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J Biol Chem, Vol. 275, Issue 6, 4499-4506, February 11, 2000

The Caudal-related Homeodomain Protein Cdx1 Inhibits Proliferation of Intestinal Epithelial Cells by Down-regulation of D-type Cyclins*

John Lynch, Eun-Ran Suh, Debra G. Silberg, Steven Rulyak, Nadine Blanchard, and Peter G. TraberDagger

From the Division of Gastroenterology, Department of Medicine and Genetics, University of Pennsylvania, Philadelphia, Pennsylvania 19104

Cdx1 is a homeodomain transcription factor that regulates intestine-specific gene expression. Experimental evidence suggests that Cdx1 may be involved in cell cycle regulation, but its role is ill defined and the mechanisms have not been explored. We used stable transfection of inducible constructs and transient expression with a replication-deficient adenovirus to induce Cdx1 expression in rat IEC6 cells, a non-transformed intestinal epithelial cell line that does not express Cdx1 protein. Expression of Cdx1 markedly reduced proliferation of IEC6 cells with accumulation of cells in the G0/G1 phase of the cell cycle. Cell cycle arrest was accompanied by an increase in the hypophosphorylated forms of the retinoblastoma protein (pRb) and the pRb-related p130 protein. Protein levels of multiple cyclin-dependent kinase inhibitors were either unchanged (p16, p18, p21, p27, and p57) or were not detected (p15 and p19). Most significantly, levels of cyclins D1 and D2 were markedly diminished with Cdx1 expression, but not cyclins D3, E, or the G1 kinases. Additionally, cyclin-dependent kinase-4 activity was decreased in association with decreased cyclin D protein. We conclude that Cdx1 regulates intestinal epithelial cell proliferation by inhibiting progression through G0/G1, most likely via modulation of cyclin D1 and D2 protein levels.

* This work was supported by National Institutes of Health NIDDK Grant PO1-DK49210 (to P. G. T.); institutional training grant support (to J. L.) from the Penn Training Program in Gastrointestinal Sciences (T32 DK07066); and the Morphology, Vector, and Molecular Biology Cores of the Center for Molecular Studies in Digestive Diseases at the University of Pennsylvania (P30-DK50306).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: 100 Centrex, Hospital of the University of Pennsylvania, 3400 Spruce St., Philadelphia, PA 19104. Fax: 215-349-5734; E-mail: traberp@mail. med.upenn.edu.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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