Identification of Domains Mediating Transcriptional Activation and Cytoplasmic Export in the Caudal Homeobox Protein Cdx-3

The caudal genes have important functions in embryonic development and cell differentiation. The caudal -related protein Cdx-2/3 (the protein designated Cdx-2 in the mouse and Cdx-3 in the hamster) is expressed in the gastrointestinal epithelium and in islet and enteroendocrine cells, where it activ...

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Bibliographic Details
Published in:The Journal of biological chemistry 1999-02, Vol.274 (9), p.6011-6019
Main Authors: Trinh, K Y, Jin, T, Drucker, D J
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Base Sequence
Biological Transport
CDX2 Transcription Factor
Cricetinae
Cytoplasm - metabolism
DNA Primers
Glucagon - genetics
Homeodomain Proteins - chemistry
Homeodomain Proteins - genetics
Homeodomain Proteins - metabolism
Humans
Mice
Molecular Sequence Data
Mutagenesis, Site-Directed
Proglucagon
Promoter Regions, Genetic
Protein Precursors - genetics
Sequence Homology, Amino Acid
Trans-Activators
Transcriptional Activation
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Summary:The caudal genes have important functions in embryonic development and cell differentiation. The caudal -related protein Cdx-2/3 (the protein designated Cdx-2 in the mouse and Cdx-3 in the hamster) is expressed in the gastrointestinal epithelium and in islet and enteroendocrine cells, where it activates proglucagon gene transcription. We show here that Cdx-3 sequences amino-terminal to the homeodomain (amino acids 1–180) function as a heterologous transcriptional activation domain when fused to the LexA DNA binding domain. A Cdx - 3-Pit-1 fusion protein containing only the first 83 amino acids of Cdx-3 linked to the POU domain of Pit-1 markedly stimulated the transcriptional activity of a Pit-1-responsive promoter. Analysis of the transcriptional properties of Cdx-3 mutants in fibroblasts and islet cells revealed distinct amino-terminal subdomains that function in a cell-specific manner. Point mutations within the amino-terminal A domain were associated with reduced transcriptional activity. Furthermore, internal deletions and selected point mutations within domain A, but not the B or C domains, resulted in accumulation of mutant Cdx-3 in the cytoplasm. Unexpectedly, mutation of an Asp-Lys-Asp motif within domain A identified a putative cytoplasmic membrane-associated export signal that mediates Cdx-3 compartmentalization. These experiments delineate unique activities for specific amino-terminal sequences that are functionally important for Cdx-3 biological activity.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.274.9.6011