Fbxw7β resides in the endoplasmic reticulum membrane and protects cells from oxidative stress

Akinobu Matsumoto, Yuki Tateishi, Ichiro Onoyama, Yasutaka Okita, Keiko Nakayama, Keiichi Nakayama

研究成果: ジャーナルへの寄稿記事

16 引用 (Scopus)

抄録

Oxidative stress has been implicated in cancer initiation and progression. Fbxw7 (also known as Fbw7, SEL-10, hCdc4, or hAgo) is the F-box protein subunit of an Skp1-Cul1-F-box (SCF)-type ubiquitin ligase complex that plays a central role in the degradation of oncoproteins such as c-Myc, c-Jun, Notch, and cyclin E. Fbxw7 is therefore thought to function as a tumor suppressor, and indeed the Fbxw7 gene is frequently mutated in many human malignancies. The Fbxw7 gene locus encodes three protein isoforms: Fbxw7α, Fbxw7β, and Fbxw7γ. Whereas Fbxw7α and Fbxw7γ are resident in the nucleus, Fbxw7β shows a cytoplasmic distribution suggestive of localization to the endoplasmic reticulum (ER). The specific function of Fbxw7β has remained unknown, however. We now show that Fbxw7β contains a putative transmembrane domain near its NH2-terminus, and topological analysis revealed that Fbxw7β is inserted in the ER membrane. Fbxw7β assembled with Skp1, Cul1, and Rbx1 to form an SCF complex, although the efficiency of this process appeared lower than that for Fbxw7α or Fbxw7γ. To explore the physiological role of Fbxw7β, we generated mice specifically lacking this isoform of Fbxw7. Although these animals did not exhibit any apparent abnormalities in development, primary cultures of neurons prepared from the mutant mice were more vulnerable to oxidative stress than were those prepared from wild-type mice. Conversely, overexpression of Fbxw7β rendered cells resistant to oxidative stress, without affecting sensitivity to ER stress or other apoptosis-inducing agents. Our results thus suggest that Fbxw7β contributes to the protection of cells from oxidative stress.

元の言語英語
ページ(範囲)749-755
ページ数7
ジャーナルCancer Science
102
発行部数4
DOI
出版物ステータス出版済み - 4 1 2011

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Endoplasmic Reticulum
Oxidative Stress
Cell Membrane
Protein Isoforms
F-Box Proteins
Cyclin E
Neoplasms
Endoplasmic Reticulum Stress
Cytoprotection
Oncogene Proteins
Protein Subunits
Ligases
Ubiquitin
Genes
Apoptosis
Neurons
Membranes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

これを引用

Fbxw7β resides in the endoplasmic reticulum membrane and protects cells from oxidative stress. / Matsumoto, Akinobu; Tateishi, Yuki; Onoyama, Ichiro; Okita, Yasutaka; Nakayama, Keiko; Nakayama, Keiichi.

:: Cancer Science, 巻 102, 番号 4, 01.04.2011, p. 749-755.

研究成果: ジャーナルへの寄稿記事

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abstract = "Oxidative stress has been implicated in cancer initiation and progression. Fbxw7 (also known as Fbw7, SEL-10, hCdc4, or hAgo) is the F-box protein subunit of an Skp1-Cul1-F-box (SCF)-type ubiquitin ligase complex that plays a central role in the degradation of oncoproteins such as c-Myc, c-Jun, Notch, and cyclin E. Fbxw7 is therefore thought to function as a tumor suppressor, and indeed the Fbxw7 gene is frequently mutated in many human malignancies. The Fbxw7 gene locus encodes three protein isoforms: Fbxw7α, Fbxw7β, and Fbxw7γ. Whereas Fbxw7α and Fbxw7γ are resident in the nucleus, Fbxw7β shows a cytoplasmic distribution suggestive of localization to the endoplasmic reticulum (ER). The specific function of Fbxw7β has remained unknown, however. We now show that Fbxw7β contains a putative transmembrane domain near its NH2-terminus, and topological analysis revealed that Fbxw7β is inserted in the ER membrane. Fbxw7β assembled with Skp1, Cul1, and Rbx1 to form an SCF complex, although the efficiency of this process appeared lower than that for Fbxw7α or Fbxw7γ. To explore the physiological role of Fbxw7β, we generated mice specifically lacking this isoform of Fbxw7. Although these animals did not exhibit any apparent abnormalities in development, primary cultures of neurons prepared from the mutant mice were more vulnerable to oxidative stress than were those prepared from wild-type mice. Conversely, overexpression of Fbxw7β rendered cells resistant to oxidative stress, without affecting sensitivity to ER stress or other apoptosis-inducing agents. Our results thus suggest that Fbxw7β contributes to the protection of cells from oxidative stress.",
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AU - Nakayama, Keiko

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