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. Author manuscript; available in PMC: 2013 Dec 17.
Published in final edited form as: Curr Colorectal Cancer Rep. 2012 Dec;8(4):10.1007/s11888-012-0143-4. doi: 10.1007/s11888-012-0143-4

Citrobacter Infection and Wnt signaling

Shahid Umar 1
PMCID: PMC3865928  NIHMSID: NIHMS410406  PMID: 24358033

Abstract

Gut flora generally contributes to a healthy environment while both commensal and pathogenic bacteria that influence the innate and adaptive immune responses, can cause acute and/or chronic mucosal inflammation. Citrobacter rodentium (C. rodentium) is a member of the family of enteropathogens that provide an excellent in vivo model to investigate the host-pathogen interactions in real-time. It is the etiologic agent for transmissible murine colonic hyperplasia (TMCH) while inflammation following C. rodentium infection is dependent upon the genetic background. Ongoing and completed studies in this model have so far established that Wnt/β-catenin, Notch and PI3K pathways regulate colonic crypt hyperplasia while epithelial-stromal cross-talk, mediated by MEK/ERK/NF-κB signaling, regulates inflammation and/or colitis in susceptible strains. The C. rodentium-induced hyperplastic state also increases the susceptibility to either mutagenic insult or in mice heterozygous for Apc gene. The ability to modulate the host response to C. rodentium infection therefore provides an opportunity to delineate the mechanisms that determine mucosal hyperplasia, intestinal inflammation, and/or neoplasia as disease outcomes.

Keywords: Microbiota, Enteric Infection, Citrobacter rodentium, Wnt Signaling, Inflammation, Inflammatory Bowel Disease, Colon Cancer

Introduction

Intestinal Microbiota and Enteric Pathogens

Humans and other multicellular eukaryotic organisms are home to a diverse population of 1014 microbes that constitute our microbiota [1]. In mammals, the gastrointestinal tract contains the most numerous and diverse microbial community [2]. Microbial colonization in humans follows a gradient along the length of the gastrointestinal tract, with a lower titre in the stomach and the duodenum (101–103 bacteria/ml) increasing to ~107 bacteria/ml in the jejunum and ileum and peaking to ~1012 bacteria/ml in the colon [3]. Most of these colonic bacteria are obligate anaerobes while facultative anaerobes are several folds lower. In both human and the murine intestine, the dominant microbiota belongs to the Firmicutes and Bacteroidetes phyla. In addition, Proteobacteria, Actinobacteria, Verrucomicrobia, Cyanobacteria and Deferribacteres have also been detected in humans and mice, and Fusobacteria in humans [46].

Several factors including host age, environmental and genetic factors, diet, and exposure to chemotherapeutic drugs and probiotics influence the composition of the microbiota. In addition, antibiotics can significantly affect the gut microbiota with long-term effects [7] and may result in super infection with antibiotic-resistant bacteria such as Clostridium difficile or vancomycin-resistant Enterococcus [8]. Microbial ligands on commensal flora are recognized by Toll-like receptors (TLRs) most commonly known as Pattern Recognition Receptors (PRRs); activation of these PPRs by the gut flora serves to protect the gut from injury [9] Interaction of gut bacteria and TLRs contributes to mucosal homeostasis and controls local inflammation [10]. It is increasingly been recognized that bacterial residents of the large bowel cannot be easily divided as being pathogenic or non-pathogenic. Many indigenous bacteria, e.g. E. coli, Bacteroides, Enterococci and Clostridium histolyticum, are known pathogens. Unequivocally however, the host’s innate intestinal immune system seems to be heavily involved.

The length of the gastrointestinal tract is inhabited by healthy intestinal microbiota from week one after birth. It exerts a homeostatic influence on the gut through direct inhibition of other microbes that lead to ‘colonization resistance’ to nonindigenous strains of bacteria, such as C. difficile, Salmonella spp. and Campylobacter jejuni. However, breakdown of the resistance predisposes humans to infection by these enteropathogens. Strikingly, the part of the intestine with the highest bacterial colonization, the colon, is also most affected by cancer, with ~150,000 annual cases in the United States [11]. Helicobacter pylori highlighted the potential for bacteria to cause cancer. It is becoming increasingly clear that chronic infection with other bacteria, notably Salmonella typhi, can also facilitate tumor development [12]. Infections caused by several bacteria (e.g. Bartonella spp., Lawsonia intracellularis and Citrobacter rodentium, [1315]) can induce cellular proliferation and prime the colonic mucosa towards neoplasia while chronic bacterial infections can inhibit apoptosis. However, the underlying cellular mechanisms are far from clear. Conversely, bacterial toxins such as PMT (Pasteurella multocida toxin) [16] or Escherichia coli cytotoxic necrotizing factor [17] interfere with cellular signaling mechanisms and could play a direct role in cancer causation and progression. Finally in colorectal cancer (CRC) patients, the fecal levels of an opportunistic pathogen Streptococcus gallolyticus are increased from 10% to about 50% [18]. This bacterium is associated with infectious endocarditis and approximately 60% of patients assessed in this group also had premalignant/malignant colonic lesions [19, 20] which largely exceeds the rates reported in the general population (~25%) [21]. Thus, it is not unprecedented to associate bacterial infection with either onset or progression of colon carcinogenesis.

Citrobacter rodentium

Enteric pathogens such as enteropathogenic Escherichia coli (EPEC), enterohaemorrhagic E. coli (EHEC) and Citrobacter rodentium (C. rodentium), all of which use attaching and effacing (A/E) lesion formation as a major mechanism of tissue targeting and infection, represent the classic genome organization [22]. Both EPEC and EHEC are poorly pathogenic in mice but infect humans and domestic animals. In contrast, C. rodentium is a natural mouse pathogen that is related to E. coli and provides an excellent in vivo model for A/E lesion forming pathogens [23]. C. rodentium also provides a model of infections that are mainly restricted to the lumen of the intestine. The mechanism by which the host responds to such infections has become a topic of great interest in recent years. In this review however due to space constraints, we will focus primarily on C. rodentium’s involvement in the activation of the Wnt signaling pathway and whether the changes accrued broaden our understanding of C. rodentium-induced pathogenesis.

Citrobacter rodentium, formerly Citrobacter freundii biotype 4280, is the etiologic agent of transmissible murine colonic hyperplasia (TMCH) while C. freundii has been reclassified as a human pathogen based on the biochemical testing that distinguishes C. rodentium from C. freundii as indole negative and positive for ornithine decarboxylase. C. rodentium is a gram-negative, facultatively anaerobic rod and is generally considered an opportunistic pathogen that is host adapted to laboratory mice. The ability to generate the A/E phenotype by these organisms requires the locus of enterocyte effacement (LEE), a pathogenicity island that encodes a type III secretion system (TTSS) and several translocated effectors [24, 25]. Translocated intimin receptor (Tir), a TTSS effector critical for intimate bacterial attachment and actin pedestal formation, becomes localized in the host plasma membrane [26, 27, 28]. The extracellular domain of Tir is recognized by the outer membrane adhesin intimin, encoded by the eae gene [29, 30]. Following oral infection of immunocompetent mice with C. rodentium, there is transient colonization and inflammation that peaks after 1 week and is cleared within 2 to 3 weeks [31]. Bacterial colonization is limited to the intestinal mucosa with little dissemination to peripheral organs. Most of the clinical signs are mild while microscopically, the infection is associated with crypt hyperplasia, goblet cell loss, and mucosal infiltration of immune cells, including T cells, macrophages, and neutrophils. A Th1 host immune response, mediated by infiltrating CD4+ T cells and macrophages, is required for efficient bacterial clearance [32]. Thus, C. rodentium infection is an excellent model for the investigation of host-pathogen immune interactions in the gut.

The hallmark pathologic lesion of C. rodentium infection is colonic hyperplasia while inflammation is dependent upon the genetic strain under investigation. Resistant strains such as NIH:Swiss and C57BL/6J (B6) experience a self-limiting disease that peaks between one and two weeks post infection, followed by a clearing of the infection and complete recovery. However, the inbred mouse strains C3H/HeJ (C3), C3H/HeOuJ (C3Ou) and FVB/N (FVB) are highly susceptible to C. rodentium infection and develop more severe symptoms leading to high rates of mortality. Khan et al. [33] first identified a role for toll-like receptor 4 (TLR4) signaling in C. rodentium pathogenesis when they found delayed mortality in TLR4-deficient C3 mice compared with C3Ou mice that express functional TLR4 when mice were inoculated with 104–106 instead of 108 CFU, which also resulted in variable onset of infection [33]. TLR4-deficient C57BL/10ScNJ mice develop less morbidity and mortality than C57BL/10J mice that express functional TLR4 when infected with C. rodentium [33]. Lebeis et al. [34] however, found no difference in mortality between C57BL/6J mice and TLR4-deficient mice infected with C. rodentium S1116 strain which apparently causes less severe colitis [35] due to a truncated lipopolysaccharide structure [36]. Intriguingly, compared with wild type C57BL/6 mice, the same strain caused a severe necrotizing colitis in MyD88-deficient mice with no crypt elongation, indicating lack of a protective regenerative response [34]. Thus, innate immune signaling is critical to protect the host while an adaptive immune response develops resulting in bacterial clearance. Finally, Diez E. et al. [37] recently showed that a single locus on proximal chromosome 15 called C. rodentium infection 1 (Cri1) is responsible for the susceptibility of C3, C3Ou and FVB mice to C. rodentium infection suggesting a common genetic cause of fatal infectious colitis in these mice following infection with C. rodentium.

More recently, a fully annotated genome of a virulent strain of C. rodentium, ICC168 has been sequenced. The genome is 5,346,659 bp in length, with an average G+C content of 54.72 % and is deposited in the EMBL/GenBank databases with accession number FN543502. This exciting development is expected to lead to mapping of all the virulence factors in its genome, in addition to identification of novel factors that bear resemblance to not only known A/E pathogens but to other related pathogens. Indeed, recent studies utilizing the ‘stable isotope labeling with amino acids in cell culture’ (SILAC), a quantitative proteomic technique [38], have analyzed the bacterial type three secretome of EPEC and C. rodentium [39, 40•]. In the future, similar approaches may help unravel the basis of host specificities of C. rodentium, EPEC and EHEC.

Wnt Signaling Pathway and Colon Cancer

Most mammalian genomes, including human, contain 19 Wnt genes that fall into 12 conserved Wnt subfamilies. Wnt proteins are ~40 kDa in size, harbor many conserved cysteines [41] and are lipid modified [42]. They bind a heterodimeric receptor complex, consisting of a Frizzled (Fzd) and an LRP5/6 protein (Figure 1). The ten mammalian Fzd proteins are seven-transmembrane receptors and have large extracellular N-terminal cysteine-rich domains [43] that bind Wnt ligands [44, 45]. Interestingly, a single Wnt can bind multiple Fzd proteins [43] and vice versa [45]. Signaling by dimeric Wnt receptors includes a ligand-induced conformational change of the receptors followed by phosphorylation of key target proteins. A crucial step in signaling is binding of Axin to the cytoplasmic tail of LRP6 when Axin is phosphorylated by at least two separate kinases, GSK3 and CK1γ in the PPPSP motif [4649••]. Wnt/β-catenin signaling pathway is regulated at many levels that includes secreted proteins that antagonize the ligand.

Figure 1. Wnt signaling pathway.

Figure 1

When Wnt is absent, the destruction complex comprising of Axin, APC and the dual kinases, CKIα and GSK-3β phosphorylate β-catenin and present it to β-TrCP for ubiquitination followed by proteasomal degradation. Wnt target genes remain repressed due to binding of repressors such as Groucho and HDAC. In the presence of Wnt, the entire degradation complex can associate with the phosphorylated LRP5/6 wherein, β-catenin can still undergo phosphorylation at the consensus sites but its ubiquitination by β-TrCP is inhibited. Newly synthesized β-catenin which escapes phosphorylation translocates to the nucleus to activate downstream targets in association with transcription factor TCF.

In the context of gastro-intestinal tract, Wnt/β-catenin signaling is critical for the maintenance of intestinal crypt cell proliferation. Wnt ligands bind intestinal stem cells and crypt epithelial progenitor cells and prevent glycogen synthase kinase 3β (GSK3β)-dependent N-terminal phosphorylation and proteosomal degradation of β-catenin [5053]. Upon receptor activation by Wnt ligands, Axin is recruited to the phosphorylated tail of LRP leading to inhibition of β-catenin ubiquitination that normally occurs within the complex. This leads to saturation of the complex by phosphorylated form of β-catenin, leading newly synthesized β-catenin to accumulate and translocate to the nucleus to initiate the transcription of Wnt target genes such as c-Myc and cyclin D1, in association with transcription factors of the T-cell factor/lymphoid enhancing factor (TCF/LEF) family [54, 51, 55] (Figure 1). Mutations in mouse TCF4 lead to loss of intestinal stem cells and almost complete lack of intestinal crypts [56] which further implicate Wnts as critical regulators of stem cell signals. It is therefore not surprising that Wnt pathway mutations leading to constitutively active Wnt signaling, are frequently observed in cancer. Germline mutations in the APC gene cause familial adenomatous polyposis [57, 58]. In most cases of sporadic colorectal cancer, loss of both APC alleles leads to inappropriate stabilization of β-catenin and the formation of constitutive complexes between β-catenin and TCF4 [59, 60]. In colorectal cancers that harbor wild-type APC, either Axin2 is mutated [61], or activating point mutations in β-catenin remove the regulatory N-terminal Ser/Thr residues [62]. Interestingly, while the aberrant activation of the Wnt pathway is required during the initiation of colorectal cancers, a recent study has shown that sustained Wnt pathway activation is also needed for colorectal tumor maintenance [63]. Finally, since Wnt signaling activity can designate colon cancer stem cells [64], it is an attractive target for new therapeutics.

