two functionally different compartments: endocrine and exocrine.
The exocrine compartment occupies most of the pancreatic mass and consists of acinar cells, which produce digestive enzymes. These enzymes are directed to the intestine through a branched network of ducts. By characterizing the two available Pdx1 cre lines, Heiser et al.
WNT Signaling in Disease
Wnt signaling is one of a handful of powerful signaling pathways that play crucial roles in the animal life by controlling the genetic programs of embryonic development and adult homeostasis. When disrupted, these signaling pathways cause developmental defects, or diseases, among them cancer. Canonical Wnt signaling also plays important roles in the maintenance of various embryonic or adult stem cells, and as recent findings demonstrated, in cancer stem cell types. This has opened new opportunities to model numerous human diseases, which have been associated with deregulated Wnt signaling. That a single cell, the fertilized egg, can generate a complete animal with a wide variety of complex tissues and organs is the most remarkable process in nature. They act in parallel or in sequence in order to regulate crucial aspects of development and morphogenesis including cellular proliferation, differentiation, cell migration, and apoptosis.
Preeclampsia PE is as a major factor in maternal and fetal morbidity and mortality. The main clinical presentations are proteinuria, hypertension and edema. Early research focused on understanding hypertension and renal dysfunction; however, additional studies on the syndrome are lacking. Over the past 20 years, increasing evidence has indicated that PE is a multisystemic syndrome that is associated with endothelial dysfunction 2 , inflammatory activation 3 , an imbalance of angiogenic factors and metabolic changes 4 , 5. Studies are currently focusing on the process of trophoblast invasion, which is an important feature of PE 6. Wnt signaling is an essential pathway in the regulation of cell proliferation, migration and death, and is conserved from hydras to humans.
Here, we describe the core Wnt/b-catenin signaling pathway, how it controls stem cells, and contributes to disease. Finally, we discuss strategies.
Wnt signaling and human diseases: what are the therapeutic implications?
Oncotarget a primarily oncology-focused, peer-reviewed, open access, biweekly journal aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. Its scope is unique. The term "oncotarget" encompasses all molecules, pathways, cellular functions, cell types, and even tissues that can be viewed as targets relevant to cancer as well as other diseases. The term was introduced in the inaugural Editorial , Introducing OncoTarget. Sponsored Conferences.
Developmental signaling pathways control a vast array of biological processes during embryogenesis and in adult life. The WNT pathway was discovered simultaneously in cancer and development. Recent advances have expanded the role of WNT to a wide range of pathologies in humans. The WNT signaling pathway is an evolutionarily conserved signal transduction pathway that regulates a wide range of cellular functions during development and adulthood.
Innate immunity against pathogenic bacteria is critical to protect host cells from invasion and infection as well as to develop an appropriate adaptive immune response. During bacterial infection, different signaling transduction pathways control the expression of a wide range of genes that orchestrate a number of molecular and cellular events to eliminate the invading microorganisms and regulate inflammation. The inflammatory response must be tightly regulated because uncontrolled inflammation may lead to tissue injury.
Wnt/β-Catenin Signaling as a Molecular Target by Pathogenic Bacteria
The Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt is a portmanteau created from the names Wingless and Int They are highly evolutionarily conserved in animals, which means they are similar across animal species from fruit flies to humans. All three pathways are activated by the binding of a Wnt-protein ligand to a Frizzled family receptor , which passes the biological signal to the Dishevelled protein inside the cell. The canonical Wnt pathway leads to regulation of gene transcription , and is thought to be negatively regulated in part by the SPATS1 gene. Wnt signaling was first identified for its role in carcinogenesis , then for its function in embryonic development.
С того места, где он стоял, казалось, что голова сотрудника лаборатории систем безопасности лишилась тела и осталась лежать на полу шифровалки. А потом медленно скрылась из виду в клубах пара. - Отчаянный парень, - пробормотал Хейл себе под нос. Он знал, что задумал Чатрукьян.
1. The Basics of WNT
Атакующие линии рвались вперед, они находились уже на волосок от пятой, и последней, стены, Последние минуты существования банка данных истекали. Сьюзан отгородилась от царившего вокруг хаоса, снова и снова перечитывая послание Танкадо. PRIME DIFFERENCE BETWEEN ELEMENTS RESPONSIBLE FOR HIROSHIMA AND NAGASAKI ГЛАВНАЯ РАЗНИЦА МЕЖДУ ЭЛЕМЕНТАМИ, ОТВЕТСТВЕННЫМИ ЗА ХИРОСИМУ И НАГАСАКИ - Это даже не вопрос! - крикнул Бринкерхофф. - Какой же может быть ответ. - Нам необходимо число, - напомнил Джабба. - Шифр-убийца имеет цифровую структуру.
И он согласился поехать. - Конечно, согласился. Вы же мой шеф. Вы заместитель директора АНБ. Он не мог отказаться. - Ты права, - проворчал Стратмор. - Поэтому я его и попросил.
Фонтейн кивнул. Иерархия допуска в банк данных была тщательно регламентирована; лица с допуском могли войти через Интернет. В зависимости от уровня допуска они попадали в те отсеки банка данных, которые соответствовали сфере их деятельности. - Поскольку мы связаны с Интернетом, - объяснял Джабба, - хакеры, иностранные правительства и акулы Фонда электронных границ кружат вокруг банка данных двадцать четыре часа в сутки, пытаясь проникнуть внутрь. - Да, - сказал Фонтейн, - и двадцать четыре часа в сутки наши фильтры безопасности их туда не пускают. Так что вы хотите сказать.
ГЛАВА 29 Все еще нервничая из-за столкновения с Хейлом, Сьюзан вглядывалась в стеклянную стену Третьего узла. В шифровалке не было ни души. Хейл замолк, уставившись в свой компьютер. Она мечтала, чтобы он поскорее ушел. Сьюзан подумала, не позвонить ли ей Стратмору.