p16INK4a gene promoter variation and differential binding of a repressor, the ras-responsive zinc-finger transcription factor, RREB
p16INK4a gene promoter variation and differential binding of a repressor, the ras-responsive zinc-finger transcription factor, RREB
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DOI：
10.1038/sj.onc.1206257
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发表时间：
2003-04-17
期刊：
影响因子：
8
通讯作者：
Mock, BA
中科院分区：
文献类型：
--
作者：
Zhang, SL;Qian, XL;Mock, BA
BALB/c 小鼠易患降植烷诱导的浆细胞肿瘤，并且在 p16(INK4a) (p16) 肿瘤抑制基因的编码区具有罕见的等位基因变异，该基因会产生活性受损的蛋白质。我们现在发现 BALB/c p16 启动子有一个等位基因变异，也可能损害 p16 活性。降植烷处理后，B 细胞中的 BALB/c p16 mRNA 水平低于 DBA/2 或 C.D2-Petr1（一种抗性 BALB/c 同源菌株，在 p16 位点周围含有 DBA/2 染色质）。在 p16 启动子区域的 BALB/c 和 DBA/2 之间发现了四个序列变异。在报告基因检测中，DBA 启动子在驱动荧光素酶表达方面的活性至少是 BALB/c 启动子的四倍。活性的大部分差异归因于 BALB/c 中的单核苷酸缺失。这一缺失为 RREB 创建了一个共有结合位点，RREB 是一种具有锌指结合基序的 ras 响应转录元件。 RREB 瞬时转染证实 p16 启动子可以通过 Ras 或 Mek 依赖性方式被 RREB 下调，并且 BALB/c 启动子比 DBA/2 对 RREB 的调节更敏感。 BALB/c 小鼠具有调节区和编码区缺陷，可能导致 p16 基因功能受损。
BALB/c mice are susceptible to the development of pristane-induced plasma cell tumors, and have a rare allelic variant in the coding region of the p16(INK4a) (p16) tumor suppressor gene that produces a protein with impaired activity. We have now found that the BALB/c p16 promoter has an allelic variant that may also compromise p16 activity. Following pristane treatment, BALB/c p16 mRNA levels in B cells were lower than that in DBA/2 or C.D2-Petr1, a resistant BALB/c congenic strain that harbors DBA/2 chromatin surrounding the p16 locus. Four sequence variants were found between BALB/c and DBA/2 in the p16 promoter region. In reporter assays, the DBA promoter was at least four times more active in driving luciferase expression than the BALB/c promoter. Most of the difference in activity was localized to a single nucleotide deletion in BALB/c. This deletion created a consensus binding site for RREB, a ras-responsive transcriptional element with zinc-finger binding motifs. Transient transfections with RREB confirmed that the p16 promoter can be downregulated by RREB, in a Ras- or Mek-dependent manner, and that the BALB/c promoter is more sensitive than DBA/2 to regulation by RREB. BALB/c mice have both regulatory and coding region defects that may contribute to the impairment of p16 gene function.