A conserved intronic response element mediates direct p53-dependent transcriptional activation of both the human and murine bax genes

Thornborrow, Edward C.; Patel, Sarah; Mastropietro, Anthony E; Schwartzfarb, Elissa M.; Manfredi, James J.

doi:10.1038/sj.onc.1205069

Cited by 113 publications

(81 citation statements)

References 27 publications

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“…The 21 kDa protein partner Bax, which overexpresses to counter the death repressor activity of Bcl-2, can enhance apoptosis. The ratio of Bcl-2 to Bax determines survival or death following an apoptotic stimulus [23][24] In this study, the combination subsequently increased Bax and decreased Bcl-2 expression resulting from p53 upregulation. The wild-type p53 gene is a negative regulator of cell growth by the transcriptional activation of p21 which plays a crucial role in controlling DNA repair, cell differentiation, and apoptosis in response to p53 activation [25] .…”

Section: Discussionmentioning

confidence: 97%

Interferon-α enhances sensitivity of human osteosarcoma U2OS cells to doxorubicin by p53-dependent apoptosis

Yuan

Zhu

Huang³

et al. 2007

Acta Pharmacol Sin

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Aim: To determine whether interferon-α (IFNα) can enhance doxorubicin sensitivity in osteosarcoma cells and its molecular mechanism. Methods: Cell viability was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Apoptosis was studied using Flow cytometry analysis, Hoechst33258 staining, DNA fragmentation assay, as well as the activation of caspase-3 and poly (ADP-ribose) polymerase. Protein expression was detected by Western blotting. The dependence of p53 was determined using p53-siRNA transfection. Results: IFNα increased doxorubicin-induced cytotoxicity to a much greater degree through apoptosis in human osteosarcoma p53-wild U2OS cells, but not p53-mutant MG63 cells. IFNα markedly upregulated p53, Bax, Mdm2, and p21, downregulated Bcl-2, and activated caspase-3 and PARP cleavage in response to doxorubicin in U2OS cells. Moreover, the siRNA-mediated silencing of p53 significantly reduced the IFNα/doxorubicin combination-induced cytotoxicity and PARP cleavage. Conclusion: IFNα enhances the sensitivity of human osteosarcoma U2OS cells to doxorubicin by p53-dependent apoptosis. The proper combination with IFNα and conventional chemotherapeutic agents may be a rational strategy for improving the treatment of osteosarcoma with functional p53.

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Section: Discussionmentioning

confidence: 97%

Interferon-α enhances sensitivity of human osteosarcoma U2OS cells to doxorubicin by p53-dependent apoptosis

Yuan

Zhu

Huang³

et al. 2007

Acta Pharmacol Sin

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“…ZNF659 and LRRC3B were both associated with 10 μmol/l cisplatin, whereas PITX2 and LARP2 were associated with 2.5 μmol/l (PITX2), 5 μmol/l (LARP2), and 20 μmol/l (PITX2) cisplatin. Particular attention may be paid to conserved intronic SNPs within LRRC3B (rs7652737) and PITX2 (rs17624452), which may provide enhancer binding sites or response elements for other genes [51]. Some of the associated nongenic SNPs are found in conserved regions of the genome.…”

Section: Discussionmentioning

confidence: 99%

Susceptibility loci involved in cisplatin-induced cytotoxicity and apoptosis

Shukla

Duan²,

Badner³

et al. 2008

Pharmacogenetics and Genomics

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Objectives-Cisplatin is a widely used chemotherapeutic agent; however, nephrotoxicity and neuropathy are obstacles for drug efficacy. Little is known about the genes or genetic variants contributing to the risk of developing these toxicities or chemotherapeutic response. Thus, we have applied a cell-based model to identify and characterize previously unknown genes that may be involved in cellular susceptibility to cisplatin.Methods-Lymphoblastoid cell lines from 27 large Centre d'Etude du Polymorphisme Humain pedigrees were used to elucidate the genetic contribution to cisplatin-induced cytotoxicity. Phenotype was defined as cell growth inhibition following exposure of cell lines to increasing concentrations of cisplatin for 48 h.Results-Significant heritability, ranging from 0.32 to 0.43 (P < 10 −7 ), was found for the cytotoxic effects of each concentration (1, 2.5, 5, 10, and 20 μmol/l) and IC50, the concentration required for 50% cell growth inhibition. Linkage analysis revealed 11 genomic regions on six chromosomes with logarithm of odds (LOD) scores above 1.5 for cytotoxic phenotypes. The highest LOD score was found on chromosome 4q21.3−q35.2 (LOD = 2.65, P = 2.4 × 10 −4 ) for 5 μmol/l cisplatin. Quantitative transmission disequilibrium tests were performed using 191 973 nonredundant single nucleotide polymorphisms (SNPs) located in the 1 LOD confidence interval of these 11 regions. Twenty SNPs, with 10 SNPs located in five genes, were significantly associated with cisplatin-induced cytotoxicity (P ≤ 1 × 10 −4 ). Four of these 20 SNPs were found to explain over 10% of the variation in cisplatininduced apoptosis.Conclusions-Our results suggest that genetic factors involved in cytotoxicity also contribute to cisplatin-induced apoptosis. These cell lines provide a paradigm to identify previously unknown pharmacogenetic variants associated with drug cytotoxicity.

