Regulation of Human (Caco-2) Intestinal Epithelial Cell Differentiation by Extracellular Matrix Proteins

Basson, Marc D.; Turowski, G; Emenaker, Nancy J.

doi:10.1006/excr.1996.0180

Cited by 103 publications

(92 citation statements)

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“…P, proximal; D, distal; ERE, estrogen response element; PDX-1, pancreatic duodenal homebox-1; C/EBP, CCAAT enhancer binding protein; HNF-1, hepatocyte nuclear factor 1; VDRE, vitamin D response element; H, human; R, rat; M, mouse. 2 D treatment, although CYP24 promoter activity was increased Ͼ100-fold under the same conditions (Fig. 2B).…”

Section: Cdx-2 (P)mentioning

confidence: 73%

“…The expression of calbindin D 9k is regulated by the hormonally active form of vitamin D, 1,25 dihydroxyvitamin D [1,25(OH) 2 D] (7,22,47). Whereas previous reports have identified putative vitamin D response elements in the calbindin D 9k promoter from various species (12,28,45), other data suggest that posttranscriptional regulation may be a more important mode of calbindin D 9k regulation by 1,25(OH) 2 D (14,15,23,46).…”

mentioning

confidence: 99%

“…Here we characterized 1,25(OH) 2 D-and differentiationmediated regulation of the human calbindin D 9k gene promoter in Caco-2 cells, an in vitro model for small intestinal differentiation (2,13,18,51). Our findings demonstrate that the calbindin D 9k gene is poorly regulated at the transcriptional level by 1,25(OH) 2 D but strongly upregulated during spontaneous differentiation to an enterocyte-like phenotype.…”

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confidence: 99%

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Control of differentiation-induced calbindin-D_9kgene expression in Caco-2 cells by cdx-2 and HNF-1α

Wang¹,

Kłopot²,

Freund³

et al. 2004

American Journal of Physiology-Gastrointestinal and Liver Physi

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(CaBP) is critical for intestinal calcium absorption; its in vivo expression is restricted to differentiated enterocytes of the small intestine. Our goal was to identify factors controlling the transcriptional regulation of this gene in the human intestine. Both the natural gene and a 4600-bp promoter construct were strongly regulated by differentiation (Ͼ100-fold) but not by treatment with 1,25(OH)2 vitamin D (Ͻ2-fold) in the Caco-2 clone TC7. Deletion-mutation studies revealed that conserved promoter sequences for cdx-2 (at Ϫ3158 bp) and hepatocyte nuclear factor (HNF)-1 (at Ϫ3131 and at Ϫ98 bp) combined to control CaBP expression during differentiation. Other putative response elements were not important for CaBP regulation in TC7 cells (CCAAT enhancer binding protein, pancreatic duodenal homebox-1 (pdx-1), a proximal cdx-2 element). Mutation of the distal HNF-1 site had the greatest impact on CaBP gene expression through disruption of HNF-1␣ binding; both basal and differentiation-mediated CaBP expression was reduced by 80%. In contrast, mutation of the distal cdx-2 element reduced only basal CaBP expression. Whereas a 60% reduction of CaBP mRNA in the duodenum of HNF-1␣ null mice confirmed the physiological importance of HNF-1␣ for CaBP gene regulation, additional studies showed that maximal CaBP expression requires the presence of both HNF-1␣ and cdx-2. Our data suggest that cdx-2 is a permissive factor that influences basal CaBP expression in enterocytes and that HNF-1␣ modulates CaBP gene expression during cellular differentiation.intestine; enterocyte; 1,25 dihydroxyvitamin D THE NORMAL FUNCTION OF INTESTINAL mucosa relies on the appropriate renewal and differentiation of cells along the cryptvillus axis (25,29). Developing therapies that promote recovery of a damaged epithelium or prevent malignancy (50) require understanding of the molecular pathways programming enterocyte differentiation. A classical approach to studying the program dictating this process has been to examine the regulation of intestine-specific genes, such as sucrase-isomaltase and lactase-phlorizin hydrolase. Extensive studies (3,4,17,19,33,40) on their promoters have identified several transcription factors important for intestinal expression of these genes [cdx-2, hepatocyte nuclear factor (HNF)-1, and GATA family members]. However, intestinal expression of villin and adenosine deaminase depends on enhancer elements in introns 1 and 2, respectively (16, 37). Thus the study of other differentiationassociated genes in intestine will provide new insight into the programming essential for development of a functional absorptive surface.One such gene encodes calbindin D 9k , an EF hand calciumbinding protein critical for calcium absorption that is expressed in the duodenum and cecum of rodents (5, 7 D (14, 15, 23, 46). In addition to vitamin D regulation, calbindin D 9k expression is restricted to the differentiated villus compartment (24,38,49,53), indicating that it is under the control of factors programming intestinal cell differen...