Bacterial infection and Wnt signaling

As mentioned earlier, there has been a trend towards studies that are focusing more on the role of bacterial infection in carcinogenesis. There is also evidence of studies that directly implicate bacterial infection in the activation of Wnt signaling. The H. pylori’s cytotoxin-associated gene secretion system activates β-catenin along with p120 and PPARδ, which promote gastric epithelial cell proliferation via activation of cyclin E1 [65]. The H. pylori-induced dysregulation of β-catenin dependent pathways may explain in part the augmentation in the risk of gastric cancer conferred by this pathogen [66•]. Similarly, C. rodentium-induced pathogenesis offers an excellent opportunity to identify changes associated with epithelial cell proliferation and mucosal priming for neoplasia. The cellular and molecular events that occur in response to C. rodentium infection are similar to those that occur in colon adenomas and carcinomas [67]. Furthermore, C. rodentium-induced colonic crypt hyperplasia increases the susceptibility of the mouse colon to neoplastic transformation [15, 68•]. We showed for the first time that colonic crypt hyperplasia in response to C. rodentium infection was associated with NF-κB activation [69] and alterations in casein kinase Iε (CKIε) that influence β-catenin signaling [70•]. This was a major first step towards delineating the mechanistic basis of C. rodentium-induced pathogenesis. Since TMCH is a self-limiting disease, we have further shown that both TLR4-induced NF-κB activation and CKIε mediated phosphorylation of β-catenin at Ser-45 (β-cat45), resulting in stabilization/nuclear translocation of β-cat45, play important roles in the regulation of proliferative and the regression phases of hyperplasia [71•, 72].

Recent studies in the TMCH model also implicate phosphatidylinositol-3-kinase (PI3K)/Akt signaling in the activation of β-catenin in intestinal stem and progenitor cells through phosphorylation at Ser-552 (p-β-catenin552). In response to C. rodentium infection, increased numbers of p-β-catenin552-stained epithelial cells were found throughout expanded crypts [73]. Furthermore, inhibition of PI3K signaling attenuated epithelial Akt activation, the Ser-552 phosphorylation and activation of β-catenin, and epithelial cell proliferative responses following C. rodentium infection. PI3K inhibition also impaired bacterial clearance despite having no impact on mucosal cytokines (IFN-γ, TNF, IL-17, and IL-1α) or chemokines (CXCL1, CXCL5, CXCL9, and CXCL10) induction [73]. Thus, while adaptive immunity including B cells and IgG antibodies is required for bacterial clearance [74], results of this study add new dimension to our understanding of how PI3K/Akt-induced activation of Wnt/β-catenin pathway can also play a role in host defense against C. rodentium independently of adaptive immune responses.

Wnt/Notch Cross-talk and Colon Cancer

Notch signaling has been shown to play an important role in cell-fate determination, as well as in cell survival and proliferation [7578]. Notch signaling is activated upon cell-to-cell contact as a result of interactions between Notch receptors and their ligands (Delta or Jagged) leading to the release of notch intracellular domain (NICD) that heterodimerizes with the DNA binding protein RBP-J (recombination signal sequence-binding protein Jκ, also called CSL, CBF1, Su (H) and LAG-1) and activates transcription of target genes such as Hes 1. There is increasing evidence that Notch signals are oncogenic in many cellular contexts, for example in T cell leukemia (T-ALL), breast and colon cancer [7983]. In addition, the cross-talk between Notch and Wnt pathways including genetic interactions in Drosophila [84], the physical binding of Notch to β-catenin [85] or their association to common cofactors [85] have been described. Moreover, GSK3β directly phosphorylates the Notch protein thus modulating its transcriptional activity [86] and β-catenin activates Jagged1 transcription thus leading to Notch activation during murine hair follicle differentiation [87]. Conversely, in different types of tumor cells, Notch activates the Wnt pathway stabilizing β-catenin by unknown mechanisms [88] or by transcriptional activation of slug [89]. More recently, Notch signaling has also been implicated in the maintenance of intestinal barrier function. Thus, accurate coordination of the Notch and Wnt signals is indispensable for maintenance of intestinal homeostasis and that aberrant regulation of the cross-talk may result in a disease state. Despite these advances, little is known regarding the mechanism that coordinates the complex cross-talk between the Notch and Wnt/β-catenin pathways as they relate to bacterial infection-induced colitis or colon carcinogenesis.

We have recently attempted to examine the interplay between the Notch and Wnt/β-catenin pathways in various genetic strains in vivo. Results of our study provide circumstantial evidence that in addition to Wnt/β-catenin pathway, Notch signaling is also activated during C. rodentium-induced TMCH and that blocking Notch signaling with γ-secretase inhibitor, dibenzazepine for 10 days results in almost complete inhibition of both Notch and Wnt/β-catenin signaling concomitant with the disruption of the intestinal barrier and onset of colitis [90•]. The chronic inhibition of the Wnt/Notch pathway cripples the ability of the colonic mucosa to regenerate itself which is not necessarily due to loss of colonic stem cells [90•]. Whether colitis in these mice predisposes them to mutagen-induced carcinogenesis is currently being investigated. Thus, the balancing act between cell proliferation and restoration of barrier integrity following C. rodentium infection seems to depend upon the interplay between the Notch and Wnt/β-catenin pathways. Since Notch signaling is constitutively activated in colorectal cancer and its inhibition suppresses the cell growth and sensitizes cancer cells to treatment-induced apoptosis, extensive studies on the potential use of γ-secretase inhibitors in the treatment of colon cancer is being carried out. Our findings present a caveat however, particularly for patients with colitis who are undergoing treatment for colorectal cancer that possible exacerbation of colitis in the aftermath of chronic Notch inhibition could jeopardize the outcome.

Effect of CR-induced inflammation on Wnt signaling

Ulcerative colitis (UC) and Crohn’s disease (CD), two components of the inflammatory bowel disease (IBD) are both characterized by an exaggerated immune response directed against luminal and/or enteric bacterial antigens while infections by murine pathogens C. rodentium [23] and Helicobacter hepaticus [91] provide surrogate examples of a similar phenomenon. It has been reported previously that ileal CD was associated with a reduced expression of TCF4, a known regulator of Paneth cell differentiation and alpha-defensin expression [92]. The levels of TCF4 mRNA were decreased in patients with ileal disease irrespective of degree of inflammation [92]. Similarly, compromised expression of TCF4 in mice heterozygous for tcf4 gene led to a significant decrease in both Paneth cell alpha-defensin levels and bacterial killing activity [92]. Thus, even though no etiologic agent has so far been identified in IBD, the inflammatory state in these patients is associated with significant alterations in the components of the Wntβ-catenin pathway. Since the C. rodentium-induced TMCH model represents the murine model of IBD, we have recently started delineating changes in the components of both NF-κB and Wnt/β-catenin pathways during C. rodentium-induced acute and/or chronic inflammatory state.

