Nuclear factor – κB-dependent regulation of p53 gene expression induced by daunomycin genotoxic drug

Hellin, Anne-Cécile; Calmant, Philippe; Gielen, Jacques; Bours, Vincent; Merville, Marie‐Paule

doi:10.1038/sj.onc.1201638

Cited by 90 publications

(85 citation statements)

References 43 publications

(63 reference statements)

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“…p53 DNA-binding to p53 promoter As previously demonstrated, the anticancer drug daunomycin induced p53 activation and NF-kB nuclear translocation in HCT116 cells (Hellin et al, 1998). Electrophoretic mobility shift assays (EMSA), performed with nuclear extracts from daunomycinstimulated or untreated HCT116 cells, showed an important increase in p53 binding to a p53 consensus probe ( Figure 3A, lanes 1 and 2).…”

Section: Wild-type P53 Activates Its Own Promotersupporting

confidence: 70%

“…Since the human p53 promoter harbors an NF-kB binding site, we examined the role of NF-kB in p53 autoregulation. The HCT 116 cells were stably transfected with an expression vector coding for a dominant-negative IkBa protein mutated at serines 32 and 36 (HCT116MT9) (Hellin et al, 1998). The mutated IkBa is resistant to both phosphorylation and proteolytic degradation, leading to NF-kB sequestration in the cytoplasm.…”

Section: P53 Autoregulation In Hct116mt9 Cellsmentioning

confidence: 99%

“…The mutated IkBa is resistant to both phosphorylation and proteolytic degradation, leading to NF-kB sequestration in the cytoplasm. By EMSA analysis, we previously demonstrated that nuclear induction of NF-kB was not detected in HCT116MT9 cells after daunomycin, TNF-a or IL1b stimulation (Hellin et al, 1998). HCT116MT9 cells were transiently cotransfected with either p53 WT-LUC, p53RE WT-LUC or p53RE MT-LUC, and wild-type p53 expression vector (pC53-SN3) in increasing amounts.…”

Section: P53 Autoregulation In Hct116mt9 Cellsmentioning

confidence: 99%

“…In HCT116 cells, daunomycin is an activator of endogenous p53 and NF-kB (Hellin et al, 1998). To study the additional e ect between these two transcription factors in response to pharmacological stimulation, HCT116 cells were transfected with p53 WT-LUC, p53 MT1-LUC (p53 mutated site) or p53 MT2-LUC (kB mutated site).…”

Section: Effect Of Daunomycin On P53 Transcriptional Regulationmentioning

confidence: 99%

“…HCT116MT9 cells (Hellin et al, 1998) were grown in the same medium supplemented with G418 (geneticin, 0.5 mg/ml active concentration, Roche, Mannheim, Germany). Cells were exposed to daunomycin (Cerubidine, Rhone-Poulenc Rorer) at 1 mM for the indicated times.…”

Section: Cell Culture and Transfectionsmentioning

confidence: 99%

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Additive effect between NF-κB subunits and p53 protein for transcriptional activation of human p53 promoter

et al. 2000

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The tumor suppressor p53 plays a pivotal role in the cellular response to DNA damage as it controls DNA repair, cell cycle arrest and apoptosis. We studied the autoregulation of human p53 gene transcription in colon cancer cell lines. Wild-type p53 has been shown to autoregulate its own transcription either positively or negatively and probably in a cell-type-speci®c manner. Indeed, a p53 binding site has been described in the human and murine p53 promoters, but a direct binding of wild-type p53 protein to this site has never been reported.In this study, we demonstrated a transactivation of human p53 promoter by wild-type p53 in human colon cancer cells. We identi®ed in the human p53 promoter a novel potential p53-responsive element that binds wildtype p53. Moreover, wild-type p53 protein transactivated a reporter plasmid containing a luciferase gene driven by a minimal promoter harboring this p53 binding site. Finally, as the p53 promoter contains an NF-kB binding site, we demonstrated an additive e ect when NF-kB subunits and p53 protein combined to transactivate the human p53 promoter. Oncogene (2000) 19, 4787 ± 4794.

