Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The majority of antigen receptor diversity in mammals is generated by V(D)J recombination. During this process DNA double strand breaks are introduced at recombination signals by lymphoid specific RAG1/2 proteins generating blunt ended signal ends and hairpinned coding ends. Rejoining of all DNA ends requires ubiquitously expressed DNA repair proteins, such as Ku70/86 and DNA ligase IV/XRCC4. In addition, the formation of coding joints depends on the function of the scid gene encoding the catalytic subunit of DNA-dependent protein kinase, DNA-PK(CS), that is somehow required for processing of coding end hairpins. Recently, it was shown that purified RAG1/2 proteins can cleave DNA hairpins in vitro, but the same activity was also described for a protein complex of the DNA repair proteins Nbs1/Mre11/Rad50. This leaves the possibility that either protein complex might be involved in coding end processing in V(D)J recombination. We have therefore analyzed V(D)J recombination in cells from patients with Nijmegen breakage syndrome, carrying a mutation in the nbs1 gene. We find that V(D)J recombination frequencies and the quality of signal and coding joining are comparable to wild-type controls, as analyzed by a cellular V(D)J recombination assay. In addition, we did not detect significant differences in CDR3 sequences of endogenous Ig lambdaL and kappaL chain gene loci cloned from peripheral blood lymphocytes of an NBS patient and of healthy individuals. These findings suggest that the Nbs1/Mre11/Rad50 complex is not involved in coding end processing of V(D)J recombination.
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PMID:Normal V(D)J recombination in cells from patients with Nijmegen breakage syndrome. 1128 95

Histone deacetylase inhibitors (HDACIs) are therapeutic drugs that inhibit deacetylase activity, thereby increasing acetylation of many proteins, including histones. HDACIs have antineoplastic effects in preclinical and clinical trials and are being considered for cancers with unmet therapeutic need, including neuroblastoma (NB). Uncertainty of how HDACI-induced protein acetylation leads to cell death, however, makes it difficult to determine which tumors are likely to be responsive to these agents. Here, we show that NB cells are sensitive to HDACIs, and that the mechanism by which HDACIs induce apoptosis involves Bax. In these cells, Bax associates with cytoplasmic Ku70, a protein that typically increases chemotherapy resistance. Our data show that in NB cells Ku70 binds to Bax in an acetylation-sensitive manner. Upon HDACI treatment, acetylated Ku70 releases Bax, allowing it to translocate to mitochondria and trigger cytochrome c release, leading to caspase-dependent death. This study shows that Ku70 is an important Bax-binding protein, and that this interaction can be therapeutically regulated in NB cells. Whereas the Bax-binding ability of Ku70 allows it to block apoptosis in response to certain agents, it is also a molecular target for the action of HDACIs, and in this context, a mediator of NB cell death.
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PMID:Ku70 acetylation mediates neuroblastoma cell death induced by histone deacetylase inhibitors. 1577 93

Histone deacetylase inhibitors constitute a promising new treatment for cancer due to their novel site of action and low toxicity. Almost all histone deacetylase inhibitors currently in clinical development have anti-proliferate activities against cells in cultures, and specifically cause cell cycle arrest, differentiation and apoptosis. Interestingly, despite their rapid advance into clinical use, the cellular responses leading to these effects remain unclear. We recently reported that histone deacetylase inhibitor treatment induces apoptosis of neuroblastoma cells by increasing the acetylation of Ku70 in the cytoplasm, resulting in the release of Bax from Ku70. Subsequently, Bax releases cytochrome c from mitochondria causing apoptosis. Here we will discuss these findings and the implications of our model for the further clinical development of histone deacetylase inhibitors in the treatment of cancer.
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PMID:Histone deacetylase inhibition induces apoptosis in neuroblastoma. 1629 13

