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• W1978595730 abstract "The caudal-related homeobox geneCdx-2/3 is a critical “master” control gene in embryogenesis. Mice heterozygous for a null mutation inCdx-2/3 exhibit multiple malfunctions including tail abnormalities, stunted growth, a homeotic shift in vertebrae, and the development of multiple intestinal adenomatous polyps, indicating thatCdx-2/3 is haplo-insufficient. In vitro studies have identified more than a half-dozen downstream target genes expressed in pancreatic and intestinal cells for this transcription factor. We have examined the transcriptional properties of the mouseCdx-2/3 promoter. This promoter could be autoregulated in pancreatic and intestinal cells that express endogenous Cdx-2/3. In contrast, Cdx-2/3 transfection represses the Cdx-2/3promoter in fibroblasts, which do not express endogenous Cdx-2/3. Since Cdx-2/3 activates proglucagon gene promoter in both pancreatic and intestinal cells and in fibroblasts, we suggest that some, yet to be identified, cell type-specific components are required for activating selected target gene promoters of Cdx-2/3, including the Cdx-2/3 promoter itself. Cdx-2/3 binds to the TATA box and another AT-rich motif, designated as DBS, within an evolutionarily conserved proximal element of the Cdx-2/3 promoter. The DBS motif is critical for the autoregulation, whereas the TATA box may act as an attenuating element for the autoregulatory loop. Finally, overexpression of Cdx-2/3 in a pancreatic cell line activated the expression of the endogenous Cdx-2/3. Taken together, our results indicate that the dose-dependent phenotype of Cdx-2/3 expression on its downstream targets in vivo could be regulated initially via a transcriptional network involving cell type-specific autoregulation of the Cdx-2/3 promoter. The caudal-related homeobox geneCdx-2/3 is a critical “master” control gene in embryogenesis. Mice heterozygous for a null mutation inCdx-2/3 exhibit multiple malfunctions including tail abnormalities, stunted growth, a homeotic shift in vertebrae, and the development of multiple intestinal adenomatous polyps, indicating thatCdx-2/3 is haplo-insufficient. In vitro studies have identified more than a half-dozen downstream target genes expressed in pancreatic and intestinal cells for this transcription factor. We have examined the transcriptional properties of the mouseCdx-2/3 promoter. This promoter could be autoregulated in pancreatic and intestinal cells that express endogenous Cdx-2/3. In contrast, Cdx-2/3 transfection represses the Cdx-2/3promoter in fibroblasts, which do not express endogenous Cdx-2/3. Since Cdx-2/3 activates proglucagon gene promoter in both pancreatic and intestinal cells and in fibroblasts, we suggest that some, yet to be identified, cell type-specific components are required for activating selected target gene promoters of Cdx-2/3, including the Cdx-2/3 promoter itself. Cdx-2/3 binds to the TATA box and another AT-rich motif, designated as DBS, within an evolutionarily conserved proximal element of the Cdx-2/3 promoter. The DBS motif is critical for the autoregulation, whereas the TATA box may act as an attenuating element for the autoregulatory loop. Finally, overexpression of Cdx-2/3 in a pancreatic cell line activated the expression of the endogenous Cdx-2/3. Taken together, our results indicate that the dose-dependent phenotype of Cdx-2/3 expression on its downstream targets in vivo could be regulated initially via a transcriptional network involving cell type-specific autoregulation of the Cdx-2/3 promoter. homeodomain days post-coitum baby hamster kidney electrophoretic mobility shift assay glutathioneS-transferase kilobase pair antisense luciferase Homeodomain (HD)1proteins are tissue-restricted transcription factors involved in fetal development, organogenesis, and cell type determination. HD proteins regulate the expression of genes involved in morphogenesis, cell growth, differentiation, and apoptosis. Alterations in HD protein expression may result in aberrant organ development, inherited diseases, and the formation of tumors (1Jonsson J. Carlsson L. Edlund T. Edlund H. Nature. 1994; 371: 606-609Crossref PubMed Scopus (1552) Google Scholar, 2Muragaki Y. Mundlos S. Upton J. Oslen B.R. Science. 1996; 272: 548-551Crossref PubMed Scopus (484) Google Scholar, 3Fishman M.C. Olson E.N. Cell. 1997; 91: 153-156Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar, 4Boncinelli E. Curr. Opin. Genet. & Dev. 1997; 7: 331-337Crossref PubMed Scopus (78) Google Scholar, 5Care A. Silvani A. Meccia E. Mattia G. Stoppacciaro A. Parmiani G. Peschle C. Colombo M.P. Mol. Cell. Biol. 1996; 16: 4842-4851Crossref PubMed Scopus (175) Google Scholar, 6Stuart E.T. Haffner R. Oren M. Gruss P. EMBO J. 1995; 14: 5638-5645Crossref PubMed Scopus (210) Google Scholar, 7Jin T. Branch D.R. Zhang X. Qi S. Youngson B. Goss P.E. Int. J. Cancer. 1999; 81: 104-112Crossref PubMed Scopus (95) Google Scholar, 8Smith R.C. Branellec D. Gorski D.H. Guo K. Perlman H. Dedieu J.F. Pastore C. Mahfoudi A. Denefle P. Isner J.M. Walsh K. Genes Dev. 1997; 11: 1674-1689Crossref PubMed Scopus (163) Google Scholar, 9Chawengsaksophak K. James R. Hammond V.E. Kontgen F. Beck F. Nature. 1997; 386: 84-87Crossref PubMed Scopus (554) Google Scholar).Cdx-2/3 is one of the three caudal-related homeobox genes identified in mammals. Cdx-2/3 maternal transcripts are expressed at pre-implantation stages and at the time of implantation in trophoectodermal cells. The embryonic expression is first seen at 8.5 days post-coitum (d.p.c.), and its expression increases in the endoderm just before the endoderm intestinal epithelial transition (∼15 d.p.c.). In adults, Cdx-2/3 is only expressed in differentiated intestinal epithelial cells, endocrine (L) cells, and in pancreatic A and B cells (10James R. Erler T. Kazenwadel J. J. Biol. Chem. 1994; 269: 15229-15237Abstract Full Text PDF PubMed Google Scholar, 11German M.S. Wang J. Chadwick R.B. Rutter W.J. Genes Dev. 1992; 6: 2165-2176Crossref PubMed Scopus (359) Google Scholar, 12Suh E. Chen L. Taylor J. Traber P.G. Mol. Cell. Biol. 1994; 14: 7340-7351Crossref PubMed Scopus (379) Google Scholar, 13Jin T. Drucker D.J. Mol. Cell. Biol. 1996; 16: 19-28Crossref PubMed Scopus (114) Google Scholar, 14Laser B. Meda P. Constant I. Philippe J. J. Biol. Chem. 1996; 271: 28984-28994Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 15Jin T. Trinh D.K. Wang F. Drucker D.J. Mol. Endocrinol. 1997; 11: 203-209Crossref PubMed Scopus (38) Google Scholar, 16Trinh K.Y. Jin T. Drucker D.J. J. Biol. Chem. 1999; 274: 6011-6019Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar). We and others (13Jin T. Drucker D.J. Mol. Cell. Biol. 1996; 16: 19-28Crossref PubMed Scopus (114) Google Scholar, 14Laser B. Meda P. Constant I. Philippe J. J. Biol. Chem. 1996; 271: 28984-28994Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 15Jin T. Trinh D.K. Wang F. Drucker D.J. Mol. Endocrinol. 