Maintenance of intestinal mucosal epithelial integrity requires cellular polyamines that regulate expression of various genes involved in cell proliferation, growth arrest and apoptosis. Our previous studies have shown that polyamines are essential for expression of the c-myc gene and that polyamine-induced c-Myc plays a critical role in stimulation of normal IEC (intestinal epithelial cell) proliferation, but the exact downstream targets of induced c-Myc are still unclear. The p21Cip1 protein is a major player in cell cycle control, which is primarily regulated at the transcriptional level. The current study was designed to determine whether induced c-Myc stimulates normal IEC proliferation by repressing p21Cip1 transcription following up-regulation of polyamines. Overexpression of the ODC (ornithine decarboxylase) gene increased levels of cellular polyamines, induced c-Myc expression and inhibited p21Cip1 transcription, as indicated by repression of p21Cip1 promoter activity and a decrease in p21Cip1 protein levels. In contrast, depletion of cellular polyamines by inhibiting ODC enzyme activity with α-difluoromethylornithine decreased c-Myc, but increased p21Cip1 transcription. Ectopic expression of wild-type c-myc not only inhibited basal levels of p21Cip1 transcription in control cells, but also prevented increased p21Cip1 in polyamine-deficient cells. Experiments using different p21Cip1 promoter mutants showed that transcriptional repression of p21Cip1 by c-Myc was mediated through Miz-1- and Sp1-binding sites within the proximal region of the p21Cip1 promoter in normal IECs. These findings confirm that p21Cip1 is one of the direct mediators of induced c-Myc following increased polyamines and that p21Cip1 repression by c-Myc is implicated in stimulation of normal IEC proliferation.
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Research Article|
August 15 2006
Polyamine-modulated c-Myc expression in normal intestinal epithelial cells regulates p21Cip1 transcription through a proximal promoter region
Lan Liu;
Lan Liu
*Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, U.S.A.
†Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201, U.S.A.
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Xin Guo;
Xin Guo
*Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, U.S.A.
†Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201, U.S.A.
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Jaladanki N. Rao;
Jaladanki N. Rao
*Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, U.S.A.
†Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201, U.S.A.
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Tongtong Zou;
Tongtong Zou
*Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, U.S.A.
†Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201, U.S.A.
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Bernard S. Marasa;
Bernard S. Marasa
*Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, U.S.A.
‡Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, U.S.A.
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Jie Chen;
Jie Chen
*Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, U.S.A.
†Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201, U.S.A.
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Jose Greenspon;
Jose Greenspon
*Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, U.S.A.
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Robert A. Casero, Jr;
Robert A. Casero, Jr
§Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21231, U.S.A.
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Jian-Ying Wang
Jian-Ying Wang
1
*Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, U.S.A.
†Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201, U.S.A.
‡Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, U.S.A.
1To whom correspondence should be addressed (email jwang@smail.umaryland.edu).
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Publisher: Portland Press Ltd
Received:
February 06 2006
Revision Received:
May 10 2006
Accepted:
May 17 2006
Accepted Manuscript online:
May 17 2006
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2006
Biochem J (2006) 398 (2): 257–267.
Article history
Received:
February 06 2006
Revision Received:
May 10 2006
Accepted:
May 17 2006
Accepted Manuscript online:
May 17 2006
Citation
Lan Liu, Xin Guo, Jaladanki N. Rao, Tongtong Zou, Bernard S. Marasa, Jie Chen, Jose Greenspon, Robert A. Casero, Jian-Ying Wang; Polyamine-modulated c-Myc expression in normal intestinal epithelial cells regulates p21Cip1 transcription through a proximal promoter region. Biochem J 1 September 2006; 398 (2): 257–267. doi: https://doi.org/10.1042/BJ20060217
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