Molecular mechanisms of cell cycle control in the mouse Y1 adrenal cell line.
Y1 adrenocortical tumor cells possess amplified and overexpressed c-Ki-ras proto-oncogene, displaying chronic high levels of the c-Ki-Ras-GTP protein. Despite this oncogenic lesion, we previously reported that Y1 cells retain tight regulatory mechanisms of cell cycle control typified by the mitogenic response triggered by FGF2 in G0/G1-arrested cells. ACTH, on the other hand, elicits cAMP/PKA-mediated antimitogenic mechanisms involving Akt/PKB dephosphorylation/deactivation and c-Myc protein degradation, blocking G1 phase progression stimulated by FGF2. In this paper we report that ACTH does not directly antagonize any of the early or late sequential steps comprising the mitogenic response triggered by FGF2. In effect, ACTH targets deactivation of constitutively phosphorylated-Akt, restraining the potential of c-Ki-Ras-GTP to subvert Y1 cell cycle control. Thus, we can consider ACTH a tumor suppressor rather than an antimitogenic hormone. In addition, we present initial results showing that high constitutive levels of c-Ki-Ras-GTP render Y1 cells susceptible to dye upon FGF2 treatment. This surprising FGF2 death-effect, that is independent of the well known FGF2-mitogenic activity, might involve a natural unsuspected mechanism for restraining oncogene-induced proliferation.
Costa
Erico T
ET
Instituto de Química, Universidade de São Paulo, São Paulo, Brazil.
Forti
Fábio L
FL
Rocha
Kátia M
KM
Moraes
Miriam S
MS
Armelin
Hugo A
HA
D000306:Adrenal Cortex Neoplasms / Q000473:pathology* / Q000503:physiopathology; D000311:Adrenal Glands / Q000473:pathology* / Q000503:physiopathology; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000818:Animals; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D051379:Mice; D008938:Mitosis / Q000187:drug effects; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000494:pharmacology
D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D016222:Fibroblast Growth Factor 2; D000324:Adrenocorticotropic Hormone; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D016283:Proto-Oncogene Proteins p21(ras)