1997; 11: 203-209Crossref PubMed Scopus (38) Google Scholar, 16Trinh K.Y. Jin T. Drucker D.J. J. Biol. Chem. 1999; 274: 6011-6019Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar) have demonstrated that Cdx-2/3 is a critical transcriptional activator for proglucagon gene in pancreatic A cells and intestinal L cells.Cdx-2/3 homozygotic null mutant mice die between 3.5 and 5.5 d.p.c., whereas heterozygotic mutants show tail abnormalities, stunted growth, and a homeotic shift in vertebrae (9Chawengsaksophak K. James R. Hammond V.E. Kontgen F. Beck F. Nature. 1997; 386: 84-87Crossref PubMed Scopus (554) Google Scholar). In addition, 90% of the heterozygotic mutants develop multiple intestinal adenomatous polyps (9Chawengsaksophak K. James R. Hammond V.E. Kontgen F. Beck F. Nature. 1997; 386: 84-87Crossref PubMed Scopus (554) Google Scholar). These extraordinary multiple malfunctions observed in the heterozygotic mutant mice indicate thatCdx-2/3 transcriptional activity must be strongly dosage-dependent since a normal cellular phenotype appears to require expression of both alleles (i.e. Cdx-2/3 exhibits haplo-insufficiency).In this paper, we have isolated the mouse Cdx-2/3 promoter and studied the transcriptional properties of this promoter. We found that although Cdx-2/3 is able to activate proglucagon gene promoter in both the Cdx-2/3-expressing pancreatic and intestinal cell lines, and the non-expressing fibroblasts, it activates its own promoter in a cell type-specific manner. Cdx-2/3 was shown to be able to bind to its TATA box and another AT-rich motif designated as DBS (downstream binding site) within an evolutionarily conserved proximal element of theCdx-2/3 promoter. The DBS motif was found to be critical for Cdx-2/3 autoactivation, whereas the TATA box may act as an attenuating element for the autoregulatory loop.DISCUSSIONThe biological significance of Cdx-2/3 has been recognized within the last few years. It has been identified, or suggested, to regulate genes expressed in intestinal cells such as sucrase-isomaltase (12Suh E. Chen L. Taylor J. Traber P.G. Mol. Cell. Biol. 1994; 14: 7340-7351Crossref PubMed Scopus (379) Google Scholar), phospholipase A/lysophospholipase (20Taylor J.K. Boll W. Levy T. Suh E. Siang S. Mantei N. Traber P.G. DNA Cell Biol. 1997; 16: 1419-1428Crossref PubMed Scopus (60) Google Scholar), lactase-phlorizin hydrolase (21Troelsen J.T. Mitchelmore C. Spodsberg N. Jensen A.M. Noren O. Sjostrom H. Biochem. J. 1997; 322: 833-838Crossref PubMed Scopus (144) Google Scholar), carbonic anhydrase 1 (22Drummond F. Sowden J. Morrison K. Edwards Y.H. Eur. J. Biochem. 1996; 236: 670-681Crossref PubMed Scopus (68) Google Scholar), Calbindin-D9k (19Lambert M. Colnot S. Suh E.R. L'Horset F. Blin C. Calliot M.E. Raymondjean M. Thomasset M. Traber P.G. Perret C. Eur. J. Biochem. 1996; 236: 778-788Crossref PubMed Scopus (79) Google Scholar, 23Colnot S. Romagnolo B. Lambert M. Cluzeaud F. Porteu A. Vandewalle A. Thomasset M. Kahn A. Perret C. J. Biol. Chem. 1998; 273: 31939-31946Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar), and vitamin D receptor (24Yamamoto H. Miyamoto K. Li B. Taketani Y. Kitano M. Inoue Y. Morita K. Pike J.W. Takeda E. J. Bone Miner. Res. 1999; 14: 240-247Crossref PubMed Scopus (150) Google Scholar). We and others (7Jin T. Branch D.R. Zhang X. Qi S. Youngson B. Goss P.E. Int. J. Cancer. 1999; 81: 104-112Crossref PubMed Scopus (95) Google Scholar, 13Jin T. Drucker D.J. Mol. Cell. Biol. 1996; 16: 19-28Crossref PubMed Scopus (114) Google Scholar, 14Laser B. Meda P. Constant I. Philippe J. J. Biol. Chem. 1996; 271: 28984-28994Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 15Jin T. Trinh D.K. Wang F. Drucker D.J. Mol. Endocrinol. 