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Effects of p27Kip1 on cell cycle status and viability in A549 lung adenocarcinoma cells

¹ Dept of Pulmonary Medicine, Yokohama City University Medical Center, Yokohama, ² Dept of Microbiology, Dokkyo University, School of Medicine, ³ Dept of Molecular Pharmacology and Neurobiology, Yokohama City University Graduate School of Medicine, Yokohama, ⁴ Dept of Pathology, Yokohama City University School of Medicine, Yokohama, and ⁵ Dept of Geriatric Medicine, University of Tokyo, Tokyo, Japan

CORRESPONDENCE: T. Matsuse, Dept of Pulmonary Medicine, Yokohama City University Medical Center, 4–57 Urahune-cho Minami-ku, Yokohama City 232-0024, Japan. Fax: 81 452412812. E-mail: matsuse-tky@umin.ac.jp

Keywords: Apoptosis, cell cycle, intracellular localisation, p27Kip1, phosphorylation

Received: August 22, 2003
Accepted January 20, 2004

T. Ishii is a Research Fellow of the Japan Society for the Promotion of Science. This study was supported by a grant from Grant-in-Aid for Scientific Research (B) (2) (#1355 7054) and partly supported by a grant from Research Fellowships of the Japan Society for the Promotion of Science for Young Scientists.

p27Kip1 is a cyclin-dependent kinase inhibitor, it negatively regulates G1 progression and is reported to modulate apoptosis. Phosphorylation of this protein is thought to regulate its intracellular localisation and affect its stability.

The aim of this study was to regulate p27Kip1 expression levels, and to examine how this protein affects cell cycle status and modulates viability in A549 lung adenocarcinoma cells. In addition, the association between phosphorylation status of p27Kip1 and its intracellular localisation was investigated, using expression vectors with cDNA of p27Kip1 or mutants in which the phosphorylation sites had been mutated.

Although overexpression of p27Kip1 reduced cell cycle progression, its removal did not change cell cycle status. Modest induction of p27Kip1 rescued adenovector-induced apoptosis and its removal with short interfering RNA increased spontaneous cell death. It was also observed that p27Kip1 localised mainly in the cytoplasm, and forced expression of p27Kip1 cDNA with the substitution of serine (S) 10, threonine (T) 157 and T198 to glutamate (phosphor-mimetic) induced its cytoplasmic localisation.

In conclusion, p27Kip1, when expressed physiologically, exists mainly in the cytoplasm, has little effect on cell cycle status and contributes viability in A549 lung adenocarcinoma cells. It was also surmised that intracellular localisation of p27Kip1 dominates its function and that its localisation was partly determined by its phosphorylation.

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