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“…S7B); this suggests that DEC1 inhibits Bax expression through another mechanism. Previous reports showed that the Bax promoter contains four E-boxes downstream of four p53-half sites (32) and a p53-RE in intron 1 (33) (Fig. S7A).…”

Section: Dec1mentioning

confidence: 99%

Differentiated embryo-chondrocyte expressed gene 1 regulates p53-dependent cell survival versus cell death through macrophage inhibitory cytokine-1

Qian

Jung

Chen

2012

Proc. Natl. Acad. Sci. U.S.A.

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Activation of p53 upon DNA damage induces an array of target genes, leading to cell cycle arrest and/or apoptosis. However, the mechanism by which the cell fate is controlled by p53 remains to be clarified. Previously, we showed that DEC1, a basic helix-loophelix transcription factor and a target of p53, is capable of inducing cell cycle arrest and mediating DNA damage-induced premature senescence. Here, we found that ectopic expression of DEC1 inhibits, whereas knockdown of DEC1 enhances, DNA damage-induced cell death. Surprisingly, we showed that the anti-cell-death activity of DEC1 is p53 dependent, but DEC1 does not directly modulate p53 expression. Instead, we showed that DEC1 inhibits the ability of p53 to induce macrophage inhibitory cytokine-1 (MIC-1), but not other prosurvival/proapoptotic targets, including p21 and Puma. Importantly, we showed that upon binding to their respective response elements on the MIC-1 promoter, DEC1 and p53 physically interact on the MIC-1 promoter via the basic helix-loop-helix domain in DEC1 and the tetramerization domain in p53, which likely weakens the DNA-binding activity of p53 to the MIC-1 promoter. Finally, we found that depletion of MIC-1 abrogates the ability of DEC1 to attenuate DNA damage-induced cell death. Together, we hypothesize that DEC1 controls the response of p53-dependent cell survival vs. cell death to a stress signal through MIC-1.Stimulated by retinoic acid 13 | growth differentiation factor 15 I n response to genotoxic stress, p53 is activated, leading to induction of cell death regulators, such as Puma, Bax, FDXR, and PolH, and cell survival regulators, such as p21, Mdm2, 14-3-3σ, and GADD45 (1-3). However, a central puzzle is how p53 determines the cell fate in response to a specific stimulus. Previously, we and others have shown that the expression level and functional domains of p53 are involved in the cell fate determination (4-7) as well as several cofactors that alter the ability of p53 to transcriptionally regulate its targets. For examples, the ASPP family proteins (8), p53β (9), and p90 (10) preferentially affect p53 to regulate proapoptotic targets, such as Bax, but not p21. Conversely, BRCA1 (11) and HZF (12) cooperate with p53 to transactivate p21 but not Bax. Interestingly, hCAS/CSE1L is able to selectively affect a set of p53 targets and p53-dependent apoptosis without directly binding to p53 (13).DEC1 belongs to a subfamily of basic helix-loop-helix (bHLH) transcription factors and is a critical regulator of the circadian rhythm (14). DEC1 is defined as a senescence marker because it is up-regulated in premalignant tumors (15). Consistent with this, our previous studies showed that DEC1 is a target of the p53 family and mediates G1 cell cycle arrest and DNA damage-induced premature senescence (16,17). Evidence also showed that DEC1 plays a role in cell death. For examples, overexpression of DEC1 inhibits serum starvation-induced apoptosis in HEK293 cells (18), and DEC1 mediates TGF-β-induced cell survival in breast cancer cells (19). H...

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A conserved intronic response element mediates direct p53-dependent transcriptional activation of both the human and murine bax genes

Cited by 113 publications

References 27 publications

Interferon-α enhances sensitivity of human osteosarcoma U2OS cells to doxorubicin by p53-dependent apoptosis

Interferon-α enhances sensitivity of human osteosarcoma U2OS cells to doxorubicin by p53-dependent apoptosis

Susceptibility loci involved in cisplatin-induced cytotoxicity and apoptosis

Differentiated embryo-chondrocyte expressed gene 1 regulates p53-dependent cell survival versus cell death through macrophage inhibitory cytokine-1

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