Journal
ONCOGENE
Volume 28, Issue 1, Pages 73-84Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2008.370
Keywords
miR-21; AP-1; PDCD4; PTEN; RAS; thyroid tumorigenesis
Funding
- AIRC (Associazione Italiana per la Ricerca sul Cancro)
- AICR (Association for International Cancer Research, UK)
- AIRC and EU-Project-SIROCCO [LSHG-CT2006037900]
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The transcription factor AP-1 plays key roles in tumorigenesis, by regulating a variety of protein-coding genes, implicated in multiple hallmarks of cancer. Among non-coding genes, no AP-1 target has been described yet in tumorigenesis. MicroRNAs (miRNAs) are negative post-transcriptional regulators of protein-coding genes. miRNA expression signatures are highly relevant in cancer and several tumor-associated miRNAs (oncomirs) play critical roles in oncogenesis. Here, we show that the miRNA miR-21, which represents the most frequently upregulated oncomir in solid tumors, is induced by AP-1 in response to RAS. By analyzing validated miR-21 targets, we have found that the tumor suppressors PTEN and PDCD4 are downregulated by RAS in an AP-1- and miR-21-dependent fashion. We further show that, given the role of PDCD4 as negative regulator of AP-1, the miR-21-mediated downregulation of PDCD4 is essential for the maximal induction of AP-1 activity in response to RAS. Our data reveal a novel mechanism of positive autoregulation of the AP-1 complex in RAS transformation and disclose the function of oncomirs as critical targets and regulators of AP-1 in tumorigenesis.
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