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J. Biol. Chem., Vol. 278, Issue 20, 17609-17614, May 16, 2003
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From the Department of Hematology and Oncology, Graduate
School of Medicine, Kyoto University, Kyoto 606-8507, Japan
kpm is a human serine/threonine
kinase that is homologous to Drosophila tumor suppressor
warts/lats and its mammalian homologue LATS1. In order to define
the biological function of kpm, we generated stable transfectants of
wild-type kpm (kpm-wt), a kinase-dead mutant of
kpm (kpm-kd), and luciferase in HeLa Tet-Off
cells under the tetracycline-responsive promoter. Western blot analysis
showed that high levels of expression of kpm-wt as well as kpm-kd with an apparent mass of 150 kDa were induced after the removal of doxycycline. Induction of kpm-wt expression resulted in a marked decline in viable cell number measured by both trypan blue dye exclusion and MTT assay, whereas that of kpm-kd or luciferase had no
effect. We then analyzed the cell cycle progression and apoptosis upon
induction of kpm expression. 2-3 days after removal of doxycycline,
cells underwent G2/M arrest, demonstrated by flow cytometric analysis of propidium iodide incorporation and MPM-2 reactivity. In vitro kinase assay showed that induction of
kpm-wt led to down-regulation of kinase activity of the
Cdc2-cyclin B complex, which was accompanied by an increase in the
hyperphosphorylated form of Cdc2 and a change of phosphorylation status
of Cdc25C. Furthermore, both DAPI staining and TUNEL assay
showed that the proportion of apoptotic cells increased as kpm
expression was induced. Taken together, these results indicate that kpm
negatively regulates cell growth by inducing G2/M arrest
and apoptotic cell death through its kinase activity.
Inhibition of Cell Growth by Conditional Expression of kpm, a
Human Homologue of Drosophila warts/lats Tumor
Suppressor*
*
This work was supported in part by grants-in-aid from the
Ministry of Education, Culture, Sports, Science and Technology.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Hematology
and Oncology, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawaracho, Sakyoku, Kyoto 606-8507, Japan. Tel.:
81-75-751-4964; Fax: 81-75-751-4963; E-mail:
thori@kuhp.kyoto-u.ac.jp.
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