1997; 11: 203-209Crossref PubMed Scopus (38) Google Scholar, 16Trinh K.Y. Jin T. Drucker D.J. J. Biol. Chem. 1999; 274: 6011-6019Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar) have demonstrated previously that Cdx-2/3 is a transcriptional activator for rat insulin promoter and the proglucagon gene promoter. Cdx-2/3 also has been shown to bind to two well defined enhancer elements in another homeobox gene, Hoxc-8 (25Taylor J.K. Levy T. Suh E.R. Traber P.G. Nucleic Acids Res. 1997; 12: 2293-2300Crossref Scopus (68) Google Scholar). Fig. 9 shows a summary of binding motifs in the downstream target gene promoters of Cdx-2/3 identified or suggested to date. In addition, Cdx-2/3 was found to play a fundamentally important role during intestinal development and differentiation (26Suh E. Traber P.G. Mol. Cell. Biol. 1996; 16: 619-625Crossref PubMed Scopus (450) Google Scholar). The existence of multiple downstream target genes with diverse recognition sites identified in vitro would suggest that Cdx-2/3, like many other HD proteins (27Chang C.P. de Vivo I. Cleary M.L. Mol. Cell. Biol. 1997; 17: 81-88Crossref PubMed Scopus (60) Google Scholar, 28Phelan M.L. Featherstone M.S. J. Biol. Chem. 1997; 272: 8635-8643Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 29Peers B. Sharma S. Johnson T. Kamps M. Monteminy M. Mol. Cell. Biol. 1995; 15: 7091-7097Crossref PubMed Scopus (145) Google Scholar, 30Yu Y. Li W. Su K. Yussa M. Han W. Perrimon N. Pick L. Nature. 1997; 385: 552-555Crossref PubMed Scopus (160) Google Scholar, 31Rauskolb C. Perfer M. Wieschaus E. Cell. 1993; 74: 1101-1112Abstract Full Text PDF PubMed Scopus (213) Google Scholar, 32Strubin M. Newwell J.W. Matthias P. Cell. 1995; 80: 497-506Abstract Full Text PDF PubMed Scopus (350) Google Scholar, 33Durocher D. Charron F. Warren R. Schwartz R.J. Nemer M. EMBO J. 1997; 16: 5687-5696Crossref PubMed Scopus (540) Google Scholar), may require co-factors to exert its multiple biological functions in vivo.The most exciting observation with respect to Cdx-2/3 was made recently in Cdx-2/3 “knock out” mice (9Chawengsaksophak K. James R. Hammond V.E. Kontgen F. Beck F. Nature. 1997; 386: 84-87Crossref PubMed Scopus (554) Google Scholar). TheCdx-2/3−/− embryos die between 3.5 and 5.5 d.p.c., suggesting that maternal transcripts of Cdx-2/3 are essential for implantation (9Chawengsaksophak K. James R. Hammond V.E. Kontgen F. Beck F. Nature. 1997; 386: 84-87Crossref PubMed Scopus (554) Google Scholar). Cdx-2/3+/−animals, however, show multiple malfunctions, including tail abnormalities, stunted growth, homeotic shift in vertebrae, and the development of multiple intestinal adenomatous polyps. The abnormalities in the Cdx-2/3+/− mice vary from one mouse to another, and no obvious abnormality was observed in their pancreas. These results would suggest that the Cdx-2/3 transcriptional activity is dosage-dependent or haplo-insufficient in selected tissues. In the Cdx-2/3+/− mutants, Cdx-2/3 is expressed in normal intestinal epithelia but not in the intestinal tumor cells. This is unlikely to be due to mutations or deletions of the remaining wild type copy of the Cdx-2/3 gene because loss of heterozygosity was not observed (9Chawengsaksophak K. James R. Hammond V.E. Kontgen F. Beck F. Nature. 1997; 386: 84-87Crossref PubMed Scopus (554) Google Scholar). Therefore the defect is at the expression level.In this study we isolated the mouse Cdx-2/3 promoter and examined the transcriptional property of this promoter. We found that Cdx-2/3 transfection activates its own promoter in cell lines that express endogenous Cdx-2/3. Therefore, the expression of Cdx-2/3, like many other HD proteins, could be autoregulated (34Serfling E. Trend Genet. 1989; 5: 131-133Abstract Full Text PDF PubMed Scopus (47) Google Scholar, 35Chen R.P. Ingraham H.A. Treacy M.N. Albert V.R. Wilson L. Rosenfeld M.G. Nature. 