In contrast to outbred mice, genetically susceptible inbred [e.g., C3H/HeNHsd (C3H)] mice exhibit significant inflammation that are superimposed upon the hyperplastic response of the colonic mucosa. Factors that determine inflammatory response are not understood as yet although variations in microbial composition between mouse strains have been predicted to contribute to differences in “host” susceptibility [93]. Since cross-talk between epithelial and mono-nuclear cells of the lamina propria is critical for sustained inflammatory axis, we systematically analyzed distribution of NF-κB activity in the epithelium and cells of the lamina propria constituting the stroma following CR infection and investigated how signaling via ERK and p38 MAPKs modulate functional NF-κB activity in various cell types in the distal colons of C3H mice. In response to C. rodentium infection, we observed distinct compartmentalization of NF-κB activity in the crypts and the crypt-denuded lamina propria in association with distinct and robust expression of pro-inflammatory cytokines and chemokines [94••]. These changes were associated with crypt hyperplasia that preceded the onset of colitis [94••]. In addition to NF-κB, in an ongoing study, we have observed significant alterations in β-catenin expression which coincides with the dual phases of hyperplasia preceding active colitis. Interestingly, β-catenin undergoes degradation at time point that coincides with the onset of colitis [manuscript under preparation]. These results clearly suggest that C. rodentium induces complex immune-mediated responses in the inbred mice which are distinct from the outbred counterparts.

Conclusions

The idea that bacterial infection could cause cancer has only recently become accepted following the discovery of Helicobacter pylori’s role in gastric carcinogenesis. Since then, a trend is emerging towards identifying other potential bacteria with pro-carcinogenic properties. As mentioned earlier, Pasteurella multocida toxin (PMT), a highly potent mitogen modifies and activates several members of the heterotrimeric G-proteins leading to upregulation of the downstream proto-oncogenes including the Rho GTPase, focal adhesion kinase, cyclooxygenase-2, β-catenin and calcium signaling components [16]. Although the etiologic role for PMT in human cancer is not yet established, it serves as a novel paradigm for a bacterial link to cancer. Similarly, infectious agents such as Human Papilloma Virus, Hepatitis B and C virus, and Helicobacter pylori, alone are responsible for an estimated 15% of the global cancer burden [95]. Finally, a recent study found a marked over-representation of Fusobacterium nucleatum in patients suffering from colorectal cancer [96]. In the future, metagenomic studies will hopefully provide a useful approach to identifying microbial sequence signatures in diseases with infectious etiology.

As far as C. rodentium is concerned, while the infection by itself doesn’t cause cellular transformation or cancer, CR-induced activation of the Wnt, Notch and NF-κB pathways causes hyperplasia of the colonic crypts that mimics adenomas or adenocarcinomas in humans. Since hyper-activation of Wnt signaling is a hallmark of colon cancer and of many other human cancers, our findings clearly suggest that the TMCH model can be used as an excellent template to study the early stages of colon carcinogenesis. Indeed, we have shown recently that following CR infection, aberrant overexpression of a calcium channel TRPV6 (transient receptor potential vanilloid-type) contributes to colonic crypt hyperplasia in mice and to colon cancer cell proliferation in humans [97]. Blocking TRPV6 with high calcium diet (1%) causes almost complete abrogation of hyperplasia. As proof of principle, we also investigated TRPV6 expression in adenomatous polyps (stage I) and advanced human cancers (stages III/IV) to determine if similarities exist with regard to TMCH model. A significant increase in TRPV6 expression, compared to normal mucosa, was observed in stage I tumor while stages III and IV cancers were negative for TRPV6 thus linking TRPV6 to early stages of colon cancer [97]. The remarkable parallel with TMCH also suggests that TMCH is not unique but shares a common final pathway in response to diverse initiating events. In conclusion, C. rodentium-induced TMCH associated with alterations in Wnt/β-catenin, Notch, PI3K and NF-κB pathways, can be used as an animal model linking bacterial infection, IBD and colorectal cancer.

Acknowledgments

This work was supported by National Institutes of Health Grant R01 CA131413 from the NCI and by Start-up funds of University of Kansas Cancer Center.

Footnotes

Disclosure

No potential conflicts of interest relevant to this article were reported.

References

Papers of particular interest, published recently, have been highlighted as follows:

• Of importance

•• Of major importance

  • 1.Whitman WB, Coleman DC, Wiebe WJ. Prokaryotes: the unseen majority. Proc Natl Acad Sci USA. 1998;95:6578–6583. doi: 10.1073/pnas.95.12.6578. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Salzman NH, Underwood MA, Bevins CL. Paneth cells, defensins, and the commensal microbiota: a hypothesis on intimate interplay at the intestinal mucosa. Semin Immunol. 2007;19:70–83. doi: 10.1016/j.smim.2007.04.002. [DOI] [PubMed] [Google Scholar]
  • 3.O’Hara AM, Shanahan F. The gut flora as a forgotten organ. EMBO Rep. 2006;7:688–693. doi: 10.1038/sj.embor.7400731. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Backhed F, Ley RE, Sonnenburg JL, Peterson DA, Gordon JI. Host-bacterial mutualism in the human intestine. Science. 2005;307:1915–1920. doi: 10.1126/science.1104816. [DOI] [PubMed] [Google Scholar]
  • 5.Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M, Gill SR, Nelson KE, Relman DA. Diversity of the human intestinal microbial flora. Science. 2005;308:1635–1638. doi: 10.1126/science.1110591. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Stecher B, Hardt WD. The role of microbiota in infectious disease. Trends Microbiol. 2008;16:107–114. doi: 10.1016/j.tim.2007.12.008. [DOI] [PubMed] [Google Scholar]
  • 7.Dethlefsen L, Huse S, Sogin ML, Relman DA. The pervasive effects of an antibiotic on the human gut microbiota, as revealed by deep 16S rRNA sequencing. PLoS Biol. 2008;6:e280. doi: 10.1371/journal.pbio.0060280. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Jernberg C, Lofmark S, Edlund C, Jansson JK. Long-term impacts of antibiotic exposure on the human intestinal microbiota. Microbiology. 2010;156:3216–3223. doi: 10.1099/mic.0.040618-0. [DOI] [PubMed] [Google Scholar]
  • 9.Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S, Medzhitov R. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell. 2004;118:229–241. doi: 10.1016/j.cell.2004.07.002. [DOI] [PubMed] [Google Scholar]
  • 10.Lee J, Mo JH, Katakura K, Alkalay I, Rucker AN, Liu YT, Lee HK, Shen C, Cojocaru G, Shenouda S, Kagnoff M, Eckmann L, Ben-Neriah Y, Raz E. Maintenance of colonic homeostasis by distinctive apical TLR9 signaling in intestinal epithelial cells. Nat Cell Biol. 2006;8:1327–1336. doi: 10.1038/ncb1500. [DOI] [PubMed] [Google Scholar]
  • 11.Jemal A, Siegel R, Ward E, Hao YP, Xu JQ, Thun MJ. Cancer Statistics, 2009. Cancer Journal for Clinicians. 2009;59:225–249. doi: 10.3322/caac.20006. [DOI] [PubMed] [Google Scholar]
  • 12.Aries V, Crowther JS, Drasar BS, Hill MJ, Williams RE. Bacteria and the aetiology of cancer of the large bowel. Gut. 1969;10:334–335. doi: 10.1136/gut.10.5.334. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Verma A, Davis GE, Ihler GM. Infection of human endothelial cells with Bartonella bacilliformis is dependent on Rho and results in activation of Rho. Infect Immun. 2000;68:5960–5969. doi: 10.1128/iai.68.10.5960-5969.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Smith DGE, Lawson GHK. Lawsonia intracellularis: getting inside the pathogenesis of proliferative enteropathy. Vet Microbiol. 2001;82:331–345. doi: 10.1016/s0378-1135(01)00397-2. [DOI] [PubMed] [Google Scholar]
  • 15.Barthold SW, Jones AM. Morphogenesis of early 1,2-dimethylhydrazine induced lesions and latent period reduction of colon carcinogenesis in mice by a variant of Citrobacter freundii. Cancer Res. 1977;37:4352–4360. [PubMed] [Google Scholar]
  • 16.Lax AJ, Grigoriadis AE. Pasteurella multocida toxin: the mitogenic toxin that stimulates signaling cascades to regulate growth and differentiation. Int J Med Microbiol. 2001;291:261–268. doi: 10.1078/1438-4221-00129. [DOI] [PubMed] [Google Scholar]
  • 17.Thomas W, Ascott ZK, Harmey D, Slice LW, Rozengurt E, Lax AJ. Cytotoxic necrotizing factor from Escherichia coli induces RhoA dependent expression of the cyclooxygenase-2 gene. Infect Immun. 2001;69:6839–6845. doi: 10.1128/IAI.69.11.6839-6845.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Klein RS, Recco RA, Catalano MT, Edberg SC, Casey JI, Steigbigel NH. Association of Streptococcus bovis with carcinoma of the colon. N Engl J Med. 1977;297:800–802. doi: 10.1056/NEJM197710132971503. [DOI] [PubMed] [Google Scholar]
  • 19.Boleij A, van Gelder MM, Swinkels DW, Tjalsma H. Clinical Importance of Streptococcus gallolyticus Infection Among Colorectal Cancer Patients. Systematic Review and Meta-analysis. Clin Infect Dis. 2011;53:870–878. doi: 10.1093/cid/cir609. [DOI] [PubMed] [Google Scholar]
  • 20.Corredoira JC, Alonso MP, Garcia JF, Casariego E, Coira A, Rodriguez A, Pita J, Louzao C, Pombo B, Lopez MJ, Varela J. Clinical characteristics and significance of Streptococcus salivarius bacteremia and Streptococcus bovis bacteremia: a prospective 16-year study. Eur J Clin Microbiol Infect Dis. 2005;24:250–255. doi: 10.1007/s10096-005-1314-x. [DOI] [PubMed] [Google Scholar]
  • 21.Lieberman DA, Weiss DG, Bond JH, Ahnen DJ, Garewal H, Chejfec G. Use of colonoscopy to screen asymptomatic adults for colorectal cancer. Veterans Affairs Cooperative Study Group 380. The New England Journal of Medicine. 2000;343:162–168. doi: 10.1056/NEJM200007203430301. [DOI] [PubMed] [Google Scholar]
  • 22.Wales AD, Woodward MJ, Pearson GR. Attaching-effacing bacteria in animals. J Comp Pathol. 2005;132:1–26. doi: 10.1016/j.jcpa.2004.09.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Luperchio SA, Schauer DB. Molecular pathogenesis of Citrobacter rodentium and transmissible murine colonic hyperplasia. Microbes Infect. 2001;3:333–340. doi: 10.1016/s1286-4579(01)01387-9. [DOI] [PubMed] [Google Scholar]
  • 24.Kenny B, Finlay BB. Protein secretion by enteropathogenic Escherichia coli is essential for transducing signals to epithelial cells. Proc Natl Acad Sci USA. 1995;92:7991–5. doi: 10.1073/pnas.92.17.7991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.McDaniel TK, Jarvis KG, Donnenberg MS, Kaper JB. A genetic locus of enterocyte effacement conserved among diverse enterobacterial pathogens. Proc Natl Acad Sci USA. 1995;92:1664–8. doi: 10.1073/pnas.92.5.1664. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Lommel S, Benesch S, Rohde M, Wehland J, Rottner K. Enterohaemorrhagic and enteropathogenic Escherichia coli use different mechanisms for actin pedestal formation that converge on N-WASP. Cell Microbiol. 2004;6:243–54. doi: 10.1111/j.1462-5822.2004.00364.x. [DOI] [PubMed] [Google Scholar]
  • 27.Frankel G, Phillips AD. Attaching effacing Escherichia coli and paradigms of Tir-triggered actin polymerization: getting off the pedestal. Cell Microbiol. 2008;10:549–56. doi: 10.1111/j.1462-5822.2007.01103.x. [DOI] [PubMed] [Google Scholar]
