Aberrant regulation and function of wild-type p53 in radioresistant melanoma cells

K. Satyamoorthy, N. H. Chehab, M. J F Waterman, M. C. Lien, W. S. El-Deiry, M. Herlyn, T. D. Halazonetis

    Research output: Contribution to journalArticle

    84 Citations (Scopus)

    Abstract

    Sporadic human tumors and the hereditary cancer predisposition syndrome Li-Fraumeni are frequently associated with mutations in the p53 tumor suppressor gene that compromise its ability to function as a DNA damage checkpoint. A subset of Li-Fraumeni patients with wild-type p53 alleles have mutations in chk2/hcds1, one of the genes signaling the presence of DNA damage to the p53 protein. This suggests that p53 may be kept inactive in human cancer by mutations targeting DNA damage signaling pathways. Melanoma cells are highly radioresistant, yet they express wild-type p53 protein, raising the possibility of defects in the pathways that activate p53 in response to DNA damage. We have described a chk2/hcds1-independent DNA damage signaling pathway that targets Ser-376 within the COOH terminus of p53 for dephosphorylation and leads to increased p53 functional activity. We now report that in several human melanoma cell lines that express wild-type p53, the phosphorylation state of Ser-376 was not regulated by DNA damage. In these cell lines, neither the endogenous wild-type p53 protein nor high levels of ectopic wild-type p53 led to cell cycle arrest or apoptosis. Thus, defective activation of p53 in response to DNA damage may underlie the radioresistance of human melanoma cells.

    Original languageEnglish
    Pages (from-to)467-474
    Number of pages8
    JournalCell Growth and Differentiation
    Volume11
    Issue number9
    Publication statusPublished - 2000

    Fingerprint

    DNA Damage
    Melanoma
    Mutation
    Hereditary Neoplastic Syndromes
    Cell Line
    Proteins
    Cell Cycle Checkpoints
    Tumor Suppressor Genes
    Neoplasms
    Alleles
    Phosphorylation
    Apoptosis
    Genes

    All Science Journal Classification (ASJC) codes

    • Cell Biology
    • Molecular Biology

    Cite this

    Satyamoorthy, K., Chehab, N. H., Waterman, M. J. F., Lien, M. C., El-Deiry, W. S., Herlyn, M., & Halazonetis, T. D. (2000). Aberrant regulation and function of wild-type p53 in radioresistant melanoma cells. Cell Growth and Differentiation, 11(9), 467-474.
    Satyamoorthy, K. ; Chehab, N. H. ; Waterman, M. J F ; Lien, M. C. ; El-Deiry, W. S. ; Herlyn, M. ; Halazonetis, T. D. / Aberrant regulation and function of wild-type p53 in radioresistant melanoma cells. In: Cell Growth and Differentiation. 2000 ; Vol. 11, No. 9. pp. 467-474.
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    abstract = "Sporadic human tumors and the hereditary cancer predisposition syndrome Li-Fraumeni are frequently associated with mutations in the p53 tumor suppressor gene that compromise its ability to function as a DNA damage checkpoint. A subset of Li-Fraumeni patients with wild-type p53 alleles have mutations in chk2/hcds1, one of the genes signaling the presence of DNA damage to the p53 protein. This suggests that p53 may be kept inactive in human cancer by mutations targeting DNA damage signaling pathways. Melanoma cells are highly radioresistant, yet they express wild-type p53 protein, raising the possibility of defects in the pathways that activate p53 in response to DNA damage. We have described a chk2/hcds1-independent DNA damage signaling pathway that targets Ser-376 within the COOH terminus of p53 for dephosphorylation and leads to increased p53 functional activity. We now report that in several human melanoma cell lines that express wild-type p53, the phosphorylation state of Ser-376 was not regulated by DNA damage. In these cell lines, neither the endogenous wild-type p53 protein nor high levels of ectopic wild-type p53 led to cell cycle arrest or apoptosis. Thus, defective activation of p53 in response to DNA damage may underlie the radioresistance of human melanoma cells.",
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    Satyamoorthy, K, Chehab, NH, Waterman, MJF, Lien, MC, El-Deiry, WS, Herlyn, M & Halazonetis, TD 2000, 'Aberrant regulation and function of wild-type p53 in radioresistant melanoma cells', Cell Growth and Differentiation, vol. 11, no. 9, pp. 467-474.

    Aberrant regulation and function of wild-type p53 in radioresistant melanoma cells. / Satyamoorthy, K.; Chehab, N. H.; Waterman, M. J F; Lien, M. C.; El-Deiry, W. S.; Herlyn, M.; Halazonetis, T. D.

    In: Cell Growth and Differentiation, Vol. 11, No. 9, 2000, p. 467-474.

    Research output: Contribution to journalArticle

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    Satyamoorthy K, Chehab NH, Waterman MJF, Lien MC, El-Deiry WS, Herlyn M et al. Aberrant regulation and function of wild-type p53 in radioresistant melanoma cells. Cell Growth and Differentiation. 2000;11(9):467-474.