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Purification of Ubiquitinated p53 Proteins from Mammalian Cells
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5'-3'-UTR interactions regulate p53 mRNA translation and provide a target for modulating p53 induction after DNA

Jing Chen1, Michael B Kastan

  • 1Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.

Genes & Development
|September 15, 2010
PubMed

Insights

Ribosomal protein L26 (RPL26) enhances p53 protein production by increasing p53 mRNA translation. A specific RNA structure in p53 mRNA

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • RNA Biology

Background:

  • The tumor suppressor protein p53 plays a critical role in cellular responses to DNA damage and stress.
  • Regulation of p53 protein levels is crucial for preventing uncontrolled cell growth and cancer.
  • Ribosomal protein L26 (RPL26) has been implicated in enhancing p53 protein induction after DNA damage.

Purpose of the Study:

  • To investigate the mechanism by which RPL26 regulates p53 mRNA translation.
  • To identify the specific RNA elements involved in RPL26-mediated translational control of p53.
  • To explore the therapeutic potential of targeting this regulatory mechanism.

Main Methods:

  • Identification and characterization of a double-stranded RNA (dsRNA) region within the 5' and 3' untranslated regions (UTRs) of human p53 mRNA.
  • Site-directed mutagenesis of complementary sequences within the p53 mRNA UTRs to disrupt or restore RPL26 binding.
  • Oligonucleotide-based inhibition of the identified RNA structure in cellular models.
  • Assessment of p53 mRNA translation, p53 protein induction, and p53-mediated cell death following DNA damage and cellular stress.

Main Results:

  • A critical dsRNA region formed by complementary sequences in the 5'- and 3'-UTRs of human p53 mRNA was identified.
  • Mutations in this region abrogated RPL26 binding to p53 mRNA and its ability to stimulate p53 translation.
  • Compensatory mutations restored RPL26 binding and p53 translational regulation.
  • Oligonucleotides targeting this dsRNA region reduced RPL26 binding, p53 induction, and p53-mediated cell death after DNA damage and stress.

Conclusions:

  • RPL26-mediated translational enhancement of p53 is dependent on a specific RNA structure formed by complementary sequences in the 5'- and 3'-UTRs of p53 mRNA.
  • This RNA structure is essential for RPL26 binding and subsequent p53 induction.
  • Targeting this RNA-RPL26 interaction with small molecules or oligonucleotides offers a potential therapeutic strategy for modulating p53 responses in various cellular conditions.

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