  • 28.Campellone KG. Cytoskeleton-modulating effectors of enteropathogenic and enterohaemorrhagic Escherichia coli: Tir, EspFU and actin pedestal assembly. FEBS J. 2010;277:2390–402. doi: 10.1111/j.1742-4658.2010.07653.x. [DOI] [PubMed] [Google Scholar]
  • 29.Jerse AE, Yu J, Tall BD, Kaper JB. A genetic locus of enteropathogenic Escherichia coli necessary for the production of attaching and effacing lesions on tissue culture cells. Proc Natl Acad Sci USA. 1990;87:7839–43. doi: 10.1073/pnas.87.20.7839. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Donnenberg MS, Kaper JB. Construction of an eae deletion mutant of enteropathogenic Escherichia coli by using a positive-selection suicide vector. Infect Immun. 1991;59:4310–7. doi: 10.1128/iai.59.12.4310-4317.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Barthold SW, Coleman GL, Bhatt PN, Osbaldiston GW, Jonas AM. The etiology of transmissible murine colonic hyperplasia. Lab Anim Sci. 1976;26:889–94. [PubMed] [Google Scholar]
  • 32.Higgins LM, Frankel G, Douce G, Dougan G, MacDonald TT. Citrobacter rodentium infection in mice elicits a mucosal Th1 cytokine response and lesions similar to those in murine inflammatory bowel disease. Infect Immun. 1999;67:3031–9. doi: 10.1128/iai.67.6.3031-3039.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Khan MA, Ma C, Knodler LA, Valdez Y, Rosenberger CM, Deng W, Finlay BB, Vallance BA. Toll-like receptor 4 contributes to colitis development but not to host defense during Citrobacter rodentium infection in mice. Infect Immun. 2006;74:2522–2536. doi: 10.1128/IAI.74.5.2522-2536.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Lebeis SL, Bommarius B, Parkos CA, Sherman MA, Kalman D. TLR signaling mediated by MyD88 is required for a protective innate immune response by neutrophils to Citrobacter rodentium. J Immunol. 2007;179:566–577. doi: 10.4049/jimmunol.179.1.566. [DOI] [PubMed] [Google Scholar]
  • 35.Luperchio SA, Newman JV, Dangler CA, Schrenzel MD, Brenner DJ, Steigerwalt AG, Schauer DB. Citrobacter rodentium, the causative agent of transmissible murine colonic hyperplasia, exhibits clonality: synonymy of C. rodentium and mouse-pathogenic Escherichia coli. J Clin Microbiol. 2000;38:4343–4350. doi: 10.1128/jcm.38.12.4343-4350.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.MacLean LL, Perry MB. Structural studies on the O-polysaccharide of the lipopolysaccharide produced by Citrobacter rodentium (ATCC 51459) Eur J Biochem. 2001;268:5740–5746. doi: 10.1046/j.0014-2956.2001.02518.x. [DOI] [PubMed] [Google Scholar]
  • 37.Diez E, Zhu L, Teatero SA, Paquet M, Roy MF, Loredo-Osti JC, Malo D, Gruenheid S. Identification and characterization of Cri1, a locus controlling mortality during Citrobacter rodentium infection in mice. Genes Immun. 2011;12:280–90. doi: 10.1038/gene.2010.76. [DOI] [PubMed] [Google Scholar]
  • 38.Ong SE, Mann MA. practical recipe for stable isotope labeling by amino acids in cell culture (SILAC) Nature Protocols. 2006;1:2650–2660. doi: 10.1038/nprot.2006.427. [DOI] [PubMed] [Google Scholar]
  • 39.Deng W, de Hoog CL, Yu HB, Li Y, Croxen MA, Thomas NA, Puente JL, Foster LJ, Finlay BB. A comprehensive proteomic analysis of the type III secretome of Citrobacter rodentium. J Biol Chem. 2010;285:6790–800. doi: 10.1074/jbc.M109.086603. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40•.Deng W, Yu HB, de Hoog CL, Stoynov N, Li Y, Foster LJ, Finlay BB. Quantitative proteomic analysis of type III secretome of enteropathogenic Escherichia coli reveals an expanded effector repertoire for attaching/effacing bacterial pathogens. Mol Cell Proteomics. 2012 doi: 10.1074/mcp.M111.013672. M111.013672. This article outlines the type III secretome of EPEC and expands the repertoire of type III secreted effectors for the A/E pathogens. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Tanaka K, Kitagawa Y, Kadowaki T. Drosophila segment polarity gene product porcupine stimulates the posttranslational N-glycosylation of wingless in the endoplasmic reticulum. J Biol Chem. 2002;277:12816–12823. doi: 10.1074/jbc.M200187200. [DOI] [PubMed] [Google Scholar]
  • 42.Willert K, Brown JD, Danenberg E, Duncan AW, Weissman IL, Reya T, Yates JR, III, Nusse R. Wnt proteins are lipid-modified and can act as stem cell growth factors. Nature. 2003;423:448–452. doi: 10.1038/nature01611. [DOI] [PubMed] [Google Scholar]
  • 43.Bhanot P, Brink M, Samos CH, Hsieh JC, Wang Y, Macke JP, Andrew D, Nathans J, Nusse R. A new member of the frizzled family from Drosophila functions as a Wingless receptor. Nature. 1996;382:225–230. doi: 10.1038/382225a0. [DOI] [PubMed] [Google Scholar]
  • 44.Dann CE, Hsieh JC, Rattner A, Sharma D, Nathans J, Leahy DJ. Insights into Wnt binding and signaling from the structures of two Frizzled cysteine-rich domains. Nature. 2001;412:86–90. doi: 10.1038/35083601. [DOI] [PubMed] [Google Scholar]
  • 45.Janda CY, Waghray D, Levin A, Thomas C, Garcia K. Structural basis of Wnt recognition by Frizzled. Science. 2012;337:59–64. doi: 10.1126/science.1222879. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Mao J, Wang J, Liu B, Pan W, Farr GH, III, Flynn C, Yuan H, Takada S, Kimelman D, Li L, Wu D. Low-density lipoprotein receptor related protein-5 binds to Axin and regulates the canonical Wnt signaling pathway. Mol Cell. 2001;7:801–809. doi: 10.1016/s1097-2765(01)00224-6. [DOI] [PubMed] [Google Scholar]
  • 47.He X, Semenov M, Tamai K, Zeng X. LDL receptor-related proteins 5 and 6 in Wnt/beta-catenin signaling: arrows point the way. Development. 2004;131:1663–1677. doi: 10.1242/dev.01117. [DOI] [PubMed] [Google Scholar]
  • 48.Tamai K, Zeng X, Liu C, Zhang X, Harada Y, Chang Z, He X. A mechanism for Wnt coreceptor activation. Mol Cell. 2004;13:149–156. doi: 10.1016/s1097-2765(03)00484-2. [DOI] [PubMed] [Google Scholar]
  • 49.Zeng X, Tamai K, Doble B, Li S, Huang H, Habas R, Okamura H, Woodgett J, He X. A dual-kinase mechanism for Wnt co-receptor phosphorylation and activation. Nature. 2005;438:873–877. doi: 10.1038/nature04185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Gregorieff A, Pinto D, Begthel H, Destrée O, Kielman M, Clevers H. Expression pattern of Wnt signaling components in the adult intestine. Gastroenterology. 2005;129:626–638. doi: 10.1016/j.gastro.2005.06.007. [DOI] [PubMed] [Google Scholar]
