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AMPK-beta1 subunit is a p53-independent stress responsive protein that inhibits tumor cell growth upon forced

Jun Li1, Ping Jiang, Megan Robinson

  • 1Cancer Molecular Sciences, Pfizer Global Research and Development, Ann Arbor Laboratories, 2800 Plymouth Road, MI 48105, USA.

Carcinogenesis
|May 29, 2003
PubMed

Insights

AMP-activated protein kinase (AMPK) beta1 subunit is not a p53 target gene. It is induced by stress, like cold shock or etoposide, independently of p53, and inhibits tumor cell growth.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Signaling

Background:

  • The p53 signaling pathway is crucial for regulating cell growth arrest and apoptosis in response to cellular stress.
  • Identifying downstream targets of p53 is essential for understanding its tumor suppressor functions.

Purpose of the Study:

  • To identify genes regulated by p53-dependent cell growth arrest and apoptosis.
  • To investigate the role of the AMP-activated protein kinase (AMPK) beta1 subunit in p53 signaling and its potential impact on tumor cell growth.

Main Methods:

  • Gene expression profiling using Affymetrix GeneChip arrays in a human lung carcinoma cell line (H1299) with temperature-sensitive p53.
  • Bioinformatic analysis to identify p53 consensus binding sites in gene promoters.
  • In vitro gel retardation and in vivo chromatin immunoprecipitation assays to assess p53 binding.
  • Northern blot analysis to confirm gene expression patterns.
  • Overexpression studies in tumor cell lines to evaluate the functional significance of AMPK beta1.

Main Results:

  • 133 genes were identified as differentially expressed in response to p53-dependent conditions.
  • The AMPK beta1 subunit was significantly induced but lacked direct p53 binding sites in its promoter or first intron.
  • AMPK beta1 induction was p53-independent, occurring in p53-null cells under cold shock and in response to etoposide.
  • Forced expression of AMPK beta1 inhibited tumor cell growth in H1299 and U2-OS cell lines.

Conclusions:

  • The AMPK beta1 subunit is not a direct downstream target of p53.
  • AMPK beta1 expression is induced by cellular stress (cold shock, etoposide) in a p53-independent manner.
  • Induced AMPK beta1 expression plays a role in inhibiting tumor cell growth, suggesting a broader role in stress-induced cell cycle arrest and apoptosis.

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