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Rapamycin reduces fibroblast proliferation without causing quiescence and induces STAT5A/B-mediated cytokine

Zoe E Gillespie1,2, Kimberly MacKay3, Michelle Sander1

  • 1a Department of Food and Bioproduct Sciences ; University of Saskatchewan ; Saskatoon , Canada.

Nucleus (Austin, Tex.)
|December 15, 2015
PubMed

Insights

Rapamycin inhibits cell proliferation and alters chromosome positioning in fibroblasts. This drug uniquely modifies gene expression, boosting cytokine production via Signal Transducer and Activator of Transcription 5A/B (STAT5A/B) signaling.

Area of Science:

  • Cell Biology
  • Genomics
  • Molecular Biology

Background:

  • Rapamycin is a known inhibitor of the Target of Rapamycin (TOR) signaling pathway.
  • The effects of rapamycin on genome organization and function in normal primary cells are not well understood.

Purpose of the Study:

  • To investigate the impact of rapamycin on chromosome organization and gene expression in primary human fibroblasts.
  • To compare the cellular response to rapamycin with that of serum-reduced quiescence.

Main Methods:

  • Primary human foreskin fibroblasts were treated with rapamycin.
  • Chromosome positioning was analyzed using microscopy.
  • Transcriptome analysis was performed to compare gene expression patterns.
  • Promoter occupancy of transcription factors was assessed.

Main Results:

  • Rapamycin treatment decreased fibroblast proliferation without inducing cell death.
  • Chromosomes 18 and 10 were repositioned in rapamycin-treated cells, similar to quiescent cells.
  • Gene expression profiles differed significantly between rapamycin-treated and quiescent cells.
  • Rapamycin upregulated cytokine genes (e.g., IL-8, LIF) and increased STAT5A/B promoter occupancy.
  • Quiescent cells upregulated genes involved in complement and coagulation cascades.

Conclusions:

  • Rapamycin treatment in fibroblasts leads to decreased proliferation and altered chromosome territory positioning.
  • Rapamycin induces STAT5A/B-mediated gene expression changes, particularly upregulation of cytokines.
  • The study highlights distinct molecular responses to rapamycin compared to serum-induced quiescence.
Keywords:
RNA-seqSTAT5A/Bprimary fibroblastquiescencerapamycin

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