Azoxymethane-induced pre-adipocyte factor 1 (Pref-1) functions as a differentiation inhibitor in colonic epithelial cells.
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, pre-adipocyte factor 1 (Pref-1), associated previously with suppression of adipocyte differentiation, was induced specifically by AOM in the distal colons of sensitive A/J mice (5.4-fold). Reverse transcription-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. Over-expression 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.
Dong
Mei
M
The University of Connecticut Health Center, Center for Molecular Medicine, Farmington, Connecticut, USA.
Guda
Kishore
K
Nambiar
Prashant R
PR
Nakanishi
Masako
M
Lichtler
Alexander C
AC
Nishikawa
Mitsuo
M
Giardina
Charles
C
Rosenberg
Daniel W
DW
D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001397:Azoxymethane / Q000494:pharmacology*; D002087:Butyrates / Q000494:pharmacology; D002135:Calcium-Binding Proteins; D002273:Carcinogens / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D003106:Colon; D017931:DNA Primers; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D007413:Intestinal Mucosa / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008806:Mice, Inbred AKR; D020133:Reverse Transcriptase Polymerase Chain Reaction
D002087:Butyrates; D002135:Calcium-Binding Proteins; D002273:Carcinogens; D017931:DNA Primers; C512925:Dlk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D000469:Alkaline Phosphatase; D053148:Caspase 3; D001397:Azoxymethane