Proliferative signaling initiated in ACTH receptors.
This article reviews recent results of studies aiming to elucidate modes of integrating signals initiated in ACTH receptors and FGF2 receptors, within the network system of signal transduction found in Y1 adrenocortical cells. These modes of signal integration should be central to the mechanisms underlying the regulation of the G0-->G1-->S transition in the adrenal cell cycle. FGF2 elicits a strong mitogenic response in G0/G1-arrested Y1 adrenocortical cells, that includes a) rapid and transient activation of extracellular signal-regulated kinases-mitogen-activated protein kinases (ERK-MAPK) (2 to 10 min), b) transcription activation of c-fos, c-jun and c-myc genes (10 to 30 min), c) induction of c-Fos and c-Myc proteins by 1 h and cyclin D1 protein by 5 h, and d) onset of DNA synthesis stimulation within 8 h. ACTH, itself a weak mitogen, interacts with FGF2 in a complex manner, blocking the FGF2 mitogenic response during the early and middle G1 phase, keeping ERK-MAPK activation and c-Fos and cyclin D1 induction at maximal levels, but post-transcriptionally inhibiting c-Myc expression. c-Fos and c-Jun proteins are mediators in both the strong and the weak mitogenic responses respectively triggered by FGF2 and ACTH. Induction of c-Fos and stimulation of DNA synthesis by ACTH are independent of PKA and are inhibited by the PKC inhibitor GF109203X. In addition, ACTH is a poor activator of ERK-MAPK, but c-Fos induction and DNA synthesis stimulation by ACTH are strongly inhibited by the inhibitor of MEK1 PD98059.
Lotfi
C F
CF
Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Brasil.
Lepique
A P
AP
Forti
F L
FL
Schwindt
T T
TT
Eichler
C B
CB
Santos
M O
MO
Rebustini
I T
IT
Hajj
G N
GN
Juliano
L
L
Armelin
H A
HA
D000302:Adrenal Cortex / Q000166:cytology*; D000306:Adrenal Cortex Neoplasms; D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D002455:Cell Division / Q000502:physiology*; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D018043:Receptors, Corticotropin / Q000502:physiology*; D017468:Receptors, Fibroblast Growth Factor / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D014407:Tumor Cells, Cultured / Q000502:physiology
D018043:Receptors, Corticotropin; D017468:Receptors, Fibroblast Growth Factor; D011493:Protein Kinase C; D020929:Mitogen-Activated Protein Kinase Kinases