  • 51.Kikuchi A, Kishida S, Yamamoto H. Regulation of Wnt signaling by protein-protein interaction and post-translational modifications. Exp Mol Med. 2006;38:1–10. doi: 10.1038/emm.2006.1. [DOI] [PubMed] [Google Scholar]
  • 52.Staal FJ, vanNoort M, Strous GJ, Clevers H. Wnt signals are transmitted through N-terminally dephosphorylated beta-catenin. EMBO Rep. 2002;3:63–68. doi: 10.1093/embo-reports/kvf002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.van Noort M, Meeldijk J, van der Zee R, Destree O, Clevers H. Wnt signaling controls the phosphorylation status of beta-catenin. J Biol Chem. 2002;277:17901–17905. doi: 10.1074/jbc.M111635200. [DOI] [PubMed] [Google Scholar]
  • 54.He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT, Morin PJ, Vogelstein B, Kinzler KW. Identification of c-MYC as a target of the APC pathway. Science. 1998;281:1509–1512. doi: 10.1126/science.281.5382.1509. [DOI] [PubMed] [Google Scholar]
  • 55.Sancho E, Batlle E, Clevers H. Live and let die in the intestinal epithelium. Curr Opin Cell Biol. 2003;15:763–770. doi: 10.1016/j.ceb.2003.10.012. [DOI] [PubMed] [Google Scholar]
  • 56.Korinek V, Barker N, Moerer P, van Donselaar E, Huls G, Peters PJ, Clevers H. Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nat Genet. 1998;19:379–383. doi: 10.1038/1270. [DOI] [PubMed] [Google Scholar]
  • 57.Kinzler KW, Nilbert MC, Su LK, Vogelstein B, Bryan TM, Levy DB, Smith KJ, Preisinger AC, Hedge P, McKechnie D, et al. Identification of FAP locus genes from chromosome 5q21. Science. 1991;253:661–665. doi: 10.1126/science.1651562. [DOI] [PubMed] [Google Scholar]
  • 58.Nishisho I, Nakamura Y, Miyoshi Y, Miki Y, Ando H, Horii A, Koyama K, Utsunomiya J, Baba S, Hedge P. Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science. 1991;253:665–669. doi: 10.1126/science.1651563. [DOI] [PubMed] [Google Scholar]
  • 59.Kinzler KW, Vogelstein B. Lessons from hereditary colorectal cancer. Cell. 1996;87:159–170. doi: 10.1016/s0092-8674(00)81333-1. [DOI] [PubMed] [Google Scholar]
  • 60.Korinek V, Barker N, Morin PJ, van Wichen D, de Weger R, Kinzler KW, Vogelstein B, Clevers H. Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC−/− colon carcinoma. Science. 1997;275:1784–1787. doi: 10.1126/science.275.5307.1784. [DOI] [PubMed] [Google Scholar]
  • 61.Liu W, Dong X, Mai M, Seelan RS, Taniguchi K, Krishnadath KK, Halling KC, Cunningham JM, Boardman LA, Qian C, Christensen E, Schmidt SS, Roche PC, Smith DI, Thibodeau SN. Mutations in AXIN2 cause colorectal cancer with defective mismatch repair by activating beta-catenin/TCF signaling. Nat Genet. 2000;26:146–147. doi: 10.1038/79859. [DOI] [PubMed] [Google Scholar]
  • 62.Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B, Kinzler KW. Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science. 1997;275:1787–1790. doi: 10.1126/science.275.5307.1787. [DOI] [PubMed] [Google Scholar]
  • 63.Scholer-Dahirel A, Schlabach MR, Loo A, Bagdasarian L, Meyer R, Guo R, Woolfenden S, Yu KK, Markovits J, Killary K, Sonkin D, Yao YM, Warmuth M, Sellers WR, Schlegel R, Stegmeier F, Mosher RE, McLaughlin ME. Maintenance of adenomatous polyposis coli (APC)-mutant colorectal cancer is dependent on Wnt/beta-catenin signaling. Proc Natl Acad Sci USA. 2011;108:17135–40. doi: 10.1073/pnas.1104182108. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64.de Sousa EM, Vermeulen L, Richel D, Medema JP. Targeting Wnt signaling in colon cancer stem cells. Clin Cancer Res. 2011;17:647–53. doi: 10.1158/1078-0432.CCR-10-1204. [DOI] [PubMed] [Google Scholar]
  • 65.Nagy TA, Wroblewski LE, Wang D, Piazuelo MB, Delgado A, Romero-Gallo J, Noto J, Israel DA, Ogden SR, Correa P, Cover TL, Peek RM., Jr β-Catenin and p120 mediate PPARδ-dependent proliferation induced by Helicobacter pylori in human and rodent epithelia. Gastroenterology. 2011;141:553–64. doi: 10.1053/j.gastro.2011.05.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66.Franco AT, Israel DA, Washington MK, Krishna U, Fox JG, Rogers AB, Neish AS, Collier-Hyams L, Perez-Perez GI, Hatakeyama M, Whitehead R, Gaus K, O’Brien DP, Romero-Gallo J, Peek RM., Jr Activation of beta-catenin by carcinogenic Helicobacter pylori. Proc Natl Acad Sci USA. 2005;102:10646–51. doi: 10.1073/pnas.0504927102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67.Reichling T, Goss KH, Carson DJ, Holdcraft RW, Ley-Ebert C, Witte D, Aronow BJ, Groden J. Transcriptional profiles of intestinal tumors in Apc(Min) mice are unique from those of embryonic intestine and identify novel gene targets dysregulated in human colorectal tumors. Cancer Res. 2005;65:166–176. [PubMed] [Google Scholar]
  • 68.Newman JV, Kosaka T, Sheppard BJ, Fox JG, Schauer DB. Bacterial infection promotes colon tumorigenesis in Apc(Min/+) mice. J Infect Dis. 2001;184:227–230. doi: 10.1086/321998. [DOI] [PubMed] [Google Scholar]
  • 69.Wang Y, Xiang GS, Kourouma F, Umar S. Citrobacter rodentium induced NF-kappaB activation in hyperproliferating colonic epithelia: role of p65 (Ser536) phosphorylation. Br J Pharmacol. 2006;48:814–824. doi: 10.1038/sj.bjp.0706784. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 70.Umar S, Wang Y, Morris AP, Sellin JH. Dual alterations in casein kinase 1ε and GSK-3β modulate β-catenin stability in hyperproliferating colonic epithelia. Am J Physiol. 2007;292:G599–G607. doi: 10.1152/ajpgi.00343.2006. [DOI] [PubMed] [Google Scholar]
  • 71•.Chandrakesan P, Ahmed I, Wang Y, Sarkar S, Singh P, Peleg S, Umar S. Novel changes in NF-κB activity during progression and regression phases of hyperplasia: Role of ERK1/2 and p38. J Biol Chem. 2010;285:33485–98. doi: 10.1074/jbc.M110.129353. This article elegantly describes the role of NF-κB in the progression and regression phases of hyperplasia. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 72.Sellin JH, Wang Y, Singh P, Umar S. β-Catenin stabilization imparts crypt progenitor phenotype to hyperproliferating colonic epithelia. Exp Cell Res. 2009;315:97–109. doi: 10.1016/j.yexcr.2008.10.019. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73.Brown JB, Cheresh P, Goretsky T, Managlia E, Grimm GR, Ryu H, Zadeh M, Dirisina R, Barrett TA. Epithelial phosphatidylinositol-3-kinase signaling is required for β-catenin activation and host defense against Citrobacter rodentium infection. Infect Immun. 2011;79:1863–72. doi: 10.1128/IAI.01025-10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 74.Maaser C, Housley MP, Iimura M, Smith JR, Vallance BA, Finlay BB, Schreiber JR, Varki NM, Kagnoff MF, Eckmann L. Clearance of Citrobacter rodentium requires B cells but not secretory immunoglobulin A (IgA) or IgM antibodies. Infect Immun. 2004;72:3315–24. doi: 10.1128/IAI.72.6.3315-3324.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75.Milano J, McKay J, Dagenais C, Foster-Brown L, Pognan F, Gadient R, Jacobs RT, Zacco A, Greenberg B, Ciaccio PJ. Modulation of Notch processing by gamma-secretase inhibitors causes intestinal goblet cell metaplasia and induction of genes known to specify gut secretory lineage differentiation. Toxicol Sci. 2004;82:341–358. doi: 10.1093/toxsci/kfh254. [DOI] [PubMed] [Google Scholar]
