OKADAIC ACID, CAMP, AND SELECTED NUTRIENTS INHIBIT HEPATOCYTE PROLIFERATION AT DIFFERENT STAGES IN G(1) - MODULATION OF THE CAMP EFFECT BY PHOSPHATASE INHIBITORS AND NUTRIENTS
G. Mellgren et al., OKADAIC ACID, CAMP, AND SELECTED NUTRIENTS INHIBIT HEPATOCYTE PROLIFERATION AT DIFFERENT STAGES IN G(1) - MODULATION OF THE CAMP EFFECT BY PHOSPHATASE INHIBITORS AND NUTRIENTS, Journal of cellular physiology, 163(2), 1995, pp. 232-240
The protein phosphatase inhibitor okadaic acid (>100 nM) caused an abr
upt and complete cessation of primary rat hepatocyte cell cycle progre
ssion at the restriction point in late G(1). A decline in the G(1)/S t
ransition rate was observed in response to elevated cAMP, excess selec
ted nutrients, and okadaic acid (<100 nM). Excess nutrients (40 mM glu
cose +/- 5 mM dihydroxyacetone) acted by imposing an incomplete block
in early G(1). The cAMP action was potentiated by the phosphatase inhi
bitor microcystin, which in itself did not affect DNA replication. Thi
s suggests that cAMP acted by phosphorylating substrate(s) that is dep
hosphorylated by a microcystin-sensitive phosphatase. The additive eff
ects of submaximal concentrations of okadaic acid and cAMP analogs ind
icated that okadaic acid and cAMP acted via different pathways. In con
clusion, okadaic acid, cAMP, and excess nutrients, acting through dist
inct pathways, inhibited hepatocytes in different parts of the G(1) ph
ase. (C) 1995 Wiley-Liss, Inc.