Indeed, a mutant of CDX2/AS in which the carboxy-terminal domain enriched in serine and arginine was eliminated failed to co-localize with ASF/SF2 or SC35 in the nucleus. Supporting its roll in pre-mRNA processing, we demonstrated that CDX2/AS can change splice site selection in human colon-derived cells using exogenous minigenes. Taken together, these data strongly suggest that CDX2 encodes two proteins, one that regulates gene transcription and a novel protein that can influence gene expression by regulating pre-mRNA processing. Whether or not CDX2/AS belongs to the SR- or SR-like families of proteins is worth considering. The RS domain of SRand SR-like proteins is required for protein-protein interactions as well as nuclear localization. The prototypical SR splicing factors contain one or two amino-terminal RNA recognition motifs followed by a carboxy-terminal RS domain enriched in serine and arginine residues. Additionally, SR proteins contain signature sequences including RDAEDA, RDADDA, and SWQDLKD. Homology searches of the entire CDX2/ AS protein failed to reveal RRMs or signature sequences characteristic of SR proteins. These observations suggest that CDX2/AS may not be a Rapamycin member of the SR family of proteins but, rather, belongs to the SR-like family of splicing factors. Interestingly, there was no clear homology in the carboxyterminal domain of CDX2/AS with the RS domain of other proteins. Despite approximately 31% amino acid consensus with the RS domain of SR- and SR-like proteins, CDX2/AS contains only two S/R dipeptides. However, the role of the RS domain in CDX2/AS in nuclear localization is similar to that of the recently identified SR-like protein NSrp70. Moreover, perinuclear localization of the carboxy-terminally truncated CDX2/AS is identical to that seen for an RS-domain deleted mutant of the SRlike protein XE7. Taken together, these data suggest that CDX2/AS should be included in the SR-like family of splicing factors. In the context of a single gene giving rise to alternatively spliced transcripts that produce proteins regulating transcription or splicing, CDX2 shares considerable similarity with the Wilms’ tumor gene, WT1. The WT1 transcript undergoes alternative splicing to produce several variants, most notably a transcription factor and a splicing factor. The unique ability of WT1 to regulate gene expression by encoding proteins that influence transcription and splicing in conjunction with the role of its various isoforms in normal cellular development and pathophysiologic processes suggests a similar function for CDX2/AS.