p53 stabilization is decreased upon NFkappaB activation: a role for NFkappaB in acquisition of resistance to chemotherapy.
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.
Tergaonkar
Vinay
V
Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
Pando
Matthew
M
Vafa
Omid
O
Wahl
Geoffrey
G
Verma
Inder
I
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000502:physiology*; D002460:Cell Line; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004795:Enzyme Stability; D005347:Fibroblasts / Q000166:cytology; D051550:I-kappa B Kinase; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D012333:RNA, Messenger / Q000378:metabolism; D012190:Retroviridae; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D000903:Antibiotics, Antineoplastic; D016328:NF-kappa B; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D017346:Protein Serine-Threonine Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse