Akt finds its new path to regulate cell cycle through modulating Skp2 activity and its destruction by APC/Cdh1

Daming Gao, Hiroyuki Inuzuka, Alan Tseng, Wenyi Wei

研究成果: Review article査読

22 被引用数 (Scopus)

抄録

Skp2 over-expression has been observed in many human cancers. However, the mechanisms underlying elevated Skp2 expression have remained elusive. We recently reported that Akt1, but not Akt2, directly controls Skp2 stability by interfering with its association with APC/Cdh1. As a result, Skp2 degradation is protected in cancer cells with elevated Akt activity. This finding expands our knowledge of how specific kinase cascades influence proteolysis governed by APC/Cdh1 complexes. However, it awaits further investigation to elucidate whether the PI3K/Akt circuit affects other APC/Cdh1 substrates. Our results further strengthen the argument that different Akt isoforms might have distinct, even opposing functions in the regulation of cell growth or migration. In addition, we noticed that Ser72 is localized in a putative Nuclear Localization Sequence (NLS), and that phosphorylation of Ser72 disrupts the NLS and thus promotes Skp2 cytoplasmic translocation. This finding links elevated Akt activity with the observed cytoplasmic Skp2 staining in aggressive breast and prostate cancer patients. Furthermore, it provides the rationale for the development of specific Akt1 inhibitors as efficient anti-cancer therapeutic agents.

本文言語English
論文番号11
ジャーナルCell Division
4
DOI
出版ステータスPublished - 2009 6月 23
外部発表はい

ASJC Scopus subject areas

  • 生化学
  • 分子生物学
  • 細胞生物学

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