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Ectopic over-expression of tristetraprolin in human cancer cells promotes biogenesis of let-7 by down-regulation of Lin28.

ABSTRACT: Tristetraprolin (TTP) is a AU-rich element (ARE) binding protein and exhibits suppressive effects on cell growth through down-regulation of ARE-containing oncogenes. The let-7 microRNA has emerged as a significant factor in tumor suppression. Both TTP and let-7 are often repressed in human cancers, thereby promoting oncogenesis by derepressing their target genes. In this work, an unexpected link between TTP and let-7 has been found in human cancer cells. TTP promotes an increase in expression of mature let-7, which leads to the inhibition of let-7 target gene CDC34 expression and suppresses cell growth. This event is associated with TTP-mediated inhibition of Lin28, which has emerged as a negative modulator of let-7. Lin28 mRNA contains ARE within its 3'-UTR and TTP enhances the decay of Lin28 mRNA through binding to its 3'-UTR. This suggests that the TTP-mediated down-regulation of Lin28 plays a key role in let-7 miRNA biogenesis in cancer cells.

SUBMITTER: Kim CW

PROVIDER: S-EPMC3351177 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Ectopic over-expression of tristetraprolin in human cancer cells promotes biogenesis of let-7 by down-regulation of Lin28.

Kim Chae Won CW Vo Mai-Tram MT Kim Hong Kyeung HK Lee Hyun Hee HH Yoon Nal Ae NA Lee Byung Ju BJ Min Young Joo YJ Joo Won Duk WD Cha Hee Jeong HJ Park Jeong Woo JW Cho Wha Ja WJ

Nucleic acids research 20111230 9

Tristetraprolin (TTP) is a AU-rich element (ARE) binding protein and exhibits suppressive effects on cell growth through down-regulation of ARE-containing oncogenes. The let-7 microRNA has emerged as a significant factor in tumor suppression. Both TTP and let-7 are often repressed in human cancers, thereby promoting oncogenesis by derepressing their target genes. In this work, an unexpected link between TTP and let-7 has been found in human cancer cells. TTP promotes an increase in expression of ...[more]

PMID: 22210895

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Project description:RationaleTumor necrosis factor-alpha (TNF-?) is a potent pro-inflammatory mediator and its expression is up-regulated in chronic obstructive pulmonary disease (COPD). Tristetraprolin (TTP) is implicated in regulation of TNF-? expression; however, whether TTP is involved in cigarette smoke-induced TNF-? expression has not been determined.MethodsTTP expression was examined by western blot analysis in murine alveolar macrophages and alveolar epithelial cells challenged without or with cigarette smoke extract (CSE). TNF-? mRNA stability, and the decay of TNF-? mRNA, were determined by real-time quantitative RT-PCR. TNF-? protein levels were examined at the same time in these cells. To identify the molecular mechanism involved, a construct expressing the human beta-globin reporter mRNA containing the TNF-? 3'-untranslated region was generated to characterize the TTP targeted site within TNF-? mRNA.ResultsCSE induced TTP down-regulation in alveolar macrophages and alveolar epithelial cells. Reduced TTP expression resulted in significantly increased TNF-? mRNA stability. Importantly, increased TNF-? mRNA stability due to impaired TTP function resulted in significantly increased TNF-? levels in these cells. Forced TTP expression abrogated the increased TNF-? mRNA stability and expression induced by CSE. By using the globin reporter construct containing TNF-? mRNA 3'-untranslated region, the data indicate that TTP directly targets the adenine- and uridine-rich region (ARE) of TNF-? mRNA and negatively regulates TNF-? expression at the post-transcriptional level.ConclusionThe data demonstrate that cigarette smoke exposure reduces TTP expression and impairs TTP function, resulting in significantly increased TNF-? mRNA stability and excessive TNF-? expression in alveolar macrophages and epithelial cells. The data suggest that TTP is a novel post-transcriptional regulator and limits excessive TNF-? expression and inflammatory response induced by cigarette smoke.

Dataset Information

Ectopic over-expression of tristetraprolin in human cancer cells promotes biogenesis of let-7 by down-regulation of Lin28.

Publications

Ectopic over-expression of tristetraprolin in human cancer cells promotes biogenesis of let-7 by down-regulation of Lin28.

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