Retinoic acid prevents phosphorylation of pRB in normal human B lymphocytes: regulation of cyclin E, cyclin A, and p21(Cip1).
The mechanisms underlying the growth-inhibitory effect of retinoids on normal human B lymphocytes are not well understood. We addressed this issue by examining the effect of retinoic acid on the cell cycle machinery involved in G1/S transition. When retinoic acid was administered to B cells stimulated into mid to late G1 by anti-IgM antibodies (anti-mu) and Staphylococcus aureus crude cell suspension (SAC), the phosphorylation of pRB required for S-phase entry was prevented in a time- and dose-dependent manner. Thus, 2-hour treatment with retinoic acid at the optimal concentration of 1 micromol/L prevented phosphorylation of pRB, and effects were noted at concentrations as low as 10 nmol/L. Based on our results, we suggest that the rapid effect of retinoic acid on pRB phosphorylation is due primarily to the reduced expression of cyclin E and cyclin A in late G1. This could lead to the diminished cyclin E- and cyclin A-associated kinase activities noted as early as 2 hours after addition of retinoic acid. Furthermore, our results imply that the transient induction of p21(Cip1) could also be involved. Thus, retinoic acid induced a rapid, but transient increased binding of p21(Cip1) to CDK2. The retinoic acid receptor (RAR) agonist TTNPB mimicked the key events affected by retinoic acid, such as pRB phosphorylation, cyclin E expression, and expression of p21(Cip1), whereas the RAR-selective antagonist Ro 41-5253 counteracted the effects of retinoic acid. This implies that retinoic acid mediates its growth-inhibitory effect on B lymphocytes via the nuclear receptors.
Naderi
S
S
Department of Medical Biochemistry, Institute group of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway.
Blomhoff
H K
HK
D001402:B-Lymphocytes / Q000166:cytology* / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects*; D002478:Cells, Cultured; D019925:Cyclin A / Q000378:metabolism*; D019927:Cyclin E / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism*; D006801:Humans; D007641:Keratolytic Agents / Q000494:pharmacology*; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology*
C493956:CDKN1A protein, human; D019925:Cyclin A; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D007641:Keratolytic Agents; D016160:Retinoblastoma Protein; D014212:Tretinoin