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A novel CDX2 isoform regulates alternative splicing.

Witek ME, Snook AE, Lin JE, Blomain ES, Xiang B, Magee MS, Magee M, Waldman SA - PLoS ONE (2014)

Bottom Line: 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.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).

View Article: PubMed Central - PubMed

Affiliation: Department of Radiation Oncology, Kimmel Cancer Center & Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.

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).

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Amino-acid alignment of the RS-like domain of CDX2/AS and that of SR and SR-like proteins revealed 31% homology.
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pone-0104293-g004: Amino-acid alignment of the RS-like domain of CDX2/AS and that of SR and SR-like proteins revealed 31% homology.

Mentions: Proteins belonging to the SR and SR-like family of splicing factors typically contain an RS domain enriched in arginine and serine dipeptides and localize to punctate nuclear foci, termed nuclear speckles. Given the enrichment of arginine and serine in the carboxy-terminal domain of CDX2/AS and its focal nuclear expression, we compared the RS domain of CDX2/AS with that of other SR and SR-like splicing factors. Indeed, CDX2/AS exhibited approximately 31% homology with SR and SR-like proteins suggesting a possible role in alternative splicing (Fig. 4).


A novel CDX2 isoform regulates alternative splicing.

Witek ME, Snook AE, Lin JE, Blomain ES, Xiang B, Magee MS, Magee M, Waldman SA - PLoS ONE (2014)

Amino-acid alignment of the RS-like domain of CDX2/AS and that of SR and SR-like proteins revealed 31% homology.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4125279&req=5

pone-0104293-g004: Amino-acid alignment of the RS-like domain of CDX2/AS and that of SR and SR-like proteins revealed 31% homology.
Mentions: Proteins belonging to the SR and SR-like family of splicing factors typically contain an RS domain enriched in arginine and serine dipeptides and localize to punctate nuclear foci, termed nuclear speckles. Given the enrichment of arginine and serine in the carboxy-terminal domain of CDX2/AS and its focal nuclear expression, we compared the RS domain of CDX2/AS with that of other SR and SR-like splicing factors. Indeed, CDX2/AS exhibited approximately 31% homology with SR and SR-like proteins suggesting a possible role in alternative splicing (Fig. 4).

Bottom Line: 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.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).

View Article: PubMed Central - PubMed

Affiliation: Department of Radiation Oncology, Kimmel Cancer Center & Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.

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).

Show MeSH
Related in: MedlinePlus