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首页> 外文学位 >Topoisomerase II beta negatively modulates retinoic acid receptor alpha function: A novel mechanism of retinoic acid resistance in acute promyelocytic leukemia.
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Topoisomerase II beta negatively modulates retinoic acid receptor alpha function: A novel mechanism of retinoic acid resistance in acute promyelocytic leukemia.

机译：拓扑异构酶IIβ负调节视黄酸受体α功能：急性早幼粒细胞白血病中视黄酸抵抗的新机制。

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摘要

Interactions between the retinoic acid receptor alpha (RARalpha) and coregulators play a key role in coordinating gene transcription and myeloid differentiation. In acute promyelocytic leukemia (APL), RARalpha is fused with the promyelocytic leukemia (PML) gene, resulting in the expression of the fusion protein PML/RARalpha. Here, I report that topoisomerase II beta (topoIIbeta) associates with and negatively modulates PML/RARalpha and RARalpha transcriptional activity, and increased levels and association of topoIIbeta cause resistance to retinoic acid (RA) in APL cell lines. Knock down of topoIIbeta was able to overcome resistance by permitting RA-induced differentiation and increased RA-gene expression. Overexpression of topoIIbeta, in clones from an RA-sensitive cell line, conferred resistance by a reduction in RA-induced expression of target genes and differentiation. Chromatin immunoprecipitation assays indicate that topoIIbeta is bound to an RA-response element, and inhibition of topoIIbeta causes hyper-acetylation of histone 3 at lysine 9 and activation of transcription. These results identify a novel mechanism of resistance in APL and provide further insights to the role of topoIIbeta in gene regulation and differentiation.;In conclusion, these studies demonstrate that topoIIbeta associates with RARalpha, binds to RAREs and plays a critical role in RA dependent transcriptional regulation and granulocytic differentiation. In addition, I show that topoIIbeta overexpression leads to RA resistance and provide evidence that topoIIbeta protein levels are regulated via a mechanism involving the PKCdelta pathway. This work has contributed to an enhanced understanding of the role of topoIIbeta in gene regulation and brings novel perspectives in the treatment of RA-resistance in APL.;Studies to determine the mechanism by which topoIIbeta protein is regulated found that levels of protein kinase C delta (PKCdelta) correlated with topoIIbeta protein expression. Moreover, activation of PKCdelta, by RA or PMA, led to an increase of topoIIbeta protein levels. Most notably, in NB4-MR2 cells, we observed increased phosphorylation levels of threonine 505 on PKCdelta, a marker of activation. Inhibition of PKCdelta was able to overcome the topoIIbeta repressive effects on RA-target genes. In addition, the combination of RA and PKCdelta inhibition led to increased expression of the granulocytic marker, CD11c, in NB4 and NB4-MR2 cells. These results suggest that PKCdelta regulates topoIIbeta expression, and a constitutively active PKCdelta in the NB4-MR2 cell line leads to overexpression of topoIIbeta.
机译：视黄酸受体α（RARalpha）和调节剂之间的相互作用在协调基因转录和髓样分化中起关键作用。在急性早幼粒细胞白血病（APL）中，RARalpha与早幼粒细胞白血病（PML）基因融合，导致融合蛋白PML / RARalpha的表达。在这里，我报道拓扑异构酶II beta（topoIIbeta）与PML / RARalpha和RARalpha转录活性缔合并对其进行负调节，并且topoIIbeta的水平和缔合水平提高，导致APL细胞系对视黄酸（RA）产生抗性。通过允许RA诱导的分化和增加RA基因表达，敲低topoIIbeta能够克服耐药性。 RA敏感细胞系克隆中topoIIbeta的过表达通过减少RA诱导的靶基因表达和分化而赋予抗药性。染色质免疫沉淀测定表明topoIIbeta与RA反应元件结合，并且对topoIIbeta的抑制导致赖氨酸9处组蛋白3的过度乙酰化和转录激活。这些结果确定了APL抗药性的新机制，并为topoIIbeta在基因调控和分化中的作用提供了进一步的见解。总之，这些研究表明topoIIbeta与RARalpha缔合，与RAREs结合并在RA依赖性转录中起关键作用。调节和粒细胞分化。此外，我证明了topoIIbeta的过表达会导致RA耐药，并提供证据表明topoIIbeta的蛋白水平是通过涉及PKCdelta途径的机制来调节的。这项工作有助于增进对topoIIbeta在基因调控中的作用的了解，并为治疗APL的RA耐药性带来了新的观点。研究确定topoIIbeta蛋白质受调控机制的研究发现，蛋白激酶Cδ水平（PKCdelta）与topoIIbeta蛋白表达相关。此外，RA或PMA对PKCdelta的激活导致topoIIbeta蛋白水平增加。最值得注意的是，在NB4-MR2细胞中，我们观察到PKCdelta（激活标记）上苏氨酸505的磷酸化水平增加。 PKCdelta的抑制能够克服对RA靶基因的topoIIbeta抑制作用。此外，RA和PKCdelta抑制的组合导致了粒细胞标记CD11c在NB4和NB4-MR2细胞中的表达增加。这些结果表明PKCdelta调节topoIIbeta的表达，并且在NB4-MR2细胞系中组成型活性PKCdelta导致topoIIbeta的过表达。

著录项

  • 作者

    McNamara, Suzan.;

  • 作者单位

    McGill University (Canada).;

  • 授予单位 McGill University (Canada).;
  • 学科 Biology Cell.;Health Sciences Oncology.;Health Sciences Medicine and Surgery.
  • 学位 Ph.D.
  • 年度 2008
  • 页码 187 p.
  • 总页数 187
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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