1990; 346: 583-586Crossref PubMed Scopus (183) Google Scholar, 36Chouinard S. Kaufman T.C. Development. 1991; 11: 1267-1280Google Scholar, 37Wu K. Wolgemuth D.J. J. Cell. Biochem. 1993; 52: 449-462Crossref PubMed Scopus (10) Google Scholar). However, in fibroblasts, which do not express Cdx-2/3, Cdx-2/3 transfection represses the expression of Cdx-2/3 promoter. This is in contrast to our previous observations in examining proglucagon gene activation where Cdx-2/3 is able to activate proglucagon gene promoter in both the pancreatic InR1-G9 cells (15Jin T. Trinh D.K. Wang F. Drucker D.J. Mol. Endocrinol. 1997; 11: 203-209Crossref PubMed Scopus (38) Google Scholar) and the BHK fibroblasts (13Jin T. Drucker D.J. Mol. Cell. Biol. 1996; 16: 19-28Crossref PubMed Scopus (114) Google Scholar). To investigate further whether Cdx-2/3 autoactivation, indeed, occurs in a cell type-specific manner, we examined the effect of Cdx-2/3 cDNA transfection over a very wide range of dosages on the expression of Cdx-2/3 and the proglucagon gene promoters in InR1-G9 cells and BHK fibroblasts. Our data clearly indicated that at all the dosages utilized, Cdx-2/3 activates both the Cdx-2/3and the proglucagon gene promoters in InR1-G9 cells. In BHK fibroblasts, Cdx-2/3 transfection activates the proglucagon gene promoter but represses the Cdx-2/3 promoter. Therefore, we suggest that Cdx-2/3 requires some as yet to be determined cell type-specific component(s) to regulate selected downstream target genes, such as Cdx-2/3 itself.It should be pointed out that although cell type-specific autoregulation of homeobox gene Cdx-2/3 has not been previously studied, cell type-specific activation by Cdx-2/3 on heterologous promoters was recently reported by Taylor et al. (25Taylor J.K. Levy T. Suh E.R. Traber P.G. Nucleic Acids Res. 1997; 12: 2293-2300Crossref Scopus (68) Google Scholar). Cdx-2/3 was shown, by Suh et al. (12Suh E. Chen L. Taylor J. Traber P.G. Mol. Cell. Biol. 1994; 14: 7340-7351Crossref PubMed Scopus (379) Google Scholar), to activate sucrase-isomaltase promoter via binding to its SIF1 enhancer cassette in the intestinal cells. Taylor et al. (25Taylor J.K. Levy T. Suh E.R. Traber P.G. Nucleic Acids Res. 1997; 12: 2293-2300Crossref Scopus (68) Google Scholar), however, found that Cdx-2/3 also activated a thymidine kinase promoter fused with one or more copies of the SIF1 enhancer cassette when transfected into intestinal Caco-2 cells. Such an activation, however, was not observed when examined in the NIH3T3 fibroblasts. Furthermore, Taylor et al. (25Taylor J.K. Levy T. Suh E.R. Traber P.G. Nucleic Acids Res. 1997; 12: 2293-2300Crossref Scopus (68) Google Scholar) found that if the Cdx-2/3 activation domain was linked to the Gal4 DNA binding domain, the chimeric protein was able to activate Gal4 enhancer constructs in the intestinal Caco-2 cell line but not in the NIH3T3 fibroblasts.Haplo-insufficiency is not common for transcription factors, especially for homeobox genes (34Serfling E. Trend Genet. 1989; 5: 131-133Abstract Full Text PDF PubMed Scopus (47) Google Scholar). One explanation is that related homeobox genes may exert overlapping or redundant biological functions. In addition, the expression of many homeobox genes, like Cdx-2/3, could be autoregulated (34Serfling E. Trend Genet. 1989; 5: 131-133Abstract Full Text PDF PubMed Scopus (47) Google Scholar, 35Chen R.P. Ingraham H.A. Treacy M.N. Albert V.R. Wilson L. Rosenfeld M.G. Nature. 1990; 346: 583-586Crossref PubMed Scopus (183) Google Scholar, 36Chouinard S. Kaufman T.C. Development. 1991; 11: 1267-1280Google Scholar, 37Wu K. Wolgemuth D.J. J. Cell. Biochem. 1993; 52: 449-462Crossref PubMed Scopus (10) Google Scholar). Therefore, via a positive regulatory loop, the expression of a homeobox gene from only one functional allele is able to attain a physiologically required level. Other homeodomain proteins, such as Otx-2 and PAX6, do exhibit haplo-insufficiency for part of their biological functions (38Okladnova O. Syagailo Y.V. Mossner R. Riederer P. Lesch K.P. Brain Res. Mol. Brain Res. 1998; 60: 177-192Crossref PubMed Scopus (42) Google Scholar, 39Suda Y. Matsuo I. Aizawa S. Mech. Dev. 1997; 69: 125-141Crossref PubMed Scopus (86) Google Scholar). An interesting question, therefore, is why one functional allele for a few homeobox genes is insufficient even though the expression of these genes can be autoregulated? Information from this study has provided one plausible explanation. In Cdx-2/3, some as yet to be defined cell type-specific components (a co-factor, and/or a signal) is critical in determining if the autoregulation will be effectively processed or not. If in an individual cell, autoregulation process failed due to, for example, the combination of loss of one functional allele and lack of a necessary signal, malfunctions including the formation of tumors may occur. It is quite possible for the existence of a critical threshold for triggering the autoregulation. In the Cdx-2/3+/− mice, since only one Cdx-2/3 wild type copy exists, the chance for the expression of Cdx-2/3 within some cells not reaching the threshold will be higher. If this hypothesis is correct, it will provide an explanation for why in the Cdx-2/3+/− mice, the various malfunctions observed vary, in degree, time, and location, from one mouse to another. To explore this hypothesis, a systematic examination of the mechanisms controlling Cdx-2/3 expression, using both in vivo and in vitro approaches, becomes an essential task.We identified two Cdx-2/3-binding sites, TATA box and DBS, within the proximal element (PE, −53 to +18) of the mouse Cdx-2/3promoter. DNA sequence from −53 to +4, which covers both the TATA box and the DBS, is 100% conserved between mouse and human (10James R. Erler T. Kazenwadel J. J. Biol. Chem. 1994; 269: 15229-15237Abstract Full Text PDF PubMed Google Scholar, 40Drummond F. Putt W. Fox M. Edwards Y.H. Ann. Hum. Genet. 1997; 61: 393-400Crossref PubMed Scopus (88) Google Scholar). It is interesting that the autoregulation of the pituitary-specific POU domain transcription factor Pit-1 is also mediated by two Pit-1-binding sites within the proximal region of the promoter (35Chen R.P. Ingraham H.A. Treacy M.N. Albert V.R. Wilson L. Rosenfeld M.G. Nature. 1990; 346: 583-586Crossref PubMed Scopus (183) Google Scholar). These two binding sites are separated by 60 nucleotides. Mutation of the 5′ Pit-1-binding site (PitB1) abolished the positive autoregulation, whereas mutation of the other binding site that is located immediately 3′ of the cap site (PitB2) markedly increased the expression of thepit-1 promoter. Therefore, PitB2 is considered as an attenuating component for the autoregulatory loop (35Chen R.P. Ingraham H.A. Treacy M.N. Albert V.R. Wilson L. Rosenfeld M.G. Nature. 