Regulation of sucrase and lactase in developing rats: Role of nuclear factors that bind to two gene regulatory elements

Hecht, A; Torbey, Camille F.; Korsmo, Helen A.; Olsen, Ward A.

doi:10.1053/gast.1997.v112.pm9041242

Cited by 37 publications

(18 citation statements)

References 4 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cdx2 regulates the intestine-specific expression of a number of genes (8,12,22,23,44). Cdx2 has also been suggested to be a tumor suppressor in the colon (4,6) or to have colon tumor-inhibitory properties (16,17,19); however, the full extent of Cdx2's antitumor effects has yet to be elucidated.…”

mentioning

confidence: 99%

Intestine-specific transcription factor Cdx2 induces E-cadherin function by enhancing the trafficking of E-cadherin to the cell membrane

Funakoshi

Kong

Crissey

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

View full text Add to dashboard Cite

Intestine-specific transcription factor Cdx2 induces E-cadherin function by enhancing the trafficking of E-cadherin to the cell membrane. Am J Physiol Gastrointest Liver Physiol 299: G1054 -G1067, 2010. First published July 29, 2010; doi:10.1152/ajpgi.00297.2010.-Cdx2 is an intestine-specific transcription factor required for normal intestinal epithelium development. Cdx2 regulates the expression of intestine-specific genes and induces cell adhesion and columnar morphogenesis. Cdx2 also has tumor-suppressor properties, including the reduction of colon cancer cell proliferation and cell invasion, the latter due to its effects on cell adhesion. E-cadherin is a cell adhesion protein required for adherens junction formation and the establishment of intestinal cell polarity. The objective of this study was to elucidate the mechanism by which Cdx2 regulates E-cadherin function. Two colon cancer cell lines were identified in which Cdx2 expression was associated with increased cell-cell adhesion and diminished cell migration. In both cell lines, Cdx2 did not directly alter E-cadherin levels but increased its trafficking to the cell membrane compartment. Cdx2 enhanced this trafficking by altering receptor tyrosine kinase (RTK) activity. Cdx2 expression diminished phosphorylated Abl and phosphorylated Rac levels, which are downstream effectors of RTKs. Specific chemical inhibition or short interfering RNA (shRNA) knockdown of c-Abl kinase phenocopied Cdx2's cell-cell adhesion effects. In Colo 205 cells, Cdx2 reduced PDGF receptor and IGF-I receptor activation. This was mediated by caveolin-1, which was induced by Cdx2. Targeted shRNA knockdown of caveolin-1 restored PDGF receptor and reversed E-cadherin membrane trafficking, despite Cdx2 expression. We conclude that Cdx2 regulates E-cadherin function indirectly by disrupting RTK activity and enhancing E-cadherin trafficking to the cell membrane compartment. This novel mechanism advances Cdx2's prodifferentiation and antitumor properties and suggests that Cdx2 may broadly regulate RTK activity in normal intestinal epithelium by modulating membrane trafficking of proteins.

show abstract

mentioning

confidence: 99%

Intestine-specific transcription factor Cdx2 induces E-cadherin function by enhancing the trafficking of E-cadherin to the cell membrane

Funakoshi

Kong

Crissey

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

View full text Add to dashboard Cite

show abstract

“…These reports support a transcriptional mechanism for regulating the lactase maturational decline. However, a lack of correlation between the decline in lactase mRNA and enzyme expression also has been described in rats (5,7,8), rabbits (9), pigs (10), and humans (8), suggesting that post-transcriptional mechanisms may also play a role in the maturational activity decline.In vitro binding studies have shown that the lactase gene promoter interacts with specific nuclear proteins from intestinal cells. The enterocyte nuclear factor, NF-LPH1, binds to and protects a distinct cis element region of the pig lactase 5Ј-flanking region, CE-LPH1, from DNase I digestion (11).…”

mentioning

confidence: 99%

mentioning

confidence: 99%

Regulation of Intestine-specific Spatiotemporal Expression by the Rat Lactase Promoter

Lee

Wang

Lin

et al. 2002

Journal of Biological Chemistry

View full text Add to dashboard Cite

Lactase gene transcription is spatially restricted to the proximal and middle small intestine of the developing mouse. To identify regions of the lactase gene involved in mediating the spatiotemporal expression pattern, transgenic mice harboring 0.8-, 1.3-, and 2.0-kb fragments of the 5-flanking region cloned upstream of a firefly-luciferase reporter were generated. Transgene expression was assessed noninvasively in living mice using a sensitive low light imaging system. Two independent, 1.3-and 2.0-kb, lactase promoter-reporter transgenic lines expressed appropriate high levels of luciferase activity in the small intestine (300 -3,000 relative light units/g) with maximal expression in the middle segments. Post-weaned 30-day transgenic offspring also demonstrated an appropriate 4-fold maturational decline in luciferase expression in the small intestine. The pattern of the 2.0-kb promoter transgene mRNA abundance most closely mimicked that of the endogenous lactase gene with respect to spatiotemporal restriction. In contrast, a 0.8-kb promoter-reporter construct expressed low level luciferase activity (<25 relative light units/g) in multiple organs and throughout the gastrointestinal tract in transgenic mice. Thus, a distinct 5-region of the lactase promoter directs intestine-specific expression in the small intestine of transgenic mice, and regulatory sequences have been localized to a 1.2-kb region upstream of the lactase transcription start site. In addition, we have demonstrated that in vivo bioluminescence imaging can be utilized for assessment of intestinal expression patterns of a luciferase reporter gene driven by lactase promoter regions in transgenic mice.Intestinal lactase-phlorizin hydrolase (LPH, 1 lactase) is the absorptive enterocyte membrane glycoprotein essential for digestive hydrolysis of lactose in milk. Lactase is present predominantly along the brush-border membrane of differentiated enterocytes lining the villi of the small intestine. Expression of the lactase gene is spatially restricted along the longitudinal axis of the gut (1). The lactase gene is expressed maximally in the proximal and middle small intestine and declines significantly in the distal segments of the intestine. Lactase gene expression is also temporally restricted in the gut during intestinal maturation. Enzyme activity is maximal in the small intestine of pre-weaned mammals and declines markedly during maturation. The maturational decline in lactase activity contrasts with a maturational increase in enzymatic activity of other intestinal hydrolases essential for digestion of solid foods (for comprehensive review see Ref. 2).Although the mechanisms regulating the spatial and temporal restriction of lactase gene expression have not been fully defined, lactase spatiotemporal restriction is largely regulated at the level of gene transcription. This is suggested by colocalization of lactase protein along the longitudinal axis of the gut and lactase mRNA transcripts detected by Northern blot and in situ hybridization (1). With...

