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Phospholipase A/Acyltransferase enzyme activity of H-rev107 inhibits the H-RAS signaling pathway
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  • 作者:Chun-Hua Wang (13)
    Rong-Yaun Shyu (8) (9)
    Chang-Chieh Wu (10)
    Tzung-Chieh Tsai (11)
    Lu-Kai Wang (12)
    Mao-Liang Chen (13)
    Shun-Yuan Jiang (13)
    Fu-Ming Tsai (13)

    13. Department of Research
    ; Taipei Tzuchi Hospital ; The Buddhist Tzuchi Medical Foundation ; New Taipei City ; Taiwan
    8. Department of Internal Medicine
    ; Taipei Tzuchi Hospital ; The Buddhist Tzuchi Medical Foundation ; New Taipei City ; Taiwan
    9. School of Medicine
    ; Tzu Chi University ; Hualien ; Taiwan
    10. Department of Surgery
    ; Tri-Service General Hospital ; National Defense Medical Center ; Taipei ; Taiwan
    11. Department of Microbiology
    ; Immunology and Biopharmaceuticals ; National Chiayi University ; Chiayi ; Taiwan
    12. Graduate Institute of Life Sciences
    ; National Defense Medical Center ; Taipei ; Taiwan
  • 关键词:H ; rev107 ; HRASLS3 ; PLA2G16 ; H ; RAS ; Phospholipase A/acyltransferase ; Acyl ; biotin exchange assay
  • 刊名:Journal of Biomedical Science
  • 出版年:2014
  • 出版时间:December 2014
  • 年:2014
  • 卷:21
  • 期:1
  • 全文大小:563 KB
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  • 刊物类别:Biomedical and Life Sciences
  • 刊物主题:Biomedicine
    Biomedicine
  • 出版者:Springer Netherlands
  • ISSN:1423-0127
文摘
Background H-rev107, also called HRASLS3 or PLA2G16, is a member of the HREV107 type II tumor suppressor gene family. Previous studies showed that H-rev107 exhibits phospholipase A/acyltransferase (PLA/AT) activity and downregulates H-RAS expression. However, the mode of action and the site of inhibition of H-RAS by H-rev107 are still unknown. Results Our results indicate that H-rev107 was co-precipitated with H-RAS and downregulated the levels of activated RAS (RAS-GTP) and ELK1-mediated transactivation in epidermal growth factor-stimulated and H-RAS-cotransfected HtTA cervical cancer cells. Furthermore, an acyl-biotin exchange assay demonstrated that H-rev107 reduced H-RAS palmitoylation. H-rev107 has been shown to be a PLA/AT that is involved in phospholipid metabolism. Treating cells with the PLA/AT inhibitor arachidonyl trifluoromethyl ketone (AACOCF3) or methyl arachidonyl fluorophosphate (MAFP) alleviated H-rev107-induced downregulation of the levels of acylated H-RAS. AACOCF3 and MAFP also increased activated RAS and ELK1-mediated transactivation in H-rev107-expressing HtTA cells following their treatment with epidermal growth factor. In contrast, treating cells with the acyl-protein thioesterase inhibitor palmostatin B enhanced H-rev107-mediated downregulation of acylated H-RAS in H-rev107-expressing cells. Palmostatin B had no effect on H-rev107-induced suppression of RAS-GTP levels or ELK1-mediated transactivation. These results suggest that H-rev107 decreases H-RAS activity through its PLA/AT activity to modulate H-RAS acylation. Conclusions We made the novel observation that H-rev107 decrease in the steady state levels of H-RAS palmitoylation through the phospholipase A/acyltransferase activity. H-rev107 is likely to suppress activation of the RAS signaling pathway by reducing the levels of palmitoylated H-RAS, which decreases the levels of GTP-bound H-RAS and also the activation of downstream molecules. Our study further suggests that the PLA/AT activity of H-rev107 may play an important role in H-rev107-mediated RAS suppression.

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