The cytotoxic mechanism of the histone deacetylase inhibitor (HDACI) Trichostatin A (TSA) was explored in a neuroblastoma (NB) model. TSA induces cell death in neuroblastic-type NB cells by increasing the acetylation of Ku70, a Bax-binding protein. Ku70 acetylation causes Bax release and activation, triggering cell death. This response to TSA depends on the CREB-binding protein (CBP) acetylating Ku70. TSA-induced cell death response correlates with CBP expression. In stromaltype NB cell lines with low levels of CBP and relative resistance to TSA, increasing CBP expression disrupts Bax-Ku70 binding and sensitizes them to TSA. Reducing CBP expression in neuroblastic cell types causes resistance. Cytotoxic response to TSA is Bax-dependent. Interestingly, depleting NB cells of Ku70 also triggers Bax-dependent cell death, suggesting that conditions that leave Bax unbound to Ku70 result in cell death. We also show that CBP, Ku70, and Bax are expressed in human NB tumors and that CBP expression varies across cell types comprising these tumors, with the highest expression observed in neuroblastic elements. Together, these results demonstrate that CBP, Bax, and Ku70 contribute to a therapeutic response to TSA against NB and identify the possibility of using these proteins to predict clinical responsiveness to HDACI treatment.
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PMID:CREB-binding protein is a mediator of neuroblastoma cell death induced by the histone deacetylase inhibitor trichostatin A. 1760 32

Topoisomerase II alpha (TopoIIalpha) and Topoisomerase II beta (TopoIIbeta) isoforms are different gene products having conserved catalytic activities. The alpha isoform is present in proliferating cell, while beta isoform is predominantly present in non-proliferating cells namely neurons suggesting its role in non-replicating functions of DNA. The functions of TopoIIalpha and TopoIIbeta isoforms are analyzed in peroxide-mediated DNA damage and double strand breaks (DSBs) repair in neuroblastoma and astrocytoma cells. The results show a strong correlation of TopoIIalpha level with the progression of DNA damage, while the TopoIIbeta expression is correlated with the DNA DSBs repair activity of cells in Ku70, Werner's helicase and pol-beta dependent pathways. The functional roles of TopoIIalpha and TopoIIbeta are assessed using siRNA mediated TopoIIalpha and TopoIIbeta knockdown in cells. The results show that TopoIIalpha-TopoIIbeta+ cells are resistant to peroxide-mediated DNA damage, while TopoIIalpha+TopoIIbeta- cells are 2-fold more sensitive to peroxide and TopoIIbeta deficiency lead to cellular apoptosis. These results are correlated with cell survival from peroxide-mediated insult. The result of this study that TopoIIalpha accelerates peroxide-mediated DNA damage, while TopoIIbeta promotes DNA DSBs repair activity should provide new directions toward understanding of normalytic ageing processes in human brain.
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PMID:Distinct roles of Topoisomerase II isoforms: DNA damage accelerating alpha, double strand break repair promoting beta. 1802 38

Neuroblastoma is a cancer that occurs in children. It develops from stem cells that normally give rise to parts of the peripheral nervous system and adrenal glands. Although most children with localized neuroblastoma are cured, children with wide-spread disease have a small chance of survival even after surgery, chemotherapy, radiation and bone marrow transplantation. Ten to fifteen percent of patients die from treatment complications, and long-term survival is less than 30%. Although contemporary molecular tumor marker discoveries have improved prognostication, few have led to new therapeutic approaches. To solve this problem, we are working to understand which molecules in the stem cells from which this cancer arises malfunction to cause neuroblastoma and apply this information to develop new models to treat this disease. Our efforts have focused on the functional regulation of a protein called Ku70, which coordinately regulates DNA repair and cell death. We propose that the incorrect balance between these two activities underlies this cancer's development, and that re-balancing with drug therapy offers a way to treat this disease.
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PMID:Ku70 acetylation in neuroblastoma pathogenesis and therapy. 2069 60

Clusterin is a ubiquitously expressed glycoprotein with multiple binding partners including IL-6, Ku70, and Bax. Clusterin blocks apoptosis by binding to activated Bax and sequestering it in the cytoplasm, thereby preventing Bax from entering mitochondria, releasing cytochrome c, and triggering apoptosis. Because increased clusterin expression correlates with aggressive behavior in tumors, clusterin inhibition might be beneficial in cancer treatment. Our recent findings indicated that, in neuroblastoma cells, cytoplasmic Bax also binds to Ku70; when Ku70 is acetylated, Bax is released and can initiate cell death. Therefore, increasing Ku70 acetylation, such as by using histone deacetylase inhibitors, may be therapeutically useful in promoting cell death in neuroblastoma tumors. Since clusterin, Bax, and Ku70 form a complex, it seemed likely that clusterin would mediate its anti-apoptotic effects by inhibiting Ku70 acetylation and blocking Bax release. Our results, however, demonstrate that while clusterin level does indeed determine the sensitivity of neuroblastoma cells to histone deacetylase inhibitor-induced cell death, it does so without affecting histone deacetylase-inhibitor-induced Ku70 acetylation. Our results suggest that in neuroblastoma, clusterin exerts its anti-apoptotic effects downstream of Ku70 acetylation, likely by directly blocking Bax activation.
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PMID:CLU blocks HDACI-mediated killing of neuroblastoma. 2104 4

