DeltaNp63 isoforms differentially regulate gene expression in squamous cell carcinoma

identification of Cox-2 as a novel p63 target

Linda Boldrup, Philip J Coates, Xiaolian Gu, Karin Nylander

    Research output: Contribution to journalArticle

    16 Citations (Scopus)

    Abstract

    The p53 homologue p63 produces six different isoforms that are important in development of epithelial tissues and squamous cell carcinoma of the head and neck (SCCHN). In SCCHN, the expression of p63 isoforms is highly complex, with over-expression of DeltaNp63 and p63beta isoforms in many tumours. To date, little is known about the functions of different DeltaNp63 isoforms and elucidating the distinctive properties of DeltaNp63 isoforms will help to clarify how they influence tumour biology. By gene expression profiling of SCCHN cells over-expressing the DeltaNp63 isoforms we identified different effects of the three isoforms, with DeltaNp63beta being more effective at gene induction than DeltaNp63alpha and DeltaNp63gamma, whereas DeltaNp63gamma was most effective at repressing gene expression. Thus, tumours expressing even low levels of DeltaNp63beta or DeltaNp63gamma may have distinct clinicopathological characteristics important for metastasis and therapeutic response. Induction of cyclooxygenase-2 (Cox-2) was shown by each isoform and data were confirmed by independent quantitative RT-PCR and western blotting. No direct binding of DeltaNp63 to the Cox-2 promoter could be seen, neither could any evidence for Cox-2 induction as a consequence of activated NF-kappaB pathway responses be found. As Cox-2 is known to inhibit radiotherapy responses in SCCHN patients, data indicate an additional mechanism through which DeltaNp63 acts to promote cell survival and influence therapeutic response of SCCHN. MIAME-compliant data have been deposited in the MIAME Express database (Accession No. E-MEXP-1842).
    Original languageEnglish
    Pages (from-to)428-436
    Number of pages9
    JournalJournal of Pathology
    Volume218
    Issue number4
    DOIs
    Publication statusPublished - 2009

    Fingerprint

    Cyclooxygenase 2
    Squamous Cell Carcinoma
    Protein Isoforms
    Gene Expression
    Neoplasms
    NF-kappa B
    Gene Expression Profiling
    Cell Survival
    Radiotherapy
    Epithelium
    Western Blotting
    Epithelial Cells
    Carcinoma, squamous cell of head and neck
    Databases
    Neoplasm Metastasis
    Polymerase Chain Reaction
    Therapeutics
    Genes

    Cite this

    Boldrup, Linda ; Coates, Philip J ; Gu, Xiaolian ; Nylander, Karin. / DeltaNp63 isoforms differentially regulate gene expression in squamous cell carcinoma : identification of Cox-2 as a novel p63 target. In: Journal of Pathology. 2009 ; Vol. 218, No. 4. pp. 428-436.
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    title = "DeltaNp63 isoforms differentially regulate gene expression in squamous cell carcinoma: identification of Cox-2 as a novel p63 target",
    abstract = "The p53 homologue p63 produces six different isoforms that are important in development of epithelial tissues and squamous cell carcinoma of the head and neck (SCCHN). In SCCHN, the expression of p63 isoforms is highly complex, with over-expression of DeltaNp63 and p63beta isoforms in many tumours. To date, little is known about the functions of different DeltaNp63 isoforms and elucidating the distinctive properties of DeltaNp63 isoforms will help to clarify how they influence tumour biology. By gene expression profiling of SCCHN cells over-expressing the DeltaNp63 isoforms we identified different effects of the three isoforms, with DeltaNp63beta being more effective at gene induction than DeltaNp63alpha and DeltaNp63gamma, whereas DeltaNp63gamma was most effective at repressing gene expression. Thus, tumours expressing even low levels of DeltaNp63beta or DeltaNp63gamma may have distinct clinicopathological characteristics important for metastasis and therapeutic response. Induction of cyclooxygenase-2 (Cox-2) was shown by each isoform and data were confirmed by independent quantitative RT-PCR and western blotting. No direct binding of DeltaNp63 to the Cox-2 promoter could be seen, neither could any evidence for Cox-2 induction as a consequence of activated NF-kappaB pathway responses be found. As Cox-2 is known to inhibit radiotherapy responses in SCCHN patients, data indicate an additional mechanism through which DeltaNp63 acts to promote cell survival and influence therapeutic response of SCCHN. MIAME-compliant data have been deposited in the MIAME Express database (Accession No. E-MEXP-1842).",
    author = "Linda Boldrup and Coates, {Philip J} and Xiaolian Gu and Karin Nylander",
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    DeltaNp63 isoforms differentially regulate gene expression in squamous cell carcinoma : identification of Cox-2 as a novel p63 target. / Boldrup, Linda; Coates, Philip J; Gu, Xiaolian; Nylander, Karin.

    In: Journal of Pathology, Vol. 218, No. 4, 2009, p. 428-436.

    Research output: Contribution to journalArticle

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    T1 - DeltaNp63 isoforms differentially regulate gene expression in squamous cell carcinoma

    T2 - identification of Cox-2 as a novel p63 target

    AU - Boldrup, Linda

    AU - Coates, Philip J

    AU - Gu, Xiaolian

    AU - Nylander, Karin

    N1 - (c) 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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    N2 - The p53 homologue p63 produces six different isoforms that are important in development of epithelial tissues and squamous cell carcinoma of the head and neck (SCCHN). In SCCHN, the expression of p63 isoforms is highly complex, with over-expression of DeltaNp63 and p63beta isoforms in many tumours. To date, little is known about the functions of different DeltaNp63 isoforms and elucidating the distinctive properties of DeltaNp63 isoforms will help to clarify how they influence tumour biology. By gene expression profiling of SCCHN cells over-expressing the DeltaNp63 isoforms we identified different effects of the three isoforms, with DeltaNp63beta being more effective at gene induction than DeltaNp63alpha and DeltaNp63gamma, whereas DeltaNp63gamma was most effective at repressing gene expression. Thus, tumours expressing even low levels of DeltaNp63beta or DeltaNp63gamma may have distinct clinicopathological characteristics important for metastasis and therapeutic response. Induction of cyclooxygenase-2 (Cox-2) was shown by each isoform and data were confirmed by independent quantitative RT-PCR and western blotting. No direct binding of DeltaNp63 to the Cox-2 promoter could be seen, neither could any evidence for Cox-2 induction as a consequence of activated NF-kappaB pathway responses be found. As Cox-2 is known to inhibit radiotherapy responses in SCCHN patients, data indicate an additional mechanism through which DeltaNp63 acts to promote cell survival and influence therapeutic response of SCCHN. MIAME-compliant data have been deposited in the MIAME Express database (Accession No. E-MEXP-1842).

    AB - The p53 homologue p63 produces six different isoforms that are important in development of epithelial tissues and squamous cell carcinoma of the head and neck (SCCHN). In SCCHN, the expression of p63 isoforms is highly complex, with over-expression of DeltaNp63 and p63beta isoforms in many tumours. To date, little is known about the functions of different DeltaNp63 isoforms and elucidating the distinctive properties of DeltaNp63 isoforms will help to clarify how they influence tumour biology. By gene expression profiling of SCCHN cells over-expressing the DeltaNp63 isoforms we identified different effects of the three isoforms, with DeltaNp63beta being more effective at gene induction than DeltaNp63alpha and DeltaNp63gamma, whereas DeltaNp63gamma was most effective at repressing gene expression. Thus, tumours expressing even low levels of DeltaNp63beta or DeltaNp63gamma may have distinct clinicopathological characteristics important for metastasis and therapeutic response. Induction of cyclooxygenase-2 (Cox-2) was shown by each isoform and data were confirmed by independent quantitative RT-PCR and western blotting. No direct binding of DeltaNp63 to the Cox-2 promoter could be seen, neither could any evidence for Cox-2 induction as a consequence of activated NF-kappaB pathway responses be found. As Cox-2 is known to inhibit radiotherapy responses in SCCHN patients, data indicate an additional mechanism through which DeltaNp63 acts to promote cell survival and influence therapeutic response of SCCHN. MIAME-compliant data have been deposited in the MIAME Express database (Accession No. E-MEXP-1842).

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