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p16( INK4a) positively regulates cyclin D1 and E2F1 through negative control of AUF1

Huda H Al-Khalaf1, Dilek Colak, Maher Al-Saif

  • 1Department of Biological and Medical Research, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Plos One
|July 30, 2011
PubMed
Abstract

Insights

The tumor suppressor p16(INK4a) controls cyclin D1 and E2F1 expression by stabilizing their mRNAs via AUF1 regulation. This reveals p16(INK4a) as a key regulator of cell cycle, transcription, and apoptosis.

Area of Science:

  • Cellular Biology
  • Molecular Oncology
  • Cancer Research

Background:

  • The cyclin-D/CDK4,6/p16(INK4a)/pRB/E2F pathway is crucial for cell cycle regulation and frequently disrupted in cancer.
  • The exact roles and interactions of pathway members, particularly p16(INK4a), remain incompletely understood.

Purpose of the Study:

  • To elucidate the precise function of p16(INK4a) in regulating the expression of key cell cycle and transcription factors.
  • To investigate the molecular mechanisms underlying p16(INK4a)-mediated control of gene expression and apoptosis.

Main Methods:

  • Utilized human and mouse cell lines for experiments.
  • Employed mRNA stabilization assays, RNA immunoprecipitation (RIP), RT-PCR, and siRNA-mediated gene silencing.
  • Conducted genome-wide gene expression microarray analysis and apoptosis assays.

Main Results:

  • Demonstrated that p16(INK4a) positively controls cyclin D1 and E2F1 expression by stabilizing their mRNAs through negative regulation of AUF1.
  • Confirmed AUF1 binding to cyclin D1 and E2F1 mRNAs and showed that AUF1 downregulation increases gene expression.
  • Identified p16(INK4a)-dependent regulation of numerous genes, including those in AUF1 and E2F1 regulons, and showed E2F1 mediates p16-dependent apoptosis induction.

Conclusions:

  • p16(INK4a) functions not only as a cell cycle inhibitor but also as a modulator of transcription and apoptosis.
  • These effects are mediated through the regulation of major transcription regulators AUF1 and E2F1, impacting mRNA stability and gene expression.

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