Ku70 was first characterized as a nuclear factor that binds DNA double-strand breaks in nonhomolog end-joining DNA repair. However, recent studies have shown that Ku70 is also found in the cytoplasm and binds Bax, preventing Bax-induced cell death. We have shown that, in neuroblastoma cells, the binding between Ku70 and Bax depends on the acetylation status of Ku70, such that, when Ku70 is acetylated, Bax is released from Ku70, triggering cell death. Thus, to survive, in neuroblastoma cells, cytoplasmic Ku70 acetylation status is carefully regulated such that Ku70 is maintained in a deacetylated state, keeping Bax complexed with Ku70. We have shown that overexpression of CREB-binding protein (CBP), a known acetyltransferase that acetylates Ku70, releases Bax from Ku70, triggering apoptosis. Although we have shown that blocking deacetylase activity using non-type-specific inhibitors also triggers Ku70 acetylation and Bax-dependent cell death, the targets of these deacetylase inhibitors in neuroblastoma cells remain unknown. Here, we demonstrate that, in neuroblastoma cells, histone deacetylase 6 (HDAC6) binds Ku70 and Bax in the cytoplasm and that knocking down HDAC6 or using an HDAC6-specific inhibitor triggers Bax-dependent cell death. Our results show that HDAC6 regulates the interaction between Ku70 and Bax in neuroblastoma cells and may be a therapeutic target in this pediatric solid tumor.
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PMID:HDAC6 deacetylates Ku70 and regulates Ku70-Bax binding in neuroblastoma. 2184 64

Ku70 was originally described as an autoantigen, but it also functions as a DNA repair protein in the nucleus and as an antiapoptotic protein by binding to Bax in the cytoplasm, blocking Bax-mediated cell death. In neuroblastoma (NB) cells, Ku70's binding with Bax is regulated by Ku70 acetylation such that increasing Ku70 acetylation results in Bax release, triggering cell death. Although regulating cytoplasmic Ku70 acetylation is important for cell survival, the role of nuclear Ku70 acetylation in DNA repair is unclear. Here, we showed that Ku70 acetylation in the nucleus is regulated by the CREB-binding protein (CBP), and that Ku70 acetylation plays an important role in DNA repair in NB cells. We treated NB cells with ionization radiation and measured DNA repair activity as well as Ku70 acetylation status. Cytoplasmic and nuclear Ku70 were acetylated after ionization radiation in NB cells. Interestingly, cytoplasmic Ku70 was redistributed to the nucleus following irradiation. Depleting CBP in NB cells results in reducing Ku70 acetylation and enhancing DNA repair activity in NB cells, suggesting nuclear Ku70 acetylation may have an inhibitory role in DNA repair. These results provide support for the hypothesis that enhancing Ku70 acetylation, through deacetylase inhibition, may potentiate the effect of ionization radiation in NB cells.
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PMID:CREB-binding protein regulates Ku70 acetylation in response to ionization radiation in neuroblastoma. 2322 95

Ku70, a DNA repair factor in the nucleus, also regulates cell death by binding to the apoptotic protein Bax in the cytoplasm. Acetylation of Ku70 triggers Bax release resulting in Bax dependent cell death. Thus dissociating Bax from Ku70, either by inhibiting histone deacetylase 6 (HDAC6) that deacetylates Ku70 or by increasing Ku70 acetylation induces cell death. Our results showed that in neuroblastoma cells, the depletion of Ku70 results in Bax-dependent cell death. This model provides a rationale for screening Ku70 acetylation modulators that can be tested in clinical trials, either alone or in combination with radiotherapy or DNA-damaging agents for the treatment of cancer.
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PMID:Regulation of ku70-bax complex in cells. 2527 82


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