Upon Ras activation, ODC (ornithine decarboxylase) is markedly induced, and numerous studies suggest that ODC expression is controlled by Ras effector pathways. ODC is therefore a potential target in the treatment and prevention of Ras-driven tumours. In the present study we compared ODC mRNA translation profiles and stability in normal and Ras12V-transformed RIE-1 (rat intestinal epithelial) cells. While translation initiation of ODC increased modestly in Ras12V cells, ODC mRNA was stabilized 8-fold. Treatment with the specific mTORC1 [mTOR (mammalian target of rapamycin) complex 1] inhibitor rapamycin or siRNA (small interfering RNA) knockdown of mTOR destabilized the ODC mRNA, but rapamycin had only a minor effect on ODC translation initiation. Inhibition of mTORC1 also reduced the association of the mRNA-binding protein HuR with the ODC transcript. We have shown previously that HuR binding to the ODC 3′UTR (untranslated region) results in significant stabilization of the ODC mRNA, which contains several AU-rich regions within its 3′UTR that may act as regulatory sequences. Analysis of ODC 3′UTR deletion constructs suggests that cis-acting elements between base 1969 and base 2141 of the ODC mRNA act to stabilize the ODC transcript. These experiments thus define a novel mechanism of ODC synthesis control. Regulation of ODC mRNA decay could be an important means of limiting polyamine accumulation and subsequent tumour development.
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February 2012
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Research Article|
January 27 2012
Ornithine decarboxylase mRNA is stabilized in an mTORC1-dependent manner in Ras-transformed cells Available to Purchase
Sofia Origanti;
Sofia Origanti
1
*Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA 17033, U.S.A.
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Shannon L. Nowotarski;
Shannon L. Nowotarski
2
*Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA 17033, U.S.A.
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Theresa D. Carr;
Theresa D. Carr
*Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA 17033, U.S.A.
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Suzanne Sass-Kuhn;
Suzanne Sass-Kuhn
*Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA 17033, U.S.A.
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Lan Xiao;
Lan Xiao
†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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Jian-Ying Wang;
Jian-Ying Wang
†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.
§Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201, U.S.A.
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Lisa M. Shantz
Lisa M. Shantz
3
*Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA 17033, U.S.A.
3To whom correspondence should be addressed (email [email protected]).
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Publisher: Portland Press Ltd
Received:
August 09 2011
Revision Received:
October 31 2011
Accepted:
November 10 2011
Accepted Manuscript online:
November 10 2011
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem J (2012) 442 (1): 199–207.
Article history
Received:
August 09 2011
Revision Received:
October 31 2011
Accepted:
November 10 2011
Accepted Manuscript online:
November 10 2011
Citation
Sofia Origanti, Shannon L. Nowotarski, Theresa D. Carr, Suzanne Sass-Kuhn, Lan Xiao, Jian-Ying Wang, Lisa M. Shantz; Ornithine decarboxylase mRNA is stabilized in an mTORC1-dependent manner in Ras-transformed cells. Biochem J 15 February 2012; 442 (1): 199–207. doi: https://doi.org/10.1042/BJ20111464
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