Ne. Zorn et Md. Sauro, RETINOIC ACID INDUCES TRANSLOCATION OF PROTEIN-KINASE-C (PKC) AND ACTIVATION OF NUCLEAR PKC (NPKC) IN RAT SPLENOCYTES, International journal of immunopharmacology, 17(4), 1995, pp. 303-311
Retinoic acid (RA), a vitamin A metabolite, has marked effects on grow
th of normal and malignant cells; however, the exact mechanism of acti
on remains unclear. The effect of two RA analogs, 13-cis-RA and all-tr
ans-RA, on transmembrane signalling processes was investigated in rat
splenocytes. Treatment of rat splenic cells with these retinoic acid a
nalogs resulted in translocation of protein kinase C (PKC) from the cy
tosol to the membrane. Previous studies have described nuclear RA rece
ptors (RARs and RXRs) for several species and the biologic activity of
RA has been shown to be mediated by specific interaction with these n
uclear receptors. Thus, activation of nuclear pool(s) of protein kinas
e C (nPKC) by RA analogs was also studied. Rat splenocyte nuclei pure
by enzymatic and electron microscope criteria demonstrated a biphasic
pattern of bell-shaped curves for both cis- and trans-RA with maximum
statistically significant peak of phosphate incorporation into endogen
ous substrates at 10(-16) M cis-RA and 10(-16)-10(-17) M trans-RA. A m
onoclonal antibody to PKC and the PKC inhibitors, H-7, sphingosine, an
d staurosporine, blocked the RA-stimulated nuclear phosphorylation. Th
e ability of RA to activate cell membrane PKC resulting in an increase
in particulate PKC activity correlates well with the activation of nP
KC since the particulate fraction would include nuclear enzyme systems
. This ability of RA to activate nPKC and possibly affect the growth s
tatus of a cell may provide a missing link to our understanding of the
cellular sites of action for this vitamin.