Proteomics analysis of H-RAS-mediated oncogenic transformation in a genetically defined human ovarian cancer model

Travis Young, Fang Mei, Jinsong Liu, Robert C. Bast, Alexander Kurosky, Xiaodong Cheng

    Research output: Contribution to journalArticle

    21 Citations (Scopus)

    Abstract

    RAS is a small GTP binding protein mutated in approximately 30% human cancer. Despite its important role in the initiation and progression of human cancer, the underlying mechanism of RAS-induced human epithelial transformation remains elusive. In this study, we probe the cellular and molecular mechanisms of RAS-mediated transformation, by profiling two human ovarian epithelial cell lines. One cell line was immortalized with SV40 T/t antigens and the human catalytic subunit of telomerase (T29), while the second cell line was transformed with an additional oncogenic rasv12 allele (T29H). In total, 32 proteins associated with RAS-mediated transformation have been identified using peptide mass fingerprinting. These protein targets are involved in several cellular pathways, including metabolism, redox balance, calcium signaling, apoptosis, and cellular methylation. One such target, the 40 kDa procaspase 4 is significantly upregulated at the protein level in RAS-transformed T29H cells, related directly to signaling through MEK, but not PI3 kinase. Cellular caspase 4 activity is, however, suppressed in the T29H cells, suggesting that the maturation process of caspase 4 is abrogated in RAS-transformed T29H cells. Consistent with this notion, transformed T29H cells were less susceptible to the toxic effects of anti-Fas antibody than were immortalized, nontransformed T29 cells, associated with less activation of caspase 4. This study demonstrates that functional proteomic analysis of a genetically defined cancer model provides a powerful approach toward systematically identifying cellular targets associated with oncogenic transformation.

    Original languageEnglish (US)
    Pages (from-to)6174-6184
    Number of pages11
    JournalOncogene
    Volume24
    Issue number40
    DOIs
    StatePublished - Sep 8 2005

    Fingerprint

    Proteomics
    Ovarian Neoplasms
    Caspases
    Polyomavirus Transforming Antigens
    Molecular Probes
    Cell Line
    Neoplasms
    Transformed Cell Line
    Proteins
    Peptide Mapping
    Calcium Signaling
    Poisons
    Telomerase
    Mitogen-Activated Protein Kinase Kinases
    Phosphatidylinositol 3-Kinases
    GTP-Binding Proteins
    Methylation
    Oxidation-Reduction
    Anti-Idiotypic Antibodies
    Epithelial Cells

    Keywords

    • Caspase 4
    • Mass spectrometry
    • Ovarian cancer
    • Proteomics
    • Ras
    • Transformation

    ASJC Scopus subject areas

    • Molecular Biology
    • Cancer Research
    • Genetics

    Cite this

    Proteomics analysis of H-RAS-mediated oncogenic transformation in a genetically defined human ovarian cancer model. / Young, Travis; Mei, Fang; Liu, Jinsong; Bast, Robert C.; Kurosky, Alexander; Cheng, Xiaodong.

    In: Oncogene, Vol. 24, No. 40, 08.09.2005, p. 6174-6184.

    Research output: Contribution to journalArticle

    Young, Travis ; Mei, Fang ; Liu, Jinsong ; Bast, Robert C. ; Kurosky, Alexander ; Cheng, Xiaodong. / Proteomics analysis of H-RAS-mediated oncogenic transformation in a genetically defined human ovarian cancer model. In: Oncogene. 2005 ; Vol. 24, No. 40. pp. 6174-6184.
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