Suppression of centrosome amplification after DNA damage depends on p27 accumulation

Eiji Sugihara, Masayuki Kanai, Soichiro Saito, Takayuki Nitta, Hideo Toyoshima, Keiko Nakayama, Keiichi I. Nakayama, Kenji Fukasawa, Manfred Schwab, Hideyuki Saya, Masanao Miwa

研究成果: Article

32 引用 (Scopus)

抄録

The centrosome plays a fundamental role in cell division, cell polarity, and cell cycle progression. Centrosome duplication is mainly controlled by cyclin-dependent kinase 2 (CDK2)/cyclin E and cyclin A complexes, which are inhibited by the CDK inhibitors p21Cip1 and p27Kip1. It is thought that abnormal activation of CDK2 induces centrosome amplification that is frequently observed in a wide range of aggressive tumors. We previously reported that overexpression of the oncogene MYCN leads to centrosome amplification after DNA damage in neuroblastoma cells. We here show that centrosome amplification after γ-irradiation was caused by suppression of p27 expression in MYCN-overexpressing cells. We further show that p27-/- and p27+/- mouse embryonic fibroblasts and p27-silenced human cells exhibited a significant increase in centrosome amplification after DNA damage. Moreover, abnormal mitotic cells with amplified centrosomes were frequently observed in p27-silenced cells. In response to DNA damage, the level of p27 gradually increased in normal cells independently of the ataxia telangiectasia mutated/p53 pathway, whereas Skp2, an F-box protein component of an SCF ubiquitin ligase complex that targets p27, was reduced. Additionally, p27 levels in MYCN-overexpressing cells were restored by treatment with Skp2 small interfering RNA, indicating that down-regulation of p27 by MYCN was due to high expression of Skp2. These results suggest that the accumulation of p27 after DNA damage is required for suppression of centrosome amplification, thereby preventing chromosomal instability.

元の言語English
ページ(範囲)4020-4029
ページ数10
ジャーナルCancer Research
66
発行部数8
DOI
出版物ステータスPublished - 2006 4 15
外部発表Yes

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Centrosome
DNA Damage
Cyclin-Dependent Kinase 2
SKP Cullin F-Box Protein Ligases
F-Box Proteins
Cyclin A
Cyclin E
Ataxia Telangiectasia
Cell Polarity
Chromosomal Instability
Neuroblastoma
Oncogenes
Cell Division
Small Interfering RNA
Cell Cycle
Down-Regulation
Fibroblasts

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

これを引用

Sugihara, E., Kanai, M., Saito, S., Nitta, T., Toyoshima, H., Nakayama, K., ... Miwa, M. (2006). Suppression of centrosome amplification after DNA damage depends on p27 accumulation. Cancer Research, 66(8), 4020-4029. https://doi.org/10.1158/0008-5472.CAN-05-3250

Suppression of centrosome amplification after DNA damage depends on p27 accumulation. / Sugihara, Eiji; Kanai, Masayuki; Saito, Soichiro; Nitta, Takayuki; Toyoshima, Hideo; Nakayama, Keiko; Nakayama, Keiichi I.; Fukasawa, Kenji; Schwab, Manfred; Saya, Hideyuki; Miwa, Masanao.

:: Cancer Research, 巻 66, 番号 8, 15.04.2006, p. 4020-4029.

研究成果: Article

Sugihara, E, Kanai, M, Saito, S, Nitta, T, Toyoshima, H, Nakayama, K, Nakayama, KI, Fukasawa, K, Schwab, M, Saya, H & Miwa, M 2006, 'Suppression of centrosome amplification after DNA damage depends on p27 accumulation', Cancer Research, 巻. 66, 番号 8, pp. 4020-4029. https://doi.org/10.1158/0008-5472.CAN-05-3250
Sugihara E, Kanai M, Saito S, Nitta T, Toyoshima H, Nakayama K その他. Suppression of centrosome amplification after DNA damage depends on p27 accumulation. Cancer Research. 2006 4 15;66(8):4020-4029. https://doi.org/10.1158/0008-5472.CAN-05-3250
Sugihara, Eiji ; Kanai, Masayuki ; Saito, Soichiro ; Nitta, Takayuki ; Toyoshima, Hideo ; Nakayama, Keiko ; Nakayama, Keiichi I. ; Fukasawa, Kenji ; Schwab, Manfred ; Saya, Hideyuki ; Miwa, Masanao. / Suppression of centrosome amplification after DNA damage depends on p27 accumulation. :: Cancer Research. 2006 ; 巻 66, 番号 8. pp. 4020-4029.
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AU - Toyoshima, Hideo

AU - Nakayama, Keiko

AU - Nakayama, Keiichi I.

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