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Blood, Vol. 94 No. 4 (August 15), 1999:
pp. 1348-1358
Retinoic Acid Prevents Phosphorylation of pRB in Normal Human B
Lymphocytes: Regulation of Cyclin E, Cyclin A, and p21Cip1
Soheil Naderi and
Heidi Kiil Blomhoff
From the Department of Medical Biochemistry, Institute group of Basic
Medical Sciences, Faculty of Medicine, University of Oslo, Oslo,
Norway.
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-µ) 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 µmol/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 p21Cip1 could also be involved.
Thus, retinoic acid induced a rapid, but transient increased binding of
p21Cip1 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
p21Cip1, 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.
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