Distinct modes of activation of phosphatidylinositol 3-kinase in response to cyclic adenosine 3', 5'-monophosphate or insulin-like growth factor I play different roles in regulation of cyclin D1 and p27Kip1 in FRTL-5 cells

Autor: Fukushima, Toshiaki, Nedachi, T., Akizawa, H., Akahori, M., Hakuno, F., Takahashi, S.
Jazyk: angličtina
Rok vydání: 2008
Předmět:
DNA Replication
medicine.medical_specialty
RNA
Messenger/genetics/metabolism

Immunoblotting
Gene Expression Regulation/drug effects
Cell Cycle/drug effects
Protein degradation
Cell Line
chemistry.chemical_compound
Phosphatidylinositol 3-Kinases
Endocrinology
Cyclin D1
Cyclin-dependent kinase
Internal medicine
medicine
Cyclic AMP
Animals
Immunoprecipitation
Phosphatidylinositol
RNA
Messenger

Insulin-Like Growth Factor I
DNA synthesis
biology
Kinase
Cyclin-Dependent Kinases/metabolism
Cell Cycle
Cyclin-Dependent Kinase Inhibitor p27/*metabolism
Cyclin D1/genetics/*metabolism
Blotting
Northern

DNA Replication/drug effects
Adenosine
Cyclin-Dependent Kinases
Cyclic AMP/*pharmacology
Rats
Enzyme Activation
Insulin-Like Growth Factor I/*pharmacology
chemistry
Gene Expression Regulation
biology.protein
Enzyme Activation/drug effects
Phosphatidylinositol 3-Kinases/*metabolism
CDK inhibitor
Cyclin-Dependent Kinase Inhibitor p27
medicine.drug
Zdroj: Endocrinology. 149(No. 7):3729-42
Popis: Bioactivities of IGFs in various cells are often potentiated in the presence of other hormones. In previous studies we showed that pretreatment of rat FRTL-5 thyroid cells with TSH or other cAMP-generating agents markedly potentiated DNA synthesis induced by IGF-I. Under these conditions we found that phosphatidylinositol (PI) 3-kinase was activated in response to either cAMP or IGF stimulus, and both activation modes were indispensable for the potentiation of DNA synthesis. The present studies were undertaken to elucidate how cAMP and/or IGF-I stimulus regulated the G1 cyclin-cyclin dependent kinase (CDK)-inhibitor system, and to determine the roles of PI 3-kinase activation by cAMP or IGF-I stimulus in this system. We found that cAMP pretreatment enhanced IGF-I-dependent increases in cyclin D1, due to synergistic increases in mRNA and elevation of translation rates. Furthermore, cAMP pretreatment enhanced IGF-I-induced protein degradation of the CDK inhibitor, p27Kip1. These changes well explained an increase in cyclin E, leading to marked activation of G1 CDKs, followed by retinoblastoma protein phosphorylation. Our results using a PI 3-kinase inhibitor showed that cAMP-dependent PI 3-kinase activation plays an important role in the increase in cyclin D1 translation. In contrast, IGF-I-dependent PI 3-kinase activation was required for the increase in cyclin D1 mRNA levels and degradation of p27Kip1. Together, the present study elucidates the role of cAMP and IGF-I in differentially activating PI 3-kinase as a mediator of multiple molecular events. These events converge in the regulation of cyclin D1 and p27Kip1, leading to cAMP-dependent potentiation of IGF-I-dependent CDK activation and DNA synthesis.
Databáze: OpenAIRE