1990; 346: 583-586Crossref PubMed Scopus (183) Google Scholar). In theCdx-2/3 promoter, the overall organization of the two Cdx-2/3-binding sites is different from that of pit-1. The 3′ DBS motif is critical for autoactivation, whereas the other binding site is the TATA box per se. It is not surprising that mutation of the TATA box almost completely abolished the promoter activity. However, Cdx-2/3-LUC fusion gene with a mutated TATA box still responds to Cdx-2/3 transfection. We suggest that in theCdx-2/3 promoter, the TATA box could act as an attenuating component in the autoregulatory loop. It should be pointed out that both general transcription factors and Cdx-2/3 bind to the proximal element of the Cdx-2/3 promoter. Based on our observation, one may propose that at a low concentration, Cdx-2/3 will bind to DBS to accelerate transcription via physically interacting with one or more general transcription factors. At a high concentration, Cdx-2/3 may compete with general transcription factors for the TATA box, resulting in repressing the expression of the promoter. Homeodomain (HD)1proteins are tissue-restricted transcription factors involved in fetal development, organogenesis, and cell type determination. HD proteins regulate the expression of genes involved in morphogenesis, cell growth, differentiation, and apoptosis. Alterations in HD protein expression may result in aberrant organ development, inherited diseases, and the formation of tumors (1Jonsson J. Carlsson L. Edlund T. Edlund H. Nature. 1994; 371: 606-609Crossref PubMed Scopus (1552) Google Scholar, 2Muragaki Y. Mundlos S. Upton J. Oslen B.R. Science. 1996; 272: 548-551Crossref PubMed Scopus (484) Google Scholar, 3Fishman M.C. Olson E.N. Cell. 1997; 91: 153-156Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar, 4Boncinelli E. Curr. Opin. Genet. & Dev. 1997; 7: 331-337Crossref PubMed Scopus (78) Google Scholar, 5Care A. Silvani A. Meccia E. Mattia G. Stoppacciaro A. Parmiani G. Peschle C. Colombo M.P. Mol. Cell. Biol. 1996; 16: 4842-4851Crossref PubMed Scopus (175) Google Scholar, 6Stuart E.T. Haffner R. Oren M. Gruss P. EMBO J. 1995; 14: 5638-5645Crossref PubMed Scopus (210) Google Scholar, 7Jin T. Branch D.R. Zhang X. Qi S. Youngson B. Goss P.E. Int. J. Cancer. 1999; 81: 104-112Crossref PubMed Scopus (95) Google Scholar, 8Smith R.C. Branellec D. Gorski D.H. Guo K. Perlman H. Dedieu J.F. Pastore C. Mahfoudi A. Denefle P. Isner J.M. Walsh K. Genes Dev. 1997; 11: 1674-1689Crossref PubMed Scopus (163) Google Scholar, 9Chawengsaksophak K. James R. Hammond V.E. Kontgen F. Beck F. Nature. 1997; 386: 84-87Crossref PubMed Scopus (554) Google Scholar). Cdx-2/3 is one of the three caudal-related homeobox genes identified in mammals. Cdx-2/3 maternal transcripts are expressed at pre-implantation stages and at the time of implantation in trophoectodermal cells. The embryonic expression is first seen at 8.5 days post-coitum (d.p.c.), and its expression increases in the endoderm just before the endoderm intestinal epithelial transition (∼15 d.p.c.). In adults, Cdx-2/3 is only expressed in differentiated intestinal epithelial cells, endocrine (L) cells, and in pancreatic A and B cells (10James R. Erler T. Kazenwadel J. J. Biol. Chem. 1994; 269: 15229-15237Abstract Full Text PDF PubMed Google Scholar, 11German M.S. Wang J. Chadwick R.B. Rutter W.J. Genes Dev. 1992; 6: 2165-2176Crossref PubMed Scopus (359) Google Scholar, 12Suh E. Chen L. Taylor J. Traber P.G. Mol. Cell. Biol. 1994; 14: 7340-7351Crossref PubMed Scopus (379) Google Scholar, 13Jin T. Drucker D.J. Mol. Cell. Biol. 1996; 16: 19-28Crossref PubMed Scopus (114) Google Scholar, 14Laser B. Meda P. Constant I. Philippe J. J. Biol. Chem. 1996; 271: 28984-28994Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 15Jin T. Trinh D.K. Wang F. Drucker D.J. Mol. Endocrinol. 1997; 11: 203-209Crossref PubMed Scopus (38) Google Scholar, 16Trinh K.Y. Jin T. Drucker D.J. J. Biol. Chem. 1999; 274: 6011-6019Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar). We and others (13Jin T. Drucker D.J. Mol. Cell. Biol. 1996; 16: 19-28Crossref PubMed Scopus (114) Google Scholar, 14Laser B. Meda P. Constant I. Philippe J. J. Biol. Chem. 1996; 271: 28984-28994Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 15Jin T. Trinh D.K. Wang F. Drucker D.J. Mol. Endocrinol. 1997; 11: 203-209Crossref PubMed Scopus (38) Google Scholar, 16Trinh K.Y. Jin T. Drucker D.J. J. Biol. Chem. 1999; 274: 6011-6019Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar) have demonstrated that Cdx-2/3 is a critical transcriptional activator for proglucagon gene in pancreatic A cells and intestinal L cells.Cdx-2/3 homozygotic null mutant mice die between 3.5 and 5.5 d.p.c., whereas heterozygotic mutants show tail abnormalities, stunted growth, and a homeotic shift in vertebrae (9Chawengsaksophak K. James R. Hammond V.E. Kontgen F. Beck F. Nature. 1997; 386: 84-87Crossref PubMed Scopus (554) Google Scholar). In addition, 90% of the heterozygotic mutants develop multiple intestinal adenomatous polyps (9Chawengsaksophak K. James R. Hammond V.E. Kontgen F. Beck F. Nature. 1997; 386: 84-87Crossref PubMed Scopus (554) Google Scholar). These extraordinary multiple malfunctions observed in the heterozygotic mutant mice indicate thatCdx-2/3 transcriptional activity must be strongly dosage-dependent since a normal cellular phenotype appears to require expression of both alleles (i.e. Cdx-2/3 exhibits haplo-insufficiency). In this paper, we have isolated the mouse Cdx-2/3 promoter and studied the transcriptional properties of this promoter. We found that although Cdx-2/3 is able to activate proglucagon gene promoter in both the Cdx-2/3-expressing pancreatic and intestinal cell lines, and the non-expressing fibroblasts, it activates its own promoter in a cell type-specific manner. Cdx-2/3 was shown to be able to bind to its TATA box and another AT-rich motif designated as DBS (downstream binding site) within an evolutionarily conserved proximal element of theCdx-2/3 promoter. The DBS motif was found to be critical for Cdx-2/3 autoactivation, whereas the TATA box may act as an attenuating element for the autoregulatory loop. DISCUSSIONThe biological significance of Cdx-2/3 has been recognized within the last few years. It has been identified, or suggested, to regulate genes expressed in intestinal cells such as sucrase-isomaltase (12Suh E. Chen L. Taylor J. Traber P.G. Mol. Cell. Biol. 1994; 14: 7340-7351Crossref PubMed Scopus (379) Google Scholar), phospholipase A/lysophospholipase (20Taylor J.K. Boll W. Levy T. Suh E. Siang S. Mantei N. Traber P.G. DNA Cell Biol. 1997; 16: 1419-1428Crossref PubMed Scopus (60) Google Scholar), lactase-phlorizin hydrolase (21Troelsen J.T. Mitchelmore C. Spodsberg N. Jensen A.M. Noren O. Sjostrom H. Biochem. J. 1997; 322: 833-838Crossref PubMed Scopus (144) Google Scholar), carbonic anhydrase 1 (22Drummond F. Sowden J. Morrison K. Edwards Y.H. Eur. J. 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Chem. 1996; 271: 28984-28994Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 15Jin T. Trinh D.K. Wang F. Drucker D.J. Mol. Endocrinol. 1997; 11: 203-209Crossref PubMed Scopus (38) Google Scholar, 16Trinh K.Y. Jin T. Drucker D.J. J. Biol. Chem. 1999; 274: 6011-6019Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar) have demonstrated previously that Cdx-2/3 is a transcriptional activator for rat insulin p" @default.
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• W1978595730 title "Cell Type-specific Autoregulation of theCaudal-related Homeobox Gene Cdx-2/3" @default.
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