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ACTH inhibits A Ras-dependent anti-apoptotic and mitogenic pathway in mouse Y1 adrenocortical cells

F L Forti1, H A Armelin

  • 1Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Brasil.

Endocrine Research
|February 24, 2001
PubMed

Insights

Mouse Y1 tumor cells show high Ras x GTP, leading to increased AKT/PKB phosphorylation. Adrenocorticotropic hormone (ACTH) inhibits this pathway, suggesting a role in ACTH-mediated growth inhibition.

Area of Science:

  • Cell biology
  • Molecular endocrinology
  • Oncology

Background:

  • Mouse Y1 adrenocortical tumor cells exhibit c-Ki-ras gene amplification and overexpression.
  • These cells display high constitutive levels of Ras x GTP, a key signaling molecule.

Purpose of the Study:

  • To investigate the role of Ras x GTP and phosphoinositide 3-kinase (PI3K) in regulating AKT/protein kinase B (PKB) phosphorylation in Y1 cells.
  • To determine the effect of adrenocorticotropic hormone (ACTH) on AKT/PKB signaling in these cells.

Main Methods:

  • Analysis of Ras x GTP levels.
  • Assessment of AKT/PKB phosphorylation status.
  • Investigation of signaling pathways involving PI3K, cyclic adenosine monophosphate (cAMP), and protein kinase A (PKA).

Main Results:

  • Y1 cells constitutively display high levels of phosphorylated AKT/PKB, dependent on Ras x GTP and PI3K.
  • ACTH rapidly induces dephosphorylation of AKT/PKB in a cAMP/PKA-dependent manner.
  • This ACTH-induced inhibition affects both anti-apoptotic and mitogenic signaling.

Conclusions:

  • The Ras/PI3K pathway is crucial for constitutive AKT/PKB activation in Y1 adrenocortical tumor cells.
  • ACTH-mediated inhibition of the AKT/PKB pathway is a significant mechanism underlying its growth-inhibitory effects on Y1 cells.
  • These findings highlight the complex interplay between oncogenic signaling and hormonal regulation in adrenocortical tumorigenesis.

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