Role of Rac1 and Cdc42 in hypoxia induced p53 and von Hippel-Lindau suppression and HIF1α activation

Authors

  • Yan Xue,

    1. The State Key Laboratory of Cancer Biology, Xijing Hospital, The Fourth Military Medical University,Xi'an, Shaanxi Province, People's Republic of China
    Search for more papers by this author
  • Feng Bi,

    Corresponding author
    1. The State Key Laboratory of Cancer Biology, Xijing Hospital, The Fourth Military Medical University,Xi'an, Shaanxi Province, People's Republic of China
    Current affiliation:
    1. Laboratory of Signal Transduction and Molecular Targeting Therapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China
    • The State Key Laboratory of Cancer Biology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi Province 710032, People's Republic of China
    Search for more papers by this author
    • Fax: +86-29-82539041.

  • Xueyong Zhang,

    Corresponding author
    1. The State Key Laboratory of Cancer Biology, Xijing Hospital, The Fourth Military Medical University,Xi'an, Shaanxi Province, People's Republic of China
    • The State Key Laboratory of Cancer Biology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi Province 710032, People's Republic of China
    Search for more papers by this author
  • Siyuan Zhang,

    1. The State Key Laboratory of Cancer Biology, Xijing Hospital, The Fourth Military Medical University,Xi'an, Shaanxi Province, People's Republic of China
    Search for more papers by this author
  • Yanglin Pan,

    1. The State Key Laboratory of Cancer Biology, Xijing Hospital, The Fourth Military Medical University,Xi'an, Shaanxi Province, People's Republic of China
    Search for more papers by this author
  • Na Liu,

    1. The State Key Laboratory of Cancer Biology, Xijing Hospital, The Fourth Military Medical University,Xi'an, Shaanxi Province, People's Republic of China
    Search for more papers by this author
  • Yongquan Shi,

    1. The State Key Laboratory of Cancer Biology, Xijing Hospital, The Fourth Military Medical University,Xi'an, Shaanxi Province, People's Republic of China
    Search for more papers by this author
  • Xuebiao Yao,

    1. Laboratory for Cell Dynamics, School of Life Science, University of Science and Technology of China,Hefei, Anhui Province, People's Republic of China
    Search for more papers by this author
  • Yi Zheng,

    1. Division of Experimental Hematology, Children's Hospital Research Foundation, University of Cincinnati,Cincinnati, OH, USA
    Search for more papers by this author
  • Daiming Fan

    1. The State Key Laboratory of Cancer Biology, Xijing Hospital, The Fourth Military Medical University,Xi'an, Shaanxi Province, People's Republic of China
    Search for more papers by this author

Abstract

Low oxygen tension can influence tumor progression by enhancing angiogenesis, a process that may involve Rho GTPases whose activities have been implicated in tumorigenesis and metastasis. In the present study, we show that hypoxia can increase the mRNA levels and intracellular activities of Rac1 and Cdc42 in a time-dependent manner. The hypoxia-stimulated activities of Rac1 and Cdc42 could be blocked by the phosphatidylinositol 3′-kinase (PI3K) inhibitor LY294002 and the protein tyrosine kinase (PTK) inhibitor genistein but were not affected by the p38MAPK inhibitor SB203580 or the MEK-1 inhibitor PD98059, suggesting that the hypoxia-mediated signals were through PI3K and PTK. Correlating with the increased activities of Rac1 and Cdc42, the expression of the pro-angiogenesis factors HIF-1α and vascular endothelial growth factor (VEGF) was upregulated by hypoxia, whereas the expression of the tumor suppressors von Hippel-Lindau and p53 was down-regulated. Dominant negative N17Rac1 and N17Cdc42 could upregulate the expression of p53 and pVHL but downregulate that of HIF-1α and VEGF under hypoxia. Furthermore, the preconditioned medium from N17Rac1 or N17Cdc42-expressing gastric cancer cells was able to inhibit the proliferation of HUVECs. Our results indicate that PI3K and PTK-mediated activations of Rac1 and Cdc42 are involved in the hypoxia-induced production of angiogenesis-promoting factors and tumor suppressors, and suggest that the Rho family GTPases Rac1 and Cdc42 may contribute to the hypoxia-mediated angiogenesis. © 2006 Wiley-Liss, Inc.

Ancillary