Repression of Dmp1 and Arf transcription by anthracyclins: critical roles of the NF-kappaB subunit p65.
Both genotoxic and oncogenic stress activates the nuclear factor-kappa B (NF-kappaB) and p53 proteins; however, the p53 activity is antagonized by NF-kappaB signaling. Dmp1 is a Myb-like transcription factor that activates the Arf-p53 pathway. The Dmp1 promoter was activated by a classical NF-kappaB activator tumor necrosis factor alpha, but repressed by treatment of cells with non-classical NF-kappaB activators, anthracyclins and UV-C. p65 and other subsets of NF-kappaB proteins were bound to the Dmp1 promoter following anthracyclin/UV-C treatment of rodent fibroblasts. This resulted in the downregulation of Dmp1 mRNA and protein. Repression of the Dmp1 transcription by anthracyclins depended on the unique NF-kappaB site on the promoter. Downregulation of p65 significantly attenuated the repression of the Dmp1 promoter by anthracyclins/UV-C. The amount of Dmp1 bound to the Arf promoter decreased significantly upon anthracyclin treatment; this, in turn, downregulated the Arf levels. Repression of the Arf promoter by p65 or anthracyclins depended on Dmp1, which was significantly attenuated in Dmp1(-/-) cells. Both Dmp1(-/-)and Arf(-/-)cells showed resistance to anthracyclin-induced cell death compared to wild-type cells; non-immortalized p65-knockdown cells were much more sensitive. Thus, the Dmp1-Arf pathway is repressed by p65 in response to genotoxic stress, which implicates a novel mechanism of p53 inactivation by NF-kappaB.
Taneja
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P
The Department of Pathology, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
Mallakin
A
A
Matise
L A
LA
Frazier
D P
DP
Choudhary
M
M
Inoue
K
K
D016475:3T3 Cells; D000818:Animals; D018943:Anthracyclines / Q000494:pharmacology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis / Q000235:genetics*; D003630:Daunorubicin / Q000494:pharmacology; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis / Q000235:genetics*; D005786:Gene Expression Regulation; D051379:Mice; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D018943:Anthracyclines; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; C513308:Dmp1 protein, mouse; D016326:Extracellular Matrix Proteins; D052002:NF-kappa B p50 Subunit; D012333:RNA, Messenger; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D004317:Doxorubicin; D003630:Daunorubicin