Colon Cancer Research Today is a free monthly online journal that collates and summarizes the latest research about Colon Cancer, including details on causes, treatment, symptoms.

Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation.

Gross I, Lhermitte B, Domon-Dell C, Duluc I, Martin E, Gaiddon C, Kedinger M, Freund JN

Development and Physiopathology of the Intestine and Pancreas, 3, avenue Molière, 67200 Strasbourg, France.

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.

Published 2 December 2005 in Oncogene, 24(54): 7955-63.
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