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Myc and PI3K/AKT signaling cooperatively repress FOXO3a-dependent PUMA and GADD45a gene expression

Stefano Amente1, Jiyuan Zhang, Miriam Lubrano Lavadera

  • 1Department of Structural and Functional Biology, University of Naples Federico II 80126 Naples, Italy.

Nucleic Acids Research
|August 13, 2011
PubMed

Insights

Myc protein inhibits cell cycle arrest by blocking growth-arresting genes like PUMA and GADD45a. This occurs when growth factors activate the PI3K/AKT pathway, leading to Myc binding to gene chromatin.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Growth factor withdrawal halts cell cycle progression by activating Forkhead box O (FOXO) transcription factors.
  • FOXO3a binds to target genes like PUMA and GADD45a, promoting cell cycle arrest.
  • Upon growth factor stimulation, FOXO3a activity is repressed, often via the PI3K/AKT pathway.

Purpose of the Study:

  • To investigate the role of Myc in the repression of FOXO3a-mediated transcription of PUMA and GADD45a.
  • To elucidate the mechanism by which Myc influences cell cycle progression in response to growth factors.

Main Methods:

  • Cell culture and serum stimulation experiments.
  • Chromatin immunoprecipitation (ChIP) assays to assess protein binding to gene promoters.
  • Western blotting to analyze protein levels and modifications (phosphorylation, acetylation, methylation).

Main Results:

  • Myc significantly and selectively represses FOXO3a-mediated transcription of PUMA and GADD45a.
  • In Myc-deprived cells, the inhibition of PUMA and GADD45a expression upon serum stimulation is impaired.
  • Myc is rapidly recruited to PUMA and GADD45a chromatin, displacing FOXO3a and altering histone modifications.

Conclusions:

  • Myc plays a crucial role in inhibiting FOXO3a-induced transcription of cell cycle-arresting genes PUMA and GADD45a.
  • Myc's action contributes to cell growth regulation by overriding cell cycle arrest signals.
  • These findings reveal a novel mechanism of Myc-mediated gene repression impacting cell proliferation.

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