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Signal transduction in G0/G1-arrested mouse Y1 adrenocortical cells stimulated by ACTH and FGF2

A P Lepique1, F L Forti, M S Moraes

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

Endocrine Research
|February 24, 2001
PubMed

Insights

Adrenocorticotropic hormone (ACTH) inhibits fibroblast growth factor 2 (FGF2) induced cell proliferation in Y1 cells. This occurs via cAMP/PKA signaling, downregulating c-Myc and dephosphorylating AKT/PKB.

Area of Science:

  • Cell Biology
  • Molecular Endocrinology
  • Cancer Research

Background:

  • Adrenocorticotropic hormone (ACTH) and fibroblast growth factor 2 (FGF2) have opposing effects on Y1 adrenocortical tumor cell proliferation.
  • ACTH acts as an anti-mitogenic agent, while FGF2 is mitogenic, with FGF2's effects occurring at the G1 phase of the cell cycle.

Purpose of the Study:

  • To elucidate the anti-mitogenic mechanisms of ACTH in Y1 cells, specifically how it counteracts FGF2-induced proliferation.
  • To investigate the roles of c-Myc and AKT/PKB signaling pathways in ACTH's anti-mitogenic effects.

Main Methods:

  • Y1 adrenocortical tumor cells were used, some with PKA deficiency.
  • Experiments involved cell cycle arrest, mitogen stimulation (ACTH and FGF2), protein analysis (c-Myc, AKT/PKB), and gene manipulation (MycER chimera).
  • Specific inhibitors (PD98059, Wortmannin) and signaling pathway activators (Ras x GTP) were employed.

Main Results:

  • ACTH, mediated by cAMP/PKA, downregulates c-Myc post-transcriptionally and dephosphorylates AKT/PKB, counteracting FGF2's pro-mitogenic signaling.
  • FGF2 stabilizes c-Myc via ERK-MAPK and upregulates AKT/PKB through PI3K, while ACTH inhibits these effects.
  • Restoration of c-Myc levels via MycER chimera reversed ACTH's anti-mitogenic effect on DNA synthesis.

Conclusions:

  • ACTH employs dual anti-mitogenic mechanisms involving c-Myc downregulation and AKT/PKB dephosphorylation, both initiated via ACTH receptors and cAMP/PKA.
  • The Mad/Max/Myc transcription factor network's activity is sensitive to c-Myc levels in Y1 cells.
  • Targeting these pathways could offer strategies for controlling adrenocortical tumor cell proliferation.

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