show abstract

“…Downstream transduction of the signal into the cell is assumed to occur by the activation of receptor substrates (IRS-1 and -2, and Shc) and tyrosine-phosphorylated proteins associating through SH 2 domain (8,9). The final step of the signal leads to the activation of the SI gene promoter with a dose-dependent accumulation of SI mRNA (6), probably by the binding of a nuclear transcription factor [hepatocyte nuclear factor 1, (10,11)] to regulatory elements located upstream of the SI gene promoter (10,11). A recent study (12) has shown that the insulin signal that stimulates BBM hydrolases would be regulated by the cascade of MAP kinases and not by PI-3 kinase or protein kinase B.…”

mentioning

confidence: 99%

“…Also, SB 203580 had no effect on mucosal mass expressed by centimeter of gut length. Although several studies (6,10,11,35,36) have documented that the regulation of the genes of SI and of maltase and their responsiveness to insulin differs from that of lactase, the effect of SB 203580 remains unexplained. It is possible that the inhibition of p38 MAP kinase determines an antiapoptotic effect upgrading cell differentiation and the responsiveness of sucrase and maltase to insulin.…”

mentioning

confidence: 99%

Ontogeny of MAP Kinases in Rat Small Intestine: Premature Stimulation by Insulin of BBM Hydrolases Is Regulated by ERKs but not by p-38 MAP Kinase

Marandi

2002

Pediatric Research

View full text Add to dashboard Cite

Although mitogen-activating protein (MAP) kinases are crucial signal transduction molecules regulating cellular proliferation, differentiation, and morphology, their ontogenic changes in the small intestine have not been analyzed. Also, it remains unknown which pathway of activated MAP kinases regulates the expression of brush border membrane hydrolases during growth. Therefore, we have analyzed the mucosal distribution, ontogeny, and responses to insulin and to inhibitors of p44, p42, and p38 MAP kinases in immature and mature enterocytes using Western blot analysis and autoradiography after immunoprecipitation, immunohistochemistry, and in vitro phosphorylation assays. Between d 10 and 40 postpartum, diphosphorylated active p44/p42 extracellular regulated protein kinases (ERKs) increased in abundance compared with total immunoprecipitated ERKs, and were highly responsive to exogenous insulin. In concordance, ERK total activity increased by 4-fold during the same period of growth and was further enhanced 2-fold by exogenous insulin. In weaning rats, ERKs were mainly located in membranes of villus cells and with less intensity in crypt cells. By contrast, p38 MAP kinase was unresponsive to insulin and was confined to nuclei. Administration to sucklings of PD 098059, a specific inhibitor of ERKs, not only inhibited the premature stimulation of sucrase, lactase, and maltase total activities in response to exogenous insulin, but also depressed the natural expression of these brush border membrane enzymes in the absence of insulin stimulation.In concordance, administration of SB 203580, a specific inhibitor of p38 MAP kinase, failed to inhibit both the response of brush border membrane hydrolases to insulin and their natural expression in the absence of insulin stimulation. We conclude that the ontogenic expression of brush border membrane hydrolases and their premature stimulation by insulin are regulated at least in part by the activation of p44/p42 The onset of weaning (d 14 -17) in the suckling rat is a critical period during which immature enterocytes exhibit elevated responsiveness to insulin (1). At this time, plasma insulin levels rise markedly (2), whereas milk-borne insulin is still active (3), allowing optimal interaction of the hormone with intestinal IR, which are located on both endoluminal and basolateral membranes of the cell (4). After weaning, the 2-fold decrease in IR concentration is associated with a reduction in responsiveness of mature enterocytes to the hormone (1, 5). Our recent studies (6, 7) suggest that the premature induction of SI is triggered by the binding of the hormone to the extracellular ␣-receptor subunit, allowing autophosphorylation of the tyrosine-kinase intrinsic to the juxtamembrane and

show abstract

Regulation of sucrase and lactase in developing rats: Role of nuclear factors that bind to two gene regulatory elements

Cited by 37 publications

References 4 publications

Intestine-specific transcription factor Cdx2 induces E-cadherin function by enhancing the trafficking of E-cadherin to the cell membrane

Intestine-specific transcription factor Cdx2 induces E-cadherin function by enhancing the trafficking of E-cadherin to the cell membrane

Regulation of Intestine-specific Spatiotemporal Expression by the Rat Lactase Promoter

Ontogeny of MAP Kinases in Rat Small Intestine: Premature Stimulation by Insulin of BBM Hydrolases Is Regulated by ERKs but not by p-38 MAP Kinase

Contact Info

Product

Resources

About