2 CACGTG MOTIFS WITH PROPER SPACING DICTATE THE CARBOHYDRATE REGULATION OF HEPATIC GENE-TRANSCRIPTION
2 CACGTG MOTIFS WITH PROPER SPACING DICTATE THE CARBOHYDRATE REGULATION OF HEPATIC GENE-TRANSCRIPTION
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DOI：
10.1074/jbc.270.37.21991
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发表时间：
1995-09-15
影响因子：
4.8
通讯作者：
TOWLE, HC
中科院分区：
文献类型：
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作者：
SHIH, HM;LIU, ZR;TOWLE, HC
研究了参与大鼠S-14基因转录诱导以响应肝细胞葡萄糖代谢增加的调控序列，并将其与肝型丙酮酸激酶（L-PK）基因的调控序列进行了比较。S-14基因的碳水化合物反应元件（ChoRE）由两个基序组成，这些基序与c-myc转录因子家族CACGTG的一致结合位点有关。这两个基序由5个碱基对分开，与L-PK ChoRE相似。在自然环境下，S-14 ChoRE需要一种新的辅助因子来支持对葡萄糖的完全反应。该因子以及肝核因子-4均能与L-PK基因结合，增强其对碳水化合物的调控。需要辅助因子来支持葡萄糖反应可以通过两种方式克服。首先，无论是L-PK基因还是S-14基因的多位点都可以独立发挥作用来支持葡萄糖反应。其次，S-14 ChoRE突变在每个位点上与一致的CACGTG基序完美匹配，不再需要辅助因子位点。两个CACGTG基序的间距，而不是间隔内碱基的性质，是控制的关键。这些观察结果表明，碳水化合物反应因子在高度特定的空间方向上与这两个基序结合，从而赋予碳水化合物代谢增加的反应。
Regulatory sequences involved in the transcriptional induction of the rat S-14 gene in response to increased glucose metabolism in the hepatocyte were investigated and compared with those of the liver-type pyruvate kinase (L-PK) gene. The carbohydrate response element (ChoRE) of the S-14 gene was found to consist of two motifs related to the consensus binding site for the c-myc family of transcription factors, CACGTG. These two motifs are separated by five base pairs, a similar arrangement to that found in the L-PK ChoRE. In its natural context, the S-14 ChoRE requires a novel accessory factor to support the full response to glucose. This factor, as well as the factor hepatic nuclear factor-4, are both capable of binding to the L-PK gene to enhance its carbohydrate regulation. The need for an accessory factor for supporting the glucose response can be overcome in two ways. First, multimers of the ChoREs of either the L-PK or S-14 genes can function independently to support the glucose response. Second, mutations in the S-14 ChoRE that create a perfect match to the consensus CACGTG motif at each locus no longer require an accessory factor site. The spacing of the two CACGTG motifs, but not the nature of the bases within the spacer, are critical for control. These observations suggest that a carbohydrate responsive factor binds to both motifs in a highly specific spatial orientation to confer the response to increased carbohydrate metabolism.