Stress via p53 pathway causes apoptosis by mitochondrial Noxa upregulation in doxorubicin-treated neuroblastoma cells

Kurata, Kenji; Yanagisawa, Ryu; Ohira, Miki; Kitagawa, Masatoshi; Nakagawara, Akira

doi:10.1038/sj.onc.1210672

Cited by 30 publications

(28 citation statements)

References 35 publications

(38 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1 A and B). Expressions of p53, Noxa, and ␤-tubulin mRNA were not different between the 2 groups (25,26). These results demonstrate in vivo induction of hepatic TLR4 expression by NS5A and support the rationale for testing the role of TLR4 in synergistic liver damage by alcohol and HCV NS5A.…”

Section: Ns5amentioning

confidence: 93%

Toll-like receptor 4 mediates synergism between alcohol and HCV in hepatic oncogenesis involving stem cell marker Nanog

Machida

Tsukamoto²,

Mkrtchyan³

et al. 2009

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

207

218

View full text Add to dashboard Cite

Alcohol synergistically enhances the progression of liver disease and the risk for liver cancer caused by hepatitis C virus (HCV). However, the molecular mechanism of this synergy remains unclear. Here, we provide the first evidence that Toll-like receptor 4 (TLR4) is induced by hepatocyte-specific transgenic (Tg) expression of the HCV nonstructural protein NS5A, and this induction mediates synergistic liver damage and tumor formation by alcohol-induced endotoxemia. We also identify Nanog, the stem/progenitor cell marker, as a novel downstream gene up-regulated by TLR4 activation and the presence of CD133/Nanog-positive cells in liver tumors of alcohol-fed NS5A Tg mice. Transplantation of p53-deficient hepatic progenitor cells transduced with TLR4 results in liver tumor development in mice following repetitive LPS injection, but concomitant transduction of Nanog shorthairpin RNA abrogates this outcome. Taken together, our study demonstrates a TLR4-dependent mechanism of synergistic liver disease by HCV and alcohol and an obligatory role for Nanog, a TLR4 downstream gene, in HCV-induced liver oncogenesis enhanced by alcohol.

show abstract

Section: Ns5amentioning

confidence: 93%

Toll-like receptor 4 mediates synergism between alcohol and HCV in hepatic oncogenesis involving stem cell marker Nanog

Machida

Tsukamoto²,

Mkrtchyan³

et al. 2009

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

207

218

View full text Add to dashboard Cite

show abstract

“…Western blot analysis was performed as previously reported (Kurata et al, 2008). After transferring to an Immobilon-P membrane (Millipore, Bedford, MA, USA), proteins were reacted with either anti-Bmi1 mouse monoclonal (229F6; Upstate, Charlottesville, VA, USA), anti-MYCN rabbit polyclonal (C-19; Santa Cruz, Santa Cruz, CA, USA) p14 (14P02; Oncogene) mouse, p16 (16P04; Neomarkers/Labvision, Fremont, CA, USA) mouse, anti-b-actin (Sigma-Aldrich) or a monoclonal anti-tubulin (Neomarkers Labvision) antibody.…”

Section: Western Blot Analysismentioning

confidence: 99%

“…Informed consent was obtained at each institution and hospital. All tumors were diagnosed clinically and pathologically as NBs and MYCN copy number was determined as previously described (Kurata et al, 2008).…”

Section: Western Blot Analysismentioning

confidence: 99%

“…The methods of semi-quantitative RT-PCR analysis were previously described (Kurata et al, 2008). Total cellular RNA to prepare RT-PCR templates was extracted from NB cell lines using Isogen (Nippon Gene K K, Tokyo, Japan), and cDNA was synthesized from 1 mg total RNA templates according to the manufacturer's protocol (RiverTra-Ace-a RT-PCR kit; TOYOBO, Osaka, Japan).…”

