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Ribosomal proteins L11 and L5 activate TAp73 by overcoming MDM2 inhibition

X Zhou1, Q Hao1, Q Zhang1

  • 1Department of Biochemistry & Molecular Biology, Tulane Cancer Center; Tulane University School of Medicine; New Orleans, Louisiana, USA.

Cell Death and Differentiation
|October 11, 2014
PubMed

Insights

Ribosomal proteins RPL5 and RPL11 activate the TAp73 tumor suppressor by disrupting MDM2 binding, inhibiting tumor growth. This novel mechanism enhances TAp73

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Biology

Background:

  • Ribosomal proteins (RPs) regulate gene expression and cellular processes.
  • Some RPs activate the tumor suppressor p53 by inhibiting MDM2.
  • The p53 homolog TAp73 plays a crucial role in tumor suppression.

Purpose of the Study:

  • To investigate the role of RPL5 and RPL11 in regulating TAp73 transcriptional activity.
  • To elucidate the mechanism by which RPL5 and RPL11 affect TAp73 function.
  • To explore the potential of RPL5 and RPL11 as therapeutic targets in cancer.

Main Methods:

  • Investigated the interaction between RPL5, RPL11, TAp73, and MDM2 using co-immunoprecipitation assays.
  • Assessed TAp73 transcriptional activity by measuring the expression of target genes (p21, Puma) using quantitative PCR.
  • Evaluated the effects of RPL5 and RPL11 on TAp73-mediated apoptosis and cell cycle arrest using flow cytometry and Western blotting.
  • Utilized RNA interference (RNAi) to knock down RPL5, RPL11, or TAp73 expression in cancer cells.

Main Results:

  • RPL5 and RPL11 associate with TAp73's transactivation domain independently of MDM2.
  • RPL5 and RPL11 disrupt the MDM2-TAp73 interaction, enhancing TAp73 transcriptional activity.
  • Overexpression of RPL5 or RPL11 promotes TAp73-mediated apoptosis and antagonizes MDM2 suppression.
  • Ablation of RPL5 or RPL11 compromises TAp73 activity, reducing p21 and Puma expression.
  • Simultaneous knockdown of TAp73 and RPL5/RPL11 rescues 5-fluorouracil-induced S-phase arrest in p53-null cells.

Conclusions:

  • RPL5 and RPL11 activate TAp73 through a novel mechanism involving direct association with TAp73 and disruption of MDM2 binding.
  • These ribosomal proteins inhibit tumor cell proliferation and growth by enhancing TAp73-mediated tumor suppression.
  • RPL5 and RPL11 represent potential therapeutic targets for enhancing TAp73-driven anti-cancer responses.

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