Stabilization of SMAR1 mRNA by PGA2 involves a stem loop structure in the 5' UTR.
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 (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 (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.
Pavithra
Lakshminarasimhan
L
National Centre for Cell Science, Ganeshkhind, Pune 411007, Maharashtra, India.
Rampalli
Shravanti
S
Sinha
Surajit
S
Sreenath
Kadreppa
K
Pestell
Richard G
RG
Chattopadhyay
Samit
S
D020121:5' Untranslated Regions / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics*; D045744:Cell Line, Tumor; D056741:Cyclin D; D016213:Cyclins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics*; D009690:Nucleic Acid Conformation; D011454:Prostaglandins A / Q000494:pharmacology*; D020871:RNA Stability / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism*
D020121:5' Untranslated Regions; D000970:Antineoplastic Agents; C417914:BANP protein, human; D018797:Cell Cycle Proteins; D056741:Cyclin D; D016213:Cyclins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011454:Prostaglandins A; D012333:RNA, Messenger; C100008:prostaglandin A2