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J. Biol. Chem., Vol. 277, Issue 48, 46831-46839, November 29, 2002
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From the Section of Gastroenterology, Veterans Affairs Boston
Healthcare System and Boston University School of Medicine,
Boston, Massachusetts, 02118
Gut-enriched Krüppel-like factor (GKLF,
KLF4) is an epithelial-specific transcription factor that expresses in
the gastrointestinal tract and mediates growth arrest of colonic
epithelium. The molecular mechanisms governing its growth inhibitory
effect have not been fully elucidated. In the present study, we showed
that induction of GKLF mRNA and protein expression by
interferon-
Gut-enriched Krüppel-like Factor Represses Ornithine
Decarboxylase Gene Expression and Functions as Checkpoint Regulator in
Colonic Cancer Cells*
treatment was associated with reduction of ornithine
decarboxylase (ODC) gene expression and enzyme activity in colon cancer
HT-29 cells. Overexpression of GKLF in HT-29 cells significantly
reduced ODC mRNA and protein levels as well as enzyme activity and
resulted in growth arrest, indicating that ODC might be a downstream
target of GKLF. This conclusion was further supported by data showing that GKLF mRNA and protein concentrations were the highest at the
G1/S boundary of the cell cycle, where ODC mRNA
and protein levels were the lowest and that overexpression of GKLF
resulted in cell arrested at the G1 phase. Reporter gene
transfection studies and electrophoretic mobility gel shift assays
demonstrated that GKLF repressed ODC promoter activity and that these
effects appeared to be mediated through interaction with a GC box in
the proximal portion of the promoter. Transfection studies using
reporter constructs and chromatin immunoprecipitation assays also
demonstrated that GKLF inhibited transactivation of the ODC gene by
interfering with the binding of Sp1 to the ODC promoter. These results
indicate that GKLF may function as a G1/S checkpoint
regulator and exert its growth arrest effect through down-regulation of
ODC gene expression. Furthermore, GKLF is a transcriptional repressor
of the ODC gene, and these effects are mediated by interaction with the
GC-rich region on the promoter.
*
This work was supported by United States Public Health
Services Grant CA-82593 (to C.-C. T.).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.
To whom correspondence should be addressed: Section of
Gastroenterology, Boston University School of Medicine, EBRC X-513, 650 Albany St., Boston, MA 02118. Tel.: 617-638-8330; Fax:
617-638-7785; E-mail: chichuan.tseng@bmc.org.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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