Retinoic acid modulates the cell-cycle in fetal rat hepatocytes and HepG2 cells by regulating cyclin-cdk activities.
Retinoic acid (RA), the most biologically active metabolite of vitamin A, is known to modulate cell proliferation, apoptosis and differentiation, with different effects depending on the cellular context. Retinoic acid can exert its effects by directly or indirectly influencing the expression of genes involved in the control of cell proliferation. In the present report we investigate the possible correlation between the antiproliferative, differentiative and apoptotic effects previously observed on rat hepatocytes and HepG2 cells, with a possible modulation of cell-cycle regulators. We demonstrate that RA induces growth arrest and differentiation in HepG2 cells by influencing the activities of cyclin-cdk complexes involved in the regulation of G1/S transition and S-phase progression, in particular by modifying the binding of these complexes to p21 and p27 inhibitors. In fetal cells, however, the induction of apoptosis and differentiation by RA was obtained via inhibition of cyclin D1-cdk4 activity, as result of an increased binding to the p16 inhibitor. Retinoic acid also modulates c-myc and Bcl-2 expression. In conclusion, our data suggest that RA could be useful to regulate the reversion of transformed phenotype and could also be utilized as a chemiopreventive agent in cells of hepatic origin.
Alisi
A
A
Department of Cellular and Developmental Biology, University La Sapienza, Rome, Italy.
Leoni
Silvia
S
Piacentani
A
A
Conti Devirgiliis
L
L
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects*; D002478:Cells, Cultured / Q000187:drug effects; D019938:Cyclin D1 / Q000187:drug effects* / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D005333:Fetus; D015870:Gene Expression / Q000187:drug effects; D019254:Genes, bcl-2 / Q000187:drug effects; D016259:Genes, myc / Q000187:drug effects; D019942:Genes, p16 / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects*; D008099:Liver; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D019938:Cyclin D1; D014212:Tretinoin; D018844:Cyclin-Dependent Kinases