p53 stabilization is decreased upon NFkappaB activation: a role for NFkappaB in acquisition of resistance to chemotherapy.
Cancer Cell
; 1(5): 493-503, 2002 Jun.
Article
in En
| MEDLINE
| ID: mdl-12124178
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.
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Database:
MEDLINE
Main subject:
Nuclear Proteins
/
Doxorubicin
/
NF-kappa B
/
Tumor Suppressor Protein p53
/
Proto-Oncogene Proteins
/
Apoptosis
/
Antibiotics, Antineoplastic
Limits:
Animals
Language:
En
Year:
2002
Type:
Article