Abstract
Chemotherapeutic agents simultaneously induce transcription factors p53 and NFkappaB. p53 induction can activate an apoptotic program, and resistance to chemotherapy correlates with the loss of a functional p53 pathway. By contrast, NFkappaB prevents apoptosis in response to chemotherapeutic agents. We have analyzed the p53 response in IKK1/2(-/-) MEFs, which lack detectable NFkappaB activity. Compared to WT fibroblasts, IKK1/2(-/-) fibroblasts showed increased cell death and p53 induction in response to the chemotherapeutic agent, doxorubicin. Reconstitution of IKK2, but not IKK1, increased Mdm2 levels and decreased doxorubicin-induced p53 stabilization and cell death. IKK2-mediated effects required its kinase function and were abrogated by coexpression of the dominant negative IkappaBalphaM, implying a role for NFkappaB in blocking chemotherapy-induced p53 and cell death.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antibiotics, Antineoplastic / pharmacology*
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Apoptosis / physiology*
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Cell Line
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Down-Regulation
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Doxorubicin / pharmacology*
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Drug Resistance, Neoplasm
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Enzyme Stability
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Fibroblasts / cytology
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I-kappa B Kinase
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Mice
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Mice, Knockout
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NF-kappa B / metabolism*
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Nuclear Proteins*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / genetics*
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-mdm2
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RNA, Messenger / metabolism
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Retroviridae
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
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Up-Regulation
Substances
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Antibiotics, Antineoplastic
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NF-kappa B
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Nuclear Proteins
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Proto-Oncogene Proteins
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RNA, Messenger
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Tumor Suppressor Protein p53
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Doxorubicin
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Mdm2 protein, mouse
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Proto-Oncogene Proteins c-mdm2
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Protein Serine-Threonine Kinases
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Chuk protein, mouse
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I-kappa B Kinase
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Ikbkb protein, mouse
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Ikbke protein, mouse