ZBP-89-induced apoptosis is p53-independent and requires JNK

Bai, Longchuan; Yoon, Sung Ok; King, Philip D.; Merchant, Juanita L.

doi:10.1038/sj.cdd.4401393

Cited by 44 publications

(43 citation statements)

References 68 publications

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“…Although Akt activation is known as a survival and anti-apoptotic response, in the present study, we found that silibinin enhances UVB-induced Akt activation, which appears to be a stress response consistent with recent reports showing that Akt is one of the substrates of DNA-PK, a genotoxic stress response gene (44). To further support this notion and to identify the pathway(s) regulating Akt activation in JB6 cells under our study conditions, we used LY294002, which in addition to its inhibitory activity toward PI 3-kinase, is also known as a potent and selective inhibitor of DNA-PK (39), which belongs to the PI 3-kinase-like kinase having a PI 3-kinase homology domain (10,39). Pre-treatment of cells with LY294002 completely abolished the silibinin-caused increase in Akt-Ser 473 phosphorylation as well as p53-Ser 15 phosphorylation and accumulation by UVB irradiation.…”

Section: Discussionmentioning

confidence: 96%

Silibinin Up-regulates DNA-Protein Kinase-dependent p53 Activation to Enhance UVB-induced Apoptosis in Mouse Epithelial JB6 Cells

Dhanalakshmi¹,

Agarwal

Singh³

et al. 2005

Journal of Biological Chemistry

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In the present study, we employed a well established JB6 mouse epithelial cell model to define the molecular mechanism of efficacy of a naturally occurring flavonoid silibinin against ultraviolet B (UVB)-induced skin tumorigenesis. UVB exposure of cells caused a moderate phosphorylation of ERK1/2 and Akt and a stronger phosphorylation of p53 at Ser 15 , which was enhanced markedly by silibinin pretreatment. Kinase activity of ERK1/2 for Elk-1 and Akt for glycogen synthase kinase-3␤ was also potently enhanced by silibinin pretreatment. Furthermore, silibinin increased the UVBinduced level of cleaved caspase 3 as well as apoptotic cells. Based on these observations, next we investigated the role of upstream kinases, ATM/ATR and DNA-PK, which act as sensors for UVB-induced DNA damage and transduce signals leading to DNA repair or apoptosis. Whereas UVB strongly activated ATM as observed by Ser 1981 phosphorylation, it was not affected by silibinin pretreatment. However, pretreatment of cells with the DNA-protein kinase (PK) inhibitor LY294002 strongly reversed silibinin-enhanced Akt-Ser 473 and p53-Ser 15 as well as ERK1/2 phosphorylation together with a dose-dependent decrease in cleaved caspase 3 and apoptosis (p < 0.05). In addition, silibinin pretreatment strongly enhanced H2A.X-Ser 139 phosphorylation and DNA-PKassociated kinase activity as well as the physical interaction of p53 with DNA-PK; pretreatment of cells with LY294002 but not caffeine abolished the silibinin-caused increase in both DNA-PK activation and p53-Ser 15 phosphorylations. Together, these findings suggest that silibinin preferentially activates the DNA-PK-p53 pathway for apoptosis in response to UVB-induced DNA damage, and that this could be a predominant mechanism of silibinin efficacy against UVB-induced skin cancer. Ultraviolet B (UVB)1 radiation plays a major role in the development of non-melanoma skin cancer, which is the most common human malignancy in the United States (1). In recent years, chemoprevention is considered to be a promising strategy for the control of this malignancy, where several studies have shown that various phytochemicals from both nutritive and non-nutritive sources protect against UVB-induced skin cancer (2-6). In this regard, silymarin (a polyphenolic flavonoid antioxidant from milk thistle) and silibinin (the bioactive component in silymarin) have also shown strong potential in preventing UV-induced skin damages and photocarcinogenesis (2, 5-7). We have demonstrated the chemopreventive efficacy of silymarin/silibinin in the SKH-1 mouse skin model, where these agents showed strong protection against UVBinduced tumor initiation, tumor promotion, and complete carcinogenesis (2). We also found that silymarin protects against chemical carcinogenesis in SENCAR mouse skin by modulating mitogen-activated protein kinases (MAPKs) and inducing apoptosis (3). In a more recent study, we observed a strong protective effect of silibinin against UVB-induced skin carcinogenesis in SKH-1 mice where topical applications before o...

