Parker Kimberly M, Ma Mark H, Manyak Steven, Altamirano Cibby V, Tang Yong M, Frantzen Malka, Mikail Amy, Roussos Evanthia, Sjak-Shie Nelida, Vescio Robert A, Berenson James R
Division of Hematology and Oncology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Cancer Genet Cytogenet. 2002 Aug;137(1):43-8. doi: 10.1016/s0165-4608(02)00541-1.
When NF-kappaB proteins are bound to IkappaBalpha, they remain in the cytosol, and are unable to act as transcription factors. Phosphorylation of IkappaBalpha at Serine32 and Serine36 has been shown to stimulate ubiquitination followed by proteasome-mediated degradation of IkappaBalpha, resulting in the release of active NF-kappaB. NF-kappaB activity is associated with bone loss and B cell growth as well as chemotherapy resistance. Because previous studies have shown abnormalities of the IkappaBalpha gene in patients with lymphoma, we determined whether alterations of this gene also occur in multiple myeloma (MM). We determined the DNA sequence of the IkappaBalpha gene from bone marrow mononuclear cells from 18 MM patients and 24 healthy subjects as well as two MM cell-lines. We identified eight polymorphisms. Statistically, the prevalence of three polymorphisms, one in exon 1 and two in exon 6, were significantly higher in MM patients (alpha>1) compared with samples from control subjects. Six of eight polymorphisms in myeloma samples have also been identified in previous studies of IkappaBalpha sequences derived from lymphoma samples. In addition, we detected two polymorphisms in the IkappaBalpha gene that have not been previously reported. Together, these results provide the basis for future evaluation the IkappaBalpha/NF-kappaB pathway in MM patients.
当核因子-κB（NF-κB）蛋白与IκBα结合时，它们会留在细胞质中，无法作为转录因子发挥作用。IκBα在丝氨酸32和丝氨酸36处的磷酸化已被证明会刺激泛素化，随后蛋白酶体介导IκBα降解，从而导致活性NF-κB的释放。NF-κB活性与骨质流失、B细胞生长以及化疗耐药性有关。由于先前的研究表明淋巴瘤患者中IκBα基因存在异常，我们确定该基因的改变是否也发生在多发性骨髓瘤（MM）中。我们测定了18例MM患者、24名健康受试者的骨髓单个核细胞以及两个MM细胞系中IκBα基因的DNA序列。我们鉴定出了8个多态性位点。从统计学角度来看，与对照样本相比，MM患者中3个多态性位点的发生率显著更高（α>1），其中1个在外显子1，2个在外显子6。骨髓瘤样本中的8个多态性位点中有6个也在先前对淋巴瘤样本来源的IκBα序列研究中被鉴定出来。此外，我们还检测到了2个先前未报道过的IκBα基因多态性位点。总之，这些结果为未来评估MM患者的IκBα/NF-κB信号通路提供了依据。
