M. Fujii et al., INHIBITORS OF CGMP-DEPENDENT PROTEIN-KINASE BLOCK SENESCENCE INDUCED BY INACTIVATION OF T-ANTIGEN IN SV40-TRANSFORMED IMMORTAL HUMAN FIBROBLASTS, Oncogene, 11(4), 1995, pp. 627-634
Immortal human fibroblasts isolated following transfection with thermo
labile simian virus 40 T antigen lost division potential upon shift up
in temperature due to heat inactivation of the antigen. Such cells sh
owed a concomitant change in the distribution of a mortality marker, m
ortalin, from a juxtanuclear cap like distribution of immortal cells t
o a uniform cytosolic distribution of mortal cells. We made an attempt
to modulate the above inducible system of cellular senescence using v
arious protein kinase inhibitors. Among the indolocarbazole type inhib
itors tested, only KT5823, defined as a specific inhibitor of cGMP-dep
endent protein kinase, blocked the loss of division potential as deter
mined by cell growth and colony forming ability. This inhibitor also p
revented the above change in mortalin distribution due to temperature
shift. In addition, the isoquinoline sulfonamide derivatives H8, H9, H
88 and H89, all shown to inhibit cGMP-dependent protein kinase, suppre
ssed the senescence. Inhibitors specific to other types of protein kin
ases, protein phosphatases or tyrosine kinases tested had no effect. S
ince there was no difference between the effective and non-effective i
nhibitors in their effects on cell cycle progression, cell cycle arres
t by itself cannot account for the above phenomenon. These results sug
gest that a signaling pathway possibly mediated by cGMP-dependent prot
ein kinase is involved in the induction of cellular senescence.