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Section: Discussionmentioning

confidence: 96%

Silibinin Up-regulates DNA-Protein Kinase-dependent p53 Activation to Enhance UVB-induced Apoptosis in Mouse Epithelial JB6 Cells

Dhanalakshmi¹,

Agarwal

Singh³

et al. 2005

Journal of Biological Chemistry

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“…The overexpression of the tumour suppressor LKB1 or the ZBP-89 protein generates an apoptotic cell death that is p53-independent but JNKdependent, suggesting that this kinase may be an apoptosis instigator (Bai et al, 2004;Lee et al, 2006). Furthermore, it has been demonstrated that sirtuins can induce apoptosis mediated by JNK signalling independent of Dp53 (Griswold et al, 2008).…”

Section: Dp53 Physically Interacts With the Dmp52 Subunit Of Tfiihmentioning

confidence: 99%

The genetic depletion or the triptolide inhibition of TFIIH in p53 deficient cells induce a JNK-dependent cell death in Drosophila

Villicaña¹,

Cruz²,

Zurita³

2013

Journal of Cell Science

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SummaryTranscription factor IIH (TFIIH) participates in transcription, nucleotide excision repair and the control of the cell cycle. In the present study, we demonstrate that the Dmp52 subunit of TFIIH in Drosophila physically interacts with the fly p53 homologue, Dp53. The depletion of Dmp52 in the wing disc generates chromosome fragility, increases apoptosis and produces wings with a reduced number of cells; cellular proliferation, however, is not affected. Interestingly, instead of suppressing the apoptotic phenotype, the depletion of Dp53 in Dmp52-depleted wing disc cells increases apoptosis and the number of cells that suffer from chromosome fragility. The apoptosis induced by the depletion of Dmp52 alone is partially dependent on the JNK pathway. In contrast, the enhanced apoptosis caused by the simultaneous depletion of Dp53 and Dmp52 is absolutely JNK-dependent. In this study, we also show that the anti-proliferative drug triptolide, which inhibits the ATPase activity of the XPB subunit of TFIIH, phenocopies the JNK-dependent massive apoptotic phenotype of Dp53-depleted wing disc cells; this observation suggests that the mechanism by which triptolide induces apoptosis in p53-deficient cancer cells involves the activation of the JNK death pathway.

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“…Direct binding of ZBP89 to p53, which causes growth arrest via p53 retention in the nucleus (Bai & Merchant 2001), has been described as well. Interestingly, ZBP89 induces apoptosis in a JNK-dependent, but p53-independent manner (Bai et al 2004). In summary, ZBP89 inhibits cell proliferation (Remington et al 1997), induces apoptosis, and cooperates or competes with SP1 promoter binding sites, for example, in the STAT1 (Bai & Merchant 2003) and the vimentin promoter (Zhang et al 2003).…”

Section: Discussionmentioning

confidence: 96%

“…We cloned two sequences into the pSuppressor Neo vector. One sequence is active in suppressing ZBP89 transcripts (5 0 -AAGATCGAAGTATGCCTCACCTT-3 0 ), and for control we used the same sequence mutated in five bps (5 0 -AAGATCGAACGTGTCCTCACCTT-3 0 ) which is ineffective in ZBP89 suppression (Bai et al 2004). The constructs were linearized and transfected into SHSY5Y cells.…”

Section: Generation Of Stable Zbp89 Knockdown Shsy5y Cellsmentioning

confidence: 99%

Neuronal insulin receptor substrate 2 (IRS2) expression is regulated by ZBP89 and SP1 binding to the IRS2 promoter

Udelhoven¹,

Pasieka²,

Leeser³

et al. 2009

Journal of Endocrinology

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Since neuronal insulin receptor substrate 2 (IRS2)-mediated signals coordinate key processes in rodent physiology such as food intake, fertility, longevity, and aging-related behavior, we analyzed the mechanisms of neuronal IRS2 expression in neuroblastoma (SHSY5Y) and hypothalamic (GT1-7) cell lines. Using dual luciferase reporter assays and IRS2 promoter deletion constructs, we identified a regulatory cassette within the IRS2 promoter between K779 and K679 bp from the translational start which is responsible for w50% of neuronal IRS2 promoter activity. Chromatin immunoprecipitation assays and electromobility shift assay revealed four overlapping ZBP89/specificity protein 1 (SP1) binding sites which alternatively bind to ZBP89 (ZNF148 as listed in the HUGO Database) or SP1. Activation of this cassette is inhibited by phosphoinositide-3-kinase (PI3K) via increased ZBP89 binding to the promoter. Serum starvation caused increased SP1 binding at one specific SP1 site and decreased binding to another, proving a regulatory interaction between the different binding sites within this promoter cassette to tightly control IRS2 expression. Mutants containing all the possible combinations of one, two, three, or all the four SP1 binding sites of the IRS2 promoter revealed that SP1 binding to one particular site is most important for promoter activation. Stable downregulation of ZBP89 using siRNA substantially increased IRS2 mRNA and protein expression. Thus, alternative binding of ZBP89 or SP1 to the described region in the IRS2 promoter regulates neuronal IRS2 expression in a PI3K-dependent manner.

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ZBP-89-induced apoptosis is p53-independent and requires JNK

Cited by 44 publications

References 68 publications

Silibinin Up-regulates DNA-Protein Kinase-dependent p53 Activation to Enhance UVB-induced Apoptosis in Mouse Epithelial JB6 Cells

Silibinin Up-regulates DNA-Protein Kinase-dependent p53 Activation to Enhance UVB-induced Apoptosis in Mouse Epithelial JB6 Cells

The genetic depletion or the triptolide inhibition of TFIIH in p53 deficient cells induce a JNK-dependent cell death in Drosophila

Neuronal insulin receptor substrate 2 (IRS2) expression is regulated by ZBP89 and SP1 binding to the IRS2 promoter

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