Alternative splicing of RNA transcripts encoded by the murine p105 NF-kappa B gene generates I kappa B gamma isoforms with different inhibitory activities.

The gene encoding the 105-kDa protein (p105) precursor of the p50 subunit of transcription factor NF-kappa B also encodes a p70 I kappa B protein, I kappa B gamma, which is identical to the C-terminal 607 amino acids of p105. Here we show that alternative RNA splicing generates I kappa B gamma isoforms with properties different from those of p70. One 63-kDa isoform, termed I kappa B gamma-1, which lacks 59 amino acids C-terminal to ankyrin repeat 7, has a novel 35-amino acid C terminus encoded by an alternative reading frame of the p105 gene. A 55-kDa isoform, I kappa B gamma-2, lacks the 190 C-terminal amino acids of p70I kappa B gamma. In contrast to p70I kappa B gamma, which is a cytoplasmic protein, I kappa B gamma-1 is found in both the cytoplasm and nucleus, whereas I kappa B gamma-2 is predominantly nuclear. The I kappa B gamma isoforms also display differences in specificity and affinity for Rel/NF-kappa B proteins. While p70I kappa B gamma inhibits p50-, p65-, and c-Rel-mediated transactivation and/or DNA binding, both I kappa B gamma-1 and I kappa B gamma-2 are specific for p50 and have different affinities for this subunit. The absence in I kappa B gamma-1 and I kappa B gamma-2 of a protein kinase A site whose phosphorylation modulates p70I kappa B gamma inhibitory activity suggests that alternative RNA splicing may be used to generate I kappa B gamma isoforms that respond differently to intracellular signals. IMAGES:

转录因子核因子κB（NF-kappa B）p50亚基的105kDa蛋白（p105）前体编码基因，同时还可编码一种p70型IκBγ（I kappa B gamma）蛋白，其序列与p105的C端607个氨基酸完全一致。本研究证实，可变RNA剪接可产生与p70 IκBγ特性迥异的IκBγ亚型：其中一种63kDa的亚型被命名为IκBγ-1，其缺失了锚蛋白重复序列（ankyrin repeat）7下游的59个氨基酸，并拥有一段由p105基因可变阅读框编码的全新35氨基酸C端序列；另一种55kDa的亚型IκBγ-2，则缺失了p70 IκBγ的C端190个氨基酸。与作为细胞质蛋白的p70 IκBγ不同，IκBγ-1同时分布于细胞质与细胞核中，而IκBγ-2则主要定位于细胞核内。IκBγ亚型对Rel/NF-κB家族蛋白的结合特异性与亲和力亦存在差异：p70 IκBγ可抑制p50、p65以及c-Rel介导的转录激活和/或DNA结合，而IκBγ-1与IκBγ-2仅对p50具有特异性，且二者对该亚基的亲和力各不相同。IκBγ-1与IκBγ-2缺失了p70 IκBγ中一个可通过磷酸化调控其抑制活性的蛋白激酶A（protein kinase A）位点，这提示可变RNA剪接或可用于产生对细胞内信号响应模式各异的IκBγ亚型。IMAGES: