Expression in hematological malignancies of a glucocorticoid receptor splice variant that augments glucocorticoid receptor-mediated effects in transfected cells.
Expression in hematological malignancies of a glucocorticoid receptor splice variant that augments glucocorticoid receptor-mediated effects in transfected cells.
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DOI：
10.1158/0008-5472.3937.61.10
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发表时间：
2001-05
期刊：
影响因子：
11.2
通讯作者：
Piet de Lange;C. Segeren;J. Koper;E. Wiemer;P. Sonneveld;A. Brinkmann;Anne White;I. Brogan;F. Jong;S. Lamberts
中科院分区：
文献类型：
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作者：
Piet de Lange;C. Segeren;J. Koper;E. Wiemer;P. Sonneveld;A. Brinkmann;Anne White;I. Brogan;F. Jong;S. Lamberts
糖皮质激素在许多血液恶性肿瘤（例如多发性骨髓瘤）的治疗中发挥着重要作用。糖皮质激素的作用是通过糖皮质激素受体α介导的，其丰度可以通过糖皮质激素受体mRNA的选择性剪接来调节。糖皮质激素受体 mRNA 的两种剪接变体已被描述：糖皮质激素受体 β（据报道对糖皮质激素受体 α 的作用具有显着的负面影响）和糖皮质激素受体 P（其影响尚不清楚）。在这项研究中，我们研究了多发性骨髓瘤细胞和许多其他血液肿瘤中这两种剪接变体在 mRNA 水平上的表达水平。尽管糖皮质激素受体 β mRNA（如果有的话）的表达水平非常低，但在大多数血液恶性肿瘤中存在相当数量（高达总糖皮质激素受体 mRNA 的 50%）的糖皮质激素受体 P mRNA。在几种细胞类型和多发性骨髓瘤细胞系的瞬时转染研究中，糖皮质激素受体 P 增加了糖皮质激素受体 α 的活性。这些结果表明，糖皮质激素受体α和糖皮质激素受体P的相对水平可能在糖皮质激素治疗血液恶性肿瘤过程中肿瘤细胞糖皮质激素抵抗的发生中发挥作用。
Glucocorticoids play an important role in the treatment of a number of hematological malignancies, such as multiple myeloma. The effects of glucocorticoids are mediated through the glucocorticoid receptor alpha, the abundance of which can be modulated by alternative splicing of the glucocorticoid receptor mRNA. Two splice variants of the glucocorticoid receptor mRNA have been described: glucocorticoid receptor beta, which reportedly has a dominant negative effect on the actions of the glucocorticoid receptor alpha, and glucocorticoid receptor P, of which the effects are unknown. In this study, we have investigated the expression levels of these two splice variants at the mRNA level in multiple myeloma cells and in a number of other hematological tumors. Although the glucocorticoid receptor beta mRNA was, if at all, expressed at very low levels, considerable amounts (up to 50% of the total glucocorticoid receptor mRNA) glucocorticoid receptor P mRNA was present in most hematological malignancies. In transient transfection studies in several cell types and in multiple myeloma cell lines, the glucocorticoid receptor P increased the activity of the glucocorticoid receptor alpha. These results suggest that the relative levels of the glucocorticoid receptor alpha and the glucocorticoid receptor P may play a role in the occurrence of glucocorticoid resistance in tumor cells during the treatment of hematological malignancies with glucocorticoids.