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Section: Wild-type P53 Activates Its Own Promotersupporting

confidence: 70%

Section: P53 Autoregulation In Hct116mt9 Cellsmentioning

confidence: 99%

Section: P53 Autoregulation In Hct116mt9 Cellsmentioning

confidence: 99%

Section: Effect Of Daunomycin On P53 Transcriptional Regulationmentioning

confidence: 99%

Section: Cell Culture and Transfectionsmentioning

confidence: 99%

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Additive effect between NF-κB subunits and p53 protein for transcriptional activation of human p53 promoter

et al. 2000

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Effect of nuclear factor κB inhibition on tumor cell sensitivity to natural killer-mediated cytolytic function

Mami‐Chouaib¹,

Ameyar²,

Dorothée³

et al. 2001

Eur. J. Immunol.

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Nuclear factor‐κB, induced in human carcinoma cell line A2780 by the new anthracycline men 10755, is devoid of transcriptional activity

Camarda

Binaschi

Maggi

et al. 2002

Intl Journal of Cancer

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Key words: anthracycline; topoisomerase II; nuclear factor-B; p53; apoptosis MEN 10755 is a new disaccharide anthracycline, currently undergoing phase II clinical evaluation, which showed, in preclinical studies, improved antineoplastic activity and reduced cardiotoxicity compared to the parent compound, DXR. [1][2][3] The mechanism of action of anthracyclines is primarily based on their ability to "poison" topo II enzymes, which are critical for cell survival; they play an important role in DNA replication, regulating the topologic state of DNA, and are involved in the condensation and segregation of chromosomes. Topo II enzymatic activity involves induction of DNA breaks and their subsequent resealing. Anthracyclines stabilize the enzyme in a covalent complex, known as the ternary complex, in which DNA, the enzyme and drug are locked. Resealing of DNA breaks is then prevented, leading to generation of lethal DNA damage. 4 It is well known that DNA damage results in activation of the transcription factor p53, 5-7 and the subsequent sequence-specific binding of p53 to DNA induces expression of genes mediating both cell-cycle arrest (i.e., p21 WAF1/CIP1 ) 8,9 and DNA repair (i.e., GADD45) 10 and suppression of antiapoptotic genes, e.g., those belonging to the IAP family. 11 The overall result of this pattern of gene regulation is the induction of cell death.On the contrary, induction of the transcription factor NF-B in response to antineoplastic agents has been revealed only recently. Data in the literature indicate that NF-B can be activated, other than by a wide array of biologic stimuli, by DNA double-strand breaks induced by chemotherapeutic drugs. 12,13 NF-B is a dimeric complex of proteins of the Rel family, which includes 5 members identified so far: NF-B1 (p50/p105), NF-B2 (p52/ p100), c-Rel, RelB and p65 (RelA); in most cell types, heterodimers of p50 and p65 are primarily found. NF-B complexes are mainly maintained inactive in the cytoplasm, bound to a protein of the IB family that masks their nuclear localization signal. 14 Complete functional activation of NF-B is achieved by phosphorylation-dependent degradation of the inhibitory IB subunit, allowing the transcription factor to translocate to the nucleus, 15 and by p65 subunit phosphorylation. 16,17 Clear evidence supports a role of NF-B in mediating an antiapoptotic response to genotoxic agents and in the induction of resistance to different chemotherapeutic drugs, 18 -22 through activation of specific target genes. Nevertheless, much debate is arising on the role of NF-B as a chemosensitizing agent; indeed, reports suggest that inhibiting NF-B-driven gene activation may be irrelevant or even detrimental to successful anticancer therapy. 23,24 This picture is further complicated by the complex relationships existing between p53 and NF-B transcription factors, which have been reported to cooperate but also to antagonize each other in gene transactivation. [25][26][27][28][29][30] We used the p53 wild-type human carcinoma cell line A2780 to investigat...

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Nuclear factor – κB-dependent regulation of p53 gene expression induced by daunomycin genotoxic drug

Cited by 90 publications

References 43 publications

Additive effect between NF-κB subunits and p53 protein for transcriptional activation of human p53 promoter

Additive effect between NF-κB subunits and p53 protein for transcriptional activation of human p53 promoter

Effect of nuclear factor κB inhibition on tumor cell sensitivity to natural killer-mediated cytolytic function

Nuclear factor‐κB, induced in human carcinoma cell line A2780 by the new anthracycline men 10755, is devoid of transcriptional activity

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