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Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av Prof. Lineu Prestes de Oliveira, 748, sala 924, São Paulo-SP, 05508-900, Brasil

(Requests for offprints should be addressed to Hugo A Armelin; Email: haarmeli{at}quim.iq.usp.br)

ACTH is the hormone known to control adrenal cortex function and maintenance in the intact animal but, in culture, it inhibits proliferation of adrenocortical cells from different mammalian species, a puzzle that has remained unsolved for nearly 30 years. In this paper we compare ACTH and fibroblast growth factor 2 (FGF2) antagonistic effects on the cell cycle in the Y1 cell line, a functional lineage of mouse adreno-cortical tumor cells. This cell line displays chronic high levels of c-Ki-Ras-GTP, high active constitutive levels of phosphatidylinositol 3-OH kinase/Protein Kinase B (PI3K/AKT) and low constitutive basal expression of c-Myc, which accounts for a minor deregulation of the cell cycle. In G₀/G₁-arrested Y1 cells, over-expression of the dominant negative mutant HaRasN17 drastically reduces c-Ki-Ras-GTP levels, eliminating basal c-Myc expression and basal S phase entry. PI3K/Akt seems to be the downstream pathway from c-Ki-ras for deregulation of c-Myc basal expression, since wortmannin abolishes c-Myc expression in serum-starved, G₀/G₁-arrested Y1 cells. FGF2 is a strong mitogen for Y1 cells, promoting – in a manner dependent on the MEK/ERK pathway – c-myc transcription induction, c-Myc protein stabilization and S phase entry in G₀/G₁-arrested Y1 cells. On the other hand, ACTH causes c-Myc protein destabilization, partially blocking S phase entry induced by FGF2, by a process dependent on the cAMP/protein kinase A (PKA) pathway. The whole pathway activated by ACTH to destabilize c-Myc protein in Y1 cells might comprise the following steps: ACTH receptor cAMP/PKA Akt deactivation GSK3 activity liberation c-Myc Thr58 phosphorylation.

We demonstrate that c-Myc regulation is a central key in the cell cycle control by these factors, since enforced expression of c-Myc through the MycER chimera abrogates the ACTH inhibitory effect over FGF2-induced S phase entry.

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