Lawrence R, Chang L J, Siebenlist U, Bressler P, Sonenshein G E
Department of Biochemistry, Boston University Medical School, Massachusetts 02118.
J Biol Chem. 1994 Nov 18;269(46):28913-8.
The NF-kappa B/Rel family of transcription factors is commonly expressed in non-hematopoietic cells in an inactive form within the cytoplasm, complexed with an inhibitor I kappa B protein. Thus, it was surprising that NF-kappa B element-driven heterologous promoter-reporter gene constructs were active upon transient transfection into vascular smooth muscle cells (VSMCs). Here, we report that VSMCs express a constitutive nuclear NF-kappa B-like activity. In electrophoretic mobility shift assays, nuclear extracts demonstrated binding to a wild type NF-kappa B element but not to those mutated at nucleotides critical for Rel-protein DNA interaction. Binding was abrogated by the presence of I kappa B-alpha. Furthermore, addition of an antibody to the p50 subunit of classical NF-kappa B (but not p65, c-Rel, or RelB) resulted in supershifted complexes. Transactivation of element-driven constructs was negatively affected by co-transfection of a vector expressing a dominant negative p50 subunit, which can dimerize with other Rel subunits but not bind DNA. The long terminal repeat of the human immunodeficiency virus-1, which is driven in part by two NF-kappa B elements, displayed strong activity within VSMCs. This activity was abrogated upon co-transfection of the vector expressing the dominant negative p50 mutant. Taken together, these experiments indicate that VSMCs constitutively express a functional NF-kappa B-like trans-acting factor, which may play a significant role in the regulation of proliferation and viral infection of these cells.
转录因子NF-κB/Rel家族通常以无活性形式存在于非造血细胞的细胞质中,并与抑制蛋白IκB结合。因此,当NF-κB元件驱动的异源启动子-报告基因构建体瞬时转染到血管平滑肌细胞(VSMC)中时具有活性,这一点令人惊讶。在此,我们报道VSMC表达一种组成性核NF-κB样活性。在电泳迁移率变动分析中,核提取物显示与野生型NF-κB元件结合,但不与在Rel蛋白与DNA相互作用的关键核苷酸处发生突变的元件结合。IκB-α的存在可消除这种结合。此外,添加针对经典NF-κB的p50亚基(而非p65、c-Rel或RelB)的抗体可导致复合物超迁移。元件驱动构建体的反式激活受到表达显性负性p50亚基载体共转染的负面影响,该显性负性p50亚基可与其他Rel亚基二聚化但不结合DNA。人类免疫缺陷病毒1的长末端重复序列部分由两个NF-κB元件驱动,在VSMC中显示出强活性。在共转染表达显性负性p50突变体的载体后,这种活性被消除。综上所述,这些实验表明VSMC组成性表达一种功能性NF-κB样反式作用因子,其可能在这些细胞的增殖和病毒感染调节中发挥重要作用。