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An autoregulatory loop mediated by miR-21 and PDCD4 controls the AP-1 activity in RAS transformation

F Talotta1, A Cimmino, M R Matarazzo

  • 1Institute of Genetics and Biophysics A. Buzzati Traverso, CNR, Naples, Italy.

Oncogene
|October 14, 2008
PubMed

Insights

The transcription factor AP-1 induces the oncomir miR-21, which downregulates tumor suppressors PTEN and PDCD4. This miR-21 feedback loop is crucial for AP-1 activity in RAS-driven cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Gene Regulation

Background:

  • The transcription factor AP-1 is crucial in cancer development, regulating protein-coding genes.
  • AP-1's role in regulating non-coding genes during tumorigenesis remains largely undescribed.
  • MicroRNAs (miRNAs) are key regulators in cancer, with some acting as oncogenes (oncomirs).

Purpose of the Study:

  • To investigate the role of AP-1 in regulating non-coding genes, specifically miRNAs, in tumorigenesis.
  • To elucidate the mechanism by which AP-1 and miR-21 interact in RAS-driven cancers.
  • To identify novel regulatory pathways involving AP-1 and oncomirs in cancer.

Main Methods:

  • Analysis of AP-1-induced gene expression.
  • Validation of miR-21 targets.
  • Assessment of PTEN and PDCD4 downregulation.
  • Investigation of feedback mechanisms in AP-1 activity.

Main Results:

  • AP-1 induces the expression of miR-21, a frequently upregulated oncomir in solid tumors, in response to RAS signaling.
  • RAS signaling, via AP-1 and miR-21, downregulates the tumor suppressors PTEN and PDCD4.
  • PDCD4, a negative regulator of AP-1, is downregulated by miR-21, creating a positive feedback loop essential for maximal AP-1 activation.

Conclusions:

  • A novel mechanism of AP-1 positive autoregulation in RAS transformation is identified.
  • Oncomirs, like miR-21, function as critical targets and regulators of AP-1 in tumorigenesis.
  • This study reveals a new layer of gene regulation in cancer involving AP-1 and miRNAs.

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