Section: Semi-quantitative Rt-pcrmentioning

confidence: 99%

See 1 more Smart Citation

Bmi1 is a MYCN target gene that regulates tumorigenesis through repression of KIF1B β and TSLC1 in neuroblastoma

et al. 2010

Self Cite

View full text Add to dashboard Cite

Recent advances in neuroblastoma (NB) research addressed that epigenetic alterations such as hypermethylation of promoter sequences, with consequent silencing of tumor-suppressor genes, can have significant roles in the tumorigenesis of NB. However, the exact role of epigenetic alterations, except for DNA hypermethylation, remains to be elucidated in NB research. In this paper, we clarified the direct binding of MYCN to Bmi1 promoter and upregulation of Bmi1 transcription by MYCN. Mutation introduction into an MYCN binding site in the Bmi1 promoter suggests that MYCN has more important roles in the transcription of Bmi1 than E2F-related Bmi1 regulation. A correlation between MYCN and polycomb protein Bmi1 expression was observed in primary NB tumors. Expression of Bmi1 resulted in the acceleration of proliferation and colony formation in NB cells. Bmi1-related inhibition of NB cell differentiation was confirmed by neurite extension assay and analysis of differentiation marker molecules. Intriguingly, the above-mentioned Bmi1-related regulation of the NB cell phenotype seems not to be mediated only by p14ARF/p16INK4a in NB cells. Expression profiling analysis using a tumor-specific cDNA microarray addressed the Bmi1-dependent repression of KIF1Bb and TSLC1, which have important roles in predicting the prognosis of NB. Chromatin immunoprecipitation assay showed that KIF1Bb and TSLC1 are direct targets of Bmi1 in NB cells. These findings suggest that MYCN induces Bmi1 expression, resulting in the repression of tumor suppressors through Polycomb group genemediated epigenetic chromosome modification. NB cell proliferation and differentiation seem to be partially dependent on the MYCN/Bmi1/tumor-suppressor pathways.

show abstract

“…Very recently, MYCN was shown to transcriptionally regulate p53 expression (23), leading to the hypothesis that p53 upregulation might be involved in MYCN-dependent sensitization to apoptosis. However, p53 induction was reproducibly shown to occur at similar levels in MYCNoverexpressing and -nonoverexpressing neuroblastoma cells, on treatment with clastogenic drugs (21,24) suggesting that, although necessary, p53 expression might not be sufficient for the induction of apoptosis in neuroblastoma cells. Additional mechanisms might contribute to the MYCN-dependent sensitization to apoptosis, some of which might be directly linked to p53 activation via post-translational modifications.…”

Section: Introductionmentioning

confidence: 99%

MYCN Sensitizes Human Neuroblastoma to Apoptosis by HIPK2 Activation through a DNA Damage Response

Petroni

Veschi

Prodosmo

et al. 2011

Molecular Cancer Research

View full text Add to dashboard Cite

MYCN amplification occurs in approximately 20% of human neuroblastomas and is associated with early tumor progression and poor outcome, despite intensive multimodal treatment. However, MYCN overexpression also sensitizes neuroblastoma cells to apoptosis. Thus, uncovering the molecular mechanisms linking MYCN to apoptosis might contribute to designing more efficient therapies for MYCN-amplified tumors. Here we show that MYCN-dependent sensitization to apoptosis requires activation of p53 and its phosphorylation at serine 46. The p53 S46 kinase HIPK2 accumulates on MYCN expression, and its depletion by RNA interference impairs p53 S46 phosphorylation and apoptosis. Remarkably, MYCN induces a DNA damage response that accounts for the inhibition of HIPK2 degradation through an ATM-and NBS1-dependent pathway. Prompted by the rare occurrence of p53 mutations and by the broad expression of HIPK2 in our human neuroblastoma series, we evaluated the effects of the p53-reactivating compound Nutlin-3 on this pathway. At variance from other tumor histotypes, in MYCN-amplified neuroblastoma, Nutlin-3 further induced HIPK2 accumulation, p53 S46 phosphorylation, and apoptosis, and in combination with clastogenic agents purged virtually the entire cell population. Altogether, our data uncover a novel mechanism linking MYCN to apoptosis that can be triggered by the p53-reactivating compound Nutlin-3, supporting its use in the most difficult-to-treat subset of neuroblastoma.

show abstract

Stress via p53 pathway causes apoptosis by mitochondrial Noxa upregulation in doxorubicin-treated neuroblastoma cells

Cited by 30 publications

References 35 publications

Toll-like receptor 4 mediates synergism between alcohol and HCV in hepatic oncogenesis involving stem cell marker Nanog

Toll-like receptor 4 mediates synergism between alcohol and HCV in hepatic oncogenesis involving stem cell marker Nanog

Bmi1 is a MYCN target gene that regulates tumorigenesis through repression of KIF1B β and TSLC1 in neuroblastoma

MYCN Sensitizes Human Neuroblastoma to Apoptosis by HIPK2 Activation through a DNA Damage Response

Contact Info

Product

Resources

About