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The Upregulation of p27Kip1 by Rapamycin Results in G1
Arrest in Exponentially Growing T-Cell Lines
Shin Kawamata,
Hitoshi Sakaida,
Toshiyuki Hori,
Michiyuki Maeda, and
Takashi Uchiyama
From the Institute for Virus Research, Chest Disease Research
Institute, Kyoto University, Kyoto, Japan.
An immunosuppressant Rapamycin (Rap) has been reported to cause G1
arrest by inhibiting p70 S6 kinase and G1 cyclin/cdks kinase activities
when added to quiescent cells with mitogens. However, antiproliferative
effects of Rap on exponentially growing cells have been poorly
investigated. We examined the intracellular events after the treatment
of Rap in exponentially growing T cells and found that Rap upregulated
a cdks inhibitor, p27Kip1 at both mRNA and protein levels
in Rap-sensitive cells. Antiproliferative effect of Rap was mainly
ascribed to the inhibition of cyclin E/cdk2 kinase activity through the
formation of cyclin E/cdk2-p27Kip1 complex rather than
inhibition of p70 S6 kinase activity. Furthermore, we showed that
Rap-sensitive cells with elevated p27Kip1 expression lost
sensitivity to Rap when antisense p27Kip1 was introduced,
which indicates that the basal level of p27Kip1 is one of
the limiting factors that determine the sensitivity to Rap in already
cycling cells. These data suggest the presence of a putative threshold
level of p27Kip1 at late G1 phase in already cycling cells.
Rap may cause G1 arrest by upregulating the amount of
p27Kip1 beyond the threshold in some Rap-sensitive cells
that are exponentially growing.
Blood, Vol. 91 No. 2 (January 15), 1998:
pp. 561-569
© 1998 by The American Society of Hematology.
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