Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation.
The Caudal-related homeodomain transcription factor Cdx2 plays a key role in intestinal cell fate determination. Reduction of Cdx2 expression is a feature of many human colon carcinomas and inactivation of one cdx2 allele facilitates the development of invasive adenocarcinoma in the murine colon. Here, we investigated the post-translational regulation of ... Cdx2. We showed that various forms of Cdx2 coexist in the intestine and colon cancer cell lines, some of them being phosphorylated forms. We found that cyclin-dependent kinase 2 phosphorylated Cdx2 in vitro and in vivo. Using site-specific mutagenesis, we identified serine 281 as a new key residue for Cdx2 phosphorylation. Intriguingly, serine 281 belongs to a conserved motif of four evenly spaced serines (the 4S motif) similar to the one controlling beta-catenin degradation by the proteasome pathway. A nonphosphorylated mutant Cdx2 lacking the 4S motif (4S>A) exhibited reduced polyubiquitination upon proteasome inhibition and increased stability compared to wild-type Cdx2. In addition, we found that this mutant was less efficient to suppress colony formation than wild-type Cdx2. Thus, our data highlight a novel post-translational mechanism controlling Cdx2 degradation via phosphorylation and polyubiquitination, which may be of importance for intestinal development and cancer.
Mesh Terms:
Adenocarcinoma, Alanine, Alkaline Phosphatase, Amino Acid Sequence, Amino Acid Substitution, Animals, COS Cells, Caco-2 Cells, Cercopithecus aethiops, Colonic Neoplasms, Consensus Sequence, Conserved Sequence, Cyclin-Dependent Kinase 2, Enzyme Inhibitors, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor, Glycine, Homeodomain Proteins, Humans, Intestinal Mucosa, Jejunum, Mice, Molecular Sequence Data, Mutagenesis, Site-Directed, Phosphorylation, Proteasome Endopeptidase Complex, Protein Processing, Post-Translational, Sequence Homology, Amino Acid, Serine, Transcription Factors, Transcription, Genetic, Ubiquitin
Adenocarcinoma, Alanine, Alkaline Phosphatase, Amino Acid Sequence, Amino Acid Substitution, Animals, COS Cells, Caco-2 Cells, Cercopithecus aethiops, Colonic Neoplasms, Consensus Sequence, Conserved Sequence, Cyclin-Dependent Kinase 2, Enzyme Inhibitors, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor, Glycine, Homeodomain Proteins, Humans, Intestinal Mucosa, Jejunum, Mice, Molecular Sequence Data, Mutagenesis, Site-Directed, Phosphorylation, Proteasome Endopeptidase Complex, Protein Processing, Post-Translational, Sequence Homology, Amino Acid, Serine, Transcription Factors, Transcription, Genetic, Ubiquitin
Oncogene
Date: Dec. 01, 2005
PubMed ID: 16027724
View in: Pubmed Google Scholar
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