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Section: Cdx-2 (P)mentioning

confidence: 73%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Control of differentiation-induced calbindin-D_9kgene expression in Caco-2 cells by cdx-2 and HNF-1α

Wang¹,

Kłopot²,

Freund³

et al. 2004

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…However, in HT-29 cells, laminin 5, which activates PI 3-kinase, is unable to induce full cell differentiation (data not shown). This discrepancy might be explained by the fact that contrary to HT-29 cells, Caco-2 cells at confluence produce laminin 1, which has been previously described to induce both enterocytic differentiation (Basson et al, 1996;De Arcangelis et al, 1996;Vachon and Beaulieu, 1995) and PI 3-kinase activation (Shaw et al, 1997). The HT-29 cell model indicates that, although necessary, PI 3-kinase signaling is not sufficient for full differentiation, which requires additional factors.…”

Section: Discussionmentioning

confidence: 93%

Laminin-5-integrin interaction signals through PI 3-kinase and Rac1b to promote assembly of adherens junctions in HT-29 cells

Chartier

Lainé

Gout

et al. 2006

Journal of Cell Science

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Human intestinal cell differentiation is mediated by signaling pathways that remain largely undefined. We and others have shown that cell migration and differentiation along the crypt-villus axis is associated with temporal and spatial modulations of the repertoire, as well as with the function of integrins and E-cadherins and their substrates. Cross-talk between integrin and cadherin signaling was previously described and seems to coordinate this differentiation process. Here, we report that engagement of α6 and, to a lesser extent, α3 integrin subunits after HT-29 cell adhesion on laminin 5 increases the expression of E-cadherin, which then organizes into nascent adherens junctions. We further identify that phosphoinositide 3-kinase (PI 3-kinase) activation plays a key role in this cross-talk. Indeed, integrin-dependent adhesion on laminin 5 stimulates PI 3-kinase activity. Immunofluorescence and immunoprecipitation experiments revealed that activated PI 3-kinase is recruited at cell-cell contacts. Using LY294002, an inhibitor of PI 3-kinase activity, we found that this activation is essential for E-cadherin connection with the cytoskeleton and for biogenesis of adherens junctions. Finally, we demonstrated that PI 3-kinase could signal through Rac1b activation to control adherens junction assembly. Our results provide a mechanistic insight into integrin-cadherin cross-talk and identify a novel role for PI 3-kinase in the establishment of adherens junctions.

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“…Dissection of integrin-ECM interactions within intestinal epithelial cells has shown differential spreading and migration on individual ECM proteins (4,5). Furthermore, EGF stimulation can modulate those functions through collagen-specific ␣1-and ␣2-integrins linking an extracellular cytokine with cellular adhesion responses (4, 51).…”

Section: Discussionmentioning

confidence: 99%

Chemokine stimulation promotes enterocyte migration through laminin-specific integrins

Agle

Vongsa

Dwinell

2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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Intestinal homeostasis is regulated in part by the single cell layer of the mucosal epithelium. This physical barrier is a prominent part of the innate immune system and possesses an intrinsic ability to heal damage and limit infection. The restitutive epithelial migration phase of healing requires dynamic integrin adhesion to the extracellular matrix. Previously, we have shown that the homeostatic chemokine CXCL12 utilizes intracellular calcium to increase enterocyte migration on laminin. The aim of these studies was to investigate integrin specificity and, in turn, functional responses elicited by CXCL12 stimulation. Analysis of cellular adhesion and spreading revealed CXCL12 preferentially activated laminin-specific integrins compared with collagen IV-binding integrins. Laminin-specific cell adhesion and spreading elicited by CXCL12 was dependent on intracellular calcium. CXCL12 increased activated β1-integrins on the surface of epithelial cells compared with untreated cells. RT-PCR confirmed expression of the laminin-binding integrins-α3β1, -α6β1, and -α6β4. Interestingly, shRNA-mediated depletion of laminin-specific α3- or α6-integrin subunits revealed differential functions. α3-Integrin knockdown reduced basal as well as inducible restitution. Depletion of α6-integrin specifically abolished CXCL12-stimulated, but not TGF-β1 or basal, migration. Depletion with either shα3-integrin or shα6-integrin prevented CXCL12-evoked cell spreading. Our data indicate that CXCL12 stimulates the inside-out activation of laminin-specific integrins to promote cell migratory functions. Together, our findings support the notion that extracellular mediators within the gastrointestinal mucosa coordinate cell-matrix interactions during epithelial restitution.

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Regulation of Human (Caco-2) Intestinal Epithelial Cell Differentiation by Extracellular Matrix Proteins

Cited by 103 publications

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Control of differentiation-induced calbindin-D_9kgene expression in Caco-2 cells by cdx-2 and HNF-1α

Control of differentiation-induced calbindin-D_9kgene expression in Caco-2 cells by cdx-2 and HNF-1α

Laminin-5-integrin interaction signals through PI 3-kinase and Rac1b to promote assembly of adherens junctions in HT-29 cells

Chemokine stimulation promotes enterocyte migration through laminin-specific integrins

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Regulation of Human (Caco-2) Intestinal Epithelial Cell Differentiation by Extracellular Matrix Proteins

Cited by 103 publications

References 0 publications

Control of differentiation-induced calbindin-D9kgene expression in Caco-2 cells by cdx-2 and HNF-1α

Control of differentiation-induced calbindin-D9kgene expression in Caco-2 cells by cdx-2 and HNF-1α

Laminin-5-integrin interaction signals through PI 3-kinase and Rac1b to promote assembly of adherens junctions in HT-29 cells

Chemokine stimulation promotes enterocyte migration through laminin-specific integrins

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Control of differentiation-induced calbindin-D_9kgene expression in Caco-2 cells by cdx-2 and HNF-1α

Control of differentiation-induced calbindin-D_9kgene expression in Caco-2 cells by cdx-2 and HNF-1α