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PML nuclear bodies contribute to the basal expression of the mTOR inhibitor DDIT4

Jayme Salsman1, Alex Stathakis1, Ellen Parker1

  • 1Department of Pathology, Dalhousie University, Halifax, Nova Scotia, B3H 4R2, Canada.

Scientific Reports
|March 24, 2017
PubMed

Insights

Promyelocytic leukemia (PML) protein loss decreases basal DDIT4 expression, impacting mTOR signaling. This discovery reveals a new mechanism linking PML to cancer progression through gene regulation.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Cellular Stress Response

Background:

  • Promyelocytic leukemia (PML) protein is crucial for PML nuclear bodies (PML NBs), which regulate nuclear proteins and gene expression.
  • PML NBs are implicated in controlling mTOR signaling and cell fate decisions under stress.
  • Few genes directly associated with PML NBs have been identified.

Purpose of the Study:

  • To investigate the relationship between PML, PML NBs, and the expression of the mTOR inhibitor DDIT4 (also known as REDD1).
  • To determine the role of PML NBs in regulating basal and stress-induced DDIT4 expression.
  • To explore the potential link between PML and DDIT4 in cancer progression.

Main Methods:

  • PML depletion in U2OS cells and fibroblasts.
  • Quantitative reverse transcription PCR (RT-qPCR) for gene expression analysis.
  • DNA and RNA immuno-fluorescence in situ hybridization (immuno-FISH) to localize PML NBs relative to DDIT4 loci.
  • Analysis of publicly available cancer genomics data.

Main Results:

  • PML depletion led to decreased basal expression of DDIT4.
  • PML NBs were found in close proximity to actively transcribed DDIT4 gene loci.
  • PML loss did not prevent DDIT4 upregulation in response to metformin, hypoxia, or genotoxic stress.
  • A significant correlation between PML and DDIT4 expression was observed in multiple cancer types.

Conclusions:

  • PML NBs regulate basal DDIT4 gene expression.
  • PML loss may contribute to mTOR pathway activation in cancer by disrupting DDIT4 regulation.
  • This study uncovers a novel mechanism linking PML to cancer progression via dysregulated DDIT4 expression.

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