  • 76.Fre S, Huyghe M, Mourikis P, Robine S, Louvard D, Artavanis-Tsakonas S. Notch signals control the fate of immature progenitor cells in the intestine. Nature. 2005;435:964–968. doi: 10.1038/nature03589. [DOI] [PubMed] [Google Scholar]
  • 77.Stanger BZ, Datar R, Murtaugh LC, Melton DA. Direct regulation of intestinal fate by Notch. Proc Natl Acad Sci USA. 2005;102:12443–12448. doi: 10.1073/pnas.0505690102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 78.van Es JH, van Gijn ME, Riccio O, van den Born M, Vooijs M, Begthel H, Cozijnsen M, Robine S, Winton DJ, Radtke F, Clevers H. Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature. 2005;435:959–963. doi: 10.1038/nature03659. [DOI] [PubMed] [Google Scholar]
  • 79.Fre S, Pallavi SK, Huyghe M, Laé M, Janssen KP, Robine S, Artavanis-Tsakonas S, Louvard D. Notch and Wnt signals cooperatively control cell proliferation and tumorigenesis in the intestine. Proc Natl Acad Sci USA. 2009;106:6309–14. doi: 10.1073/pnas.0900427106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 80.Koch U, Radtke F. Notch and cancer: a double-edged sword. Cell Mol Life Sci. 2007;64:2746–62. doi: 10.1007/s00018-007-7164-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 81.Shih IeM, Wang TL. Notch signaling, γ-secretase inhibitors, and cancer therapy. Cancer Res. 2007;67:1879–82. doi: 10.1158/0008-5472.CAN-06-3958. [DOI] [PubMed] [Google Scholar]
  • 82.Roy M, Pear WS, Aster JC. The multifaceted role of Notch in cancer. Curr Opin Genet Dev. 2007;17:52–9. doi: 10.1016/j.gde.2006.12.001. [DOI] [PubMed] [Google Scholar]
  • 83.Wang Z, Li Y, Banerjee S, Sarkar FH. Exploitation of the Notch signaling pathway as a novel target for cancer therapy. Anticancer Res. 2008;28:3621–30. [PubMed] [Google Scholar]
  • 84.Hayward P, Brennan K, Sanders P, Balayo T, DasGupta R, Perrimon N, Martinez Arias A. Notch modulates Wnt signaling by associating with Armadillo/beta-catenin and regulating its transcriptional activity. Development. 2005;132:1819–1830. doi: 10.1242/dev.01724. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 85.Kwon C, Cheng P, King IN, Andersen P, Shenje L, Nigam V, Srivastava D. Notch post-translationally regulates β-catenin protein in stem and progenitor cells. Nat Cell Biol. 2011;13:1244–51. doi: 10.1038/ncb2313. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 86.Espinosa L, Inglés-Esteve J, Aguilera C, Bigas A. Phosphorylation by glycogen synthase kinase-3 beta down-regulates Notch activity, a link for Notch and Wnt pathways. J Biol Chem. 2003;278:32227–35. doi: 10.1074/jbc.M304001200. [DOI] [PubMed] [Google Scholar]
  • 87.Estrach S, Ambler CA, Celso CL, Hozumi K, Watt FM. Jagged 1 is a β-catenin target gene required for ectopic hair follicle formation in adult epidermis. Development. 2006;133:4427–4438. doi: 10.1242/dev.02644. [DOI] [PubMed] [Google Scholar]
  • 88.Balint K, Xiao M, Pinnix CC, Soma A, Veres I, Juhasz I, Brown EJ, Capobianco AJ, Herlyn M, Liu ZJ. Activation of Notch1 signaling is required for beta-catenin mediated human primary melanoma progression. J Clin Invest. 2005;115:3166–3176. doi: 10.1172/JCI25001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 89.Leong KG, Niessen K, Kulic I, Raouf A, Eaves C, Pollet I, Karsan A. Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin. J Exp Med. 2007;204:2935–2948. doi: 10.1084/jem.20071082. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 90•.Ahmed I, Chandrakesan P, Tawfik O, Xia L, Anant S, Umar S. Critical roles of Notch and Wnt/β-catenin pathways in the regulation of hyperplasia and/or colitis in response to bacterial infection. Infection and Immunity. doi: 10.1128/IAI.00236-12. This article describes the Wnt/Notch cross-talk in the regulation of hyperplasia and/or colitis following C. rodentium infection. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 91.Li X, Fox JG, Whary MT, Yan L, Shames B, Zhao Z. SCID/NCr mice naturally infected with Helicobacter hepaticus develop progressive hepatitis, proliferative typhlitis, and colitis. Infect Immun. 1998;66:5477–84. doi: 10.1128/iai.66.11.5477-5484.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 92.Wehkamp J, Wang G, Kübler I, Nuding S, Gregorieff A, Schnabel A, Kays RJ, Fellermann K, Burk O, Schwab M, Clevers H, Bevins CL, Stange EF. The Paneth cell alpha-defensin deficiency of ileal Crohn’s disease is linked to Wnt/Tcf-4. J Immunol. 2007;179:3109–18. doi: 10.4049/jimmunol.179.5.3109. [DOI] [PubMed] [Google Scholar]
  • 93.Willing BP, Vacharaksa A, Croxen M, Thanachayanont T, Finlay BB. Altering host resistance to infections through microbial transplantation. PLoS One. 2011;6:e26988. doi: 10.1371/journal.pone.0026988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 94••.Chandrakesan P, Ahmed I, Chinthalapally A, Singh P, Awasthi S, Anant S, Umar S. Distinct compartmentalization of Nuclear Factor--denuded lamina propria precede and accompany hyperplasia and/or colitis following bacterial infection. Infection and Immunity. 2012;80:753–767. doi: 10.1128/IAI.06101-11. This article describes the epithelial-stromal cross-talk in the regulation of hyperplasia and/or colitis following bacterial infection. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 95.Parkin DM. The global health burden of infection-associated cancers in the year 2002. Int J Cancer. 2006;118:3030–44. doi: 10.1002/ijc.21731. [DOI] [PubMed] [Google Scholar]
  • 96.Castellarin M, Warren RL, Freeman JD, Dreolini L, Krzywinski M, Strauss J, Barnes R, Watson P, Allen-Vercoe E, Moore RA, Holt RA. Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma. Genome Res. 2012;22:299–306. doi: 10.1101/gr.126516.111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 97.Peleg S, Sellin JH, Wang Y, Freeman MR, Umar S. Suppression of aberrant transient receptor potential cation channel, subfamily V, member 6 expression in hyperproliferative colonic crypts by dietary calcium. Am J Physiol. 2010;299:G593–601. doi: 10.1152/ajpgi.00193.2010. [DOI] [PMC free article] [PubMed] [Google Scholar]

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