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Involvement of p21cip-1 and p27kip-1 in the molecular mechanisms of steel
factor-induced proliferative synergy in vitro and of p21cip-1 in the
maintenance of stem/progenitor cells in vivo
C Mantel, Z Luo, J Canfield, S Braun, C Deng and HE Broxmeyer
Department of Medicine (Hematology/Oncology), Indiana University School of
Medicine, Indianapolis 46202-5121, USA.
Steel factor (SLF) is a hematopoietic cytokine that synergizes with other
growth factors to induce a greatly enhanced proliferative state of
hematopoietic progenitor cells and factor-dependent cell lines. Even though
the in vivo importance of SLF in the maintenance and responsiveness of stem
and progenitor cells is well documented, the molecular mechanism involved
in its synergistic effects are mainly unknown. Some factor-dependent
myeloid cell lines respond to the synergistic proliferative effects of SLF
plus other cytokines in a manner similar to that of normal myeloid
progenitor cells from bone marrow and cord blood. We show here that SLF can
synergize with granulocyte-macrophage colony-stimulating factor (GM-CSF) to
induce an enhanced phosphorylation of the retinoblastoma gene product and a
synergistic increase in the total intracellular protein level of the
cyclin-dependent kinase inhibitor, p21cip-1, which is correlated with a
simultaneous decrease in p27kip-1 in the human factor-dependent myeloid
cell line, M07e. Moreover, these cytokines synergize to increase p21cip- 1
binding and decrease p27kip-1 binding to cyclin-dependent kinase-2 (cdk2),
an enzyme required for normal cell cycle progression; these inverse events
correlated with increased cdk2 kinase activity. It is also shown that
exogenous purified p21cip-1 can displace p27kip-1 already bound to cdk2 in
vitro. These data implicate increased p21cip-1 and decreased p27kip-1
intracellular concentrations and their stoichiometric interplay in the
enhanced proliferative status of cells stimulated by the combination of SLF
and GM-CSF. In support of these findings, it is shown that hematopoietic
progenitor cells from mice lacking p21cip-1 are defective in SLF
synergistic proliferative response in vitro. Moreover, the cycling status
of marrow and spleen progenitors and absolute numbers of marrow progenitors
were significantly decreased in the p21cip-1 -/-, compared with the +/+
mice. We conclude that the cdk threshold regulators p21cip-1 and p27kip- 1
play a critical role in the normal mitogenic response of M07e cells and
murine myeloid progenitor cells to these cytokines and particularly in the
SLF synergistic proliferative response that is important to the normal
maintenance of the stem/progenitor cell compartment.
Volume 88,
Issue 10,
pp. 3710-3719,
11/15/1996
Copyright © 1996 by The American Society of Hematology
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