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Nucleic Acids Research Advance Access published online on August 28, 2007
Nucleic Acids Research, doi:10.1093/nar/gkm649
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© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

RNA

Stabilization of SMAR1 mRNA by PGA2 involves a stem–loop structure in the 5' UTR

Lakshminarasimhan Pavithra1, Shravanti Rampalli1,3, Surajit Sinha1, Kadreppa Sreenath1, Richard G. Pestell2 and Samit Chattopadhyay1,*

1National Centre for Cell Science, Ganeshkhind, Pune 411007, Maharashtra, India and 2Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, USA

*To whom correspondence should be addressed. Tel: 91 20 2569 0922; Fax: 91 20 2569 2259; Email: samit{at}nccs.res.in

Received July 6, 2007. Revised August 3, 2007. Accepted August 3, 2007.

Prostaglandins are anticancer agents known to inhibit tumor cell proliferation both in vitro and in vivo by affecting the mRNA stability. Here we report that a MAR-binding protein SMAR1 is a target of Prostaglandin A2 (PGA2) induced growth arrest. We identify a regulatory mechanism leading to stabilization of SMAR1 transcript. Our results show that a minor stem and loop structure present in the 5' UTR of SMAR1 ({varphi}1-UTR) is critical for nucleoprotein complex formation that leads to SMAR1 stabilization in response to PGA2. This results in an increased SMAR1 transcript and altered protein levels, that in turn causes downregulation of Cyclin D1 gene, essential for G1/S phase transition. We also provide evidence for the presence of a variant 5' UTR SMAR1 ({varphi}17-UTR) in breast cancer-derived cell lines. This form lacks the minor stem and loop structure required for mRNA stabilization in response to PGA2. As a consequence of this, there is a low level of endogenous tumor suppressor protein SMAR1 in breast cancer-derived cell lines. Our studies provide a mechanistic insight into the regulation of tumor suppressor protein SMAR1 by a cancer therapeutic PGA2, that leads to repression of Cyclin D1 gene.

Present address: Shravanti Rampalli, Post doctoral fellow, Molecular medicine program, OHRI, 725, Park Dale Avenue, Ottawa ONKIY4E9, Canada


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