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Purification of Ubiquitinated p53 Proteins from Mammalian Cells
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Purification of Ubiquitinated p53 Proteins from Mammalian Cells

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Nrf2-lncRNA controls cell fate by modulating p53-dependent Nrf2 activation as an miRNA sponge for Plk2 and p21cip1

Min Sung Joo1,2, Sol-Bi Shin3,4, Eun Jung Kim1,2

  • 1College of Pharmacy, Seoul National University, Seoul, South Korea.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|March 22, 2019
PubMed

Insights

A novel long noncoding RNA (lncRNA), Nrf2-lncRNA, acts as a molecular rheostat. It activates the antioxidative Nrf2 pathway by sponging miRNAs, influencing cell fate and patient survival in cancer.

Area of Science:

  • Molecular Biology
  • Cellular Signaling
  • Cancer Research

Background:

  • The role of long noncoding RNAs (lncRNAs) in regulating cellular antioxidative capacity is largely unexplored.
  • Nuclear factor erythroid-2-related factor 2 (Nrf2) is a key regulator of cellular defense mechanisms against oxidative stress.

Purpose of the Study:

  • To identify and characterize novel lncRNAs involved in controlling antioxidative capacity.
  • To elucidate the mechanism by which a newly identified lncRNA, Nrf2-lncRNA, regulates Nrf2 activation and cellular fate.

Main Methods:

  • Identification of Nrf2-lncRNA from the upstream region of the microRNA 122 gene.
  • Experimental validation of Nrf2-lncRNA's cytoplasmic localization and competing endogenous RNA (ceRNA) activity.
  • Investigation of Nrf2-lncRNA's interaction with specific microRNAs (miRNAs) and target proteins (Plk2, p21cip1) under p53-activating conditions.
  • Correlation analysis of Nrf2-lncRNA expression with patient survival rates in hepatocellular carcinoma.

Main Results:

  • Nrf2-lncRNA functions as a miRNA sponge for miR-128 and miR-224, promoting the translation of polo-like kinase 2 (Plk2) and cyclin-dependent kinase inhibitor 1 (p21cip1).
  • This ceRNA activity induces the formation of a Plk2/Nrf2/p21cip1 complex, leading to Nrf2 activation under conditions of DNA damage and serum deprivation.
  • Nrf2-lncRNA expression decreases with apoptosis initiation, acting as a rheostat for cell fate determination.
  • Higher Nrf2-lncRNA levels correlate with improved recurrence-free survival in hepatocellular carcinoma patients.

Conclusions:

  • Nrf2-lncRNA fine-tunes cell fate decisions by modulating p53-dependent Nrf2 activation through its function as an miRNA sponge.
  • This mechanism enhances cellular antioxidative capacity under stress conditions, impacting cell survival and potentially cancer prognosis.
Keywords:
DNA damage responseand miR-122ceRNAhepatocelluar carcinomaoxidative stress

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