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Carcinogenesis Advance Access published online on August 5, 2004
Carcinogenesis, doi:10.1093/carcin/bgh237
© 2004 by Oxford University Press
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Received November 28, 2003
Revised July 10, 2004
Accepted July 18, 2004

CARCINOGENESIS

Azoxymethane-induced preadipocytes factor 1 (Pref-1) functions as a differentiation inhibitor in colonic epithelial cells

Mei Dong 1, Kishore Guda 1, Prashant R. Nambiar 1, Masako Nakanishi 1, Alexander C. Lichtler 2, Mitsuo Nishikawa 3, Charles Giardina 4, Daniel W. Rosenberg 1*

1 The University of Connecticut Health Center, Center for Molecular Medicine, Farmington, CT
2 The University of Connecticut Health Center, Department of Genetics and Developmental Biology, Farmington, CT
3 R&D Collaboration, Pharmaceutical Division, Kirin Brewery Company Limited, Tokyo, Japan
4 The University of Connecticut, Department of Molecular and Cell Biology, Storrs, CT

* To whom correspondence should be addressed. E-mail: Rosenberg{at}nso2.uchc.edu.


  Abstract

Inbred mice differ dramatically in their sensitivity to the colon carcinogen, azoxymethane (AOM). Identifying genes associated with this differential susceptibility in mice may ultimately reveal molecular mechanisms responsible for colon carcinogenesis. A cDNA array approach was taken to study gene expression changes induced by AOM in the colons of sensitive (A/J) and resistant (AKR) mice. Among the genes represented on the array, preadipocyte factor 1 (Pref-1), previously associated with suppression of adipocyte differentiation, was induced specifically by AOM in the distal colons of sensitive A/J mice (5.4-fold). RT-PCR followed by sequence analysis revealed the presence of four alternative splice variants of Pref-1 mRNA in the colon. The potential significance of Pref-1 in colon tumorigenesis was explored in colon cancer cells infected with a retroviral construct containing the major splice variant. Overexpression of Pref-1A in HT-29 cells led to a marked resistance to butyrate-induced differentiation and growth inhibition. Our data indicate that Pref-1, a protein that suppresses differentiation and promotes colonocyte growth, may account in part for the sensitivity of A/J mice to AOM-induced carcinogenesis. In addition, detection of Pref-1 in a human colon tumor cell line suggests that it may also participate in human colon tumorigenesis.


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