Signal transduction in G0/G1-arrested mouse Y1 adrenocortical cells stimulated by ACTH and FGF2.
In G0/G1 cell cycle arrested mouse Y1 adrenocortical tumor cells ACTH39, a weak mitogen and strong anti-mitogenic agent, blocks FGF2 mitogenic activity at G1 phase, keeping untouched ERK-MAPK activation and c-Fos protein induction. Here we report two anti-mitogenic mechanisms initiated in ACTH receptors and mediated by cAMP/PKA: a) post-transcriptional down regulation of c-Myc protein; b) dephosphorylation of AKT/PKB. In Y-1 cells the activity of the Mad/Max/Myc network of transcription factors seems to be regulated by c-Myc levels. FGF2 induces c-myc gene and stabilizes c-Myc protein by a process dependent on ERK-MAPK (PD98059 sensitive), but not on PI3K (Wortmannin resistant). ACTH39, on the other hand, causes rapid decrease in c-Myc levels induced by FGF2 in wild type Y1 cells, but not in PKA-deficient Y1 clones. The ACTH inhibition of DNA synthesis stimulated by FGF2 is reversed by transient transfection and induction of the MycER chimera (fusion of c-Myc and estrogen-receptor), suggesting that c-Myc down regulation is an efficient anti-mitogenic mechanism activated by ACTH. Y1 cells display high constitutive levels of AKT/PKB, that is dependent on elevated Ras x GTP. FGF2 up regulates Ras x GTP, PI3K and AKT/PKB. ACTH antagonizes this mitogenic effect of FGF2, promoting rapid dephosphorylation of AKT/PKB.
Lepique
A P
AP
Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Brasil.
Forti
F L
FL
Moraes
M S
MS
Armelin
H A
HA
D000302:Adrenal Cortex / Q000187:drug effects / Q000473:pathology*; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology*; D000818:Animals; D015536:Down-Regulation; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D016193:G1 Phase / Q000502:physiology*; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D016192:Resting Phase, Cell Cycle / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D016222:Fibroblast Growth Factor 2; D000324:Adrenocorticotropic Hormone; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt