title: A novel CDX2 isoform regulates alternative splicing.
abstract: Gene expression is a dynamic and coordinated process coupling transcription with pre-mRNA processing. This regulation enables tissue-specific transcription factors to induce expression of specific transcripts that are subsequently amplified by alternative splicing allowing for increased proteome complexity and functional diversity. The intestine-specific transcription factor CDX2 regulates development and maintenance of the intestinal epithelium by inducing expression of genes characteristic of the mature enterocyte phenotype. Here, sequence analysis of CDX2 mRNA from colonic mucosa-derived tissues revealed an alternatively spliced transcript (CDX2/AS) that encodes a protein with a truncated homeodomain and a novel carboxy-terminal domain enriched in serine and arginine residues (RS domain). CDX2 and CDX2/AS exhibited distinct nuclear expression patterns with minimal areas of co-localization. CDX2/AS did not activate the CDX2-dependent promoter of guanylyl cyclase C nor inhibit transcriptional activity of CDX2. Unlike CDX2, CDX2/AS co-localized with the putative splicing factors ASF/SF2 and SC35. CDX2/AS altered splicing patterns of CD44v5 and Tra2-β1 minigenes in Lovo colon cancer cells independent of CDX2 expression. These data demonstrate unique dual functions of the CDX2 gene enabling it to regulate gene expression through both transcription (CDX2) and pre-mRNA processing (CDX2/AS).
authors.affiliation: Department of Radiation Oncology, Kimmel Cancer Center & Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Witek
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.
authors.forename: Adam E
authors.initials: AE
authors.lastname: Snook
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.
authors.forename: Jieru E
authors.initials: JE
authors.lastname: Lin
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.
authors.forename: Erik S
authors.initials: ES
authors.lastname: Blomain
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.
authors.forename: Bo
authors.initials: B
authors.lastname: Xiang
authors.forename: Michael S
authors.initials: MS
authors.lastname: Magee
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Magee
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Waldman
mesh_terms: D017398:Alternative Splicing / Q000502:physiology*; D000818:Animals; D000071616:CDX2 Transcription Factor; D045744:Cell Line, Tumor; D003106:Colon / Q000166:cytology / Q000378:metabolism*; D020895:Enterocytes / Q000166:cytology / Q000378:metabolism*; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis / Q000235:genetics; D051916:Membrane Cofactor Protein / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D012261:Ribonucleoproteins / Q000235:genetics / Q000378:metabolism; D000068103:Serine-Arginine Splicing Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C497483:CD44 protein, human; C497857:CD46 protein, human; D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; D018398:Homeodomain Proteins; D018960:Hyaluronan Receptors; D051916:Membrane Cofactor Protein; D009687:Nuclear Proteins; D020033:Protein Isoforms; D012261:Ribonucleoproteins; C000595779:SRSF1 protein, human; C073288:SRSF2 protein, human; D000068103:Serine-Arginine Splicing Factors
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