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首页> 外文期刊>Molecular and Cellular Biology >Transcription of the rat glucagon gene by the cyclic AMP response element-binding protein CREB is modulated by adjacent CREB-associated proteins.
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Transcription of the rat glucagon gene by the cyclic AMP response element-binding protein CREB is modulated by adjacent CREB-associated proteins.

机译：环状AMP反应元件结合蛋白CREB对大鼠胰高血糖素基因的转录受邻近的CREB相关蛋白调控。

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摘要

The cyclic AMP (cAMP) response element (CRE) of the rat glucagon gene (Glu-CRE, 5'-TGACGTCA-3') mediates transcriptional responses to 8-bromo-cAMP and protein kinase A (PKA) in a glucagon-producing hamster islet cell line (InR1G9). By several different DNA-protein binding assays, we show that the transcription factor CREB binds to the CRE octamer and that additional nuclear proteins bind to sequences adjacent to the CRE. Mutation of the Glu-CRE octamer attenuates both the binding of CREB and cAMP-dependent PKA-stimulated transcriptional activity in transient transfection experiments but does not affect the binding of adjacent CREB-associated proteins. Progressive deletions and clustered point mutations of the sequences flanking the Glu-CRE identify sequences (5'-TCATT-3') located both 5' and 3' to the core CRE octamer that bind several proteins. Two proteins with molecular masses of 80 and 100 kDa bind to each of the 5' and 3' TCATT sites. Formation of additional protein-DNA complexes containing 45- and 20-kDa proteins depends upon the integrity of both TCATT sequences. Deletion or point mutation of the TCATT motif located on the 3' side of the CRE octamer results in enhanced transcriptional responses to PKA, suggesting that the CREB-associated proteins decrease the ability of CREB to mediate PKA-stimulated transcription. Results from these studies demonstrate that nucleotides flanking the core CRE octamer can influence the activity of the CRE by serving as binding sites for proteins that modulate the function of CREB and suggest a mechanism to explain why some consensus palindromic CREs are less responsive to cAMP stimulation than others.
机译：大鼠胰高血糖素基因（Glu-CRE，5'-TGACGTCA-3'）的环状AMP（cAMP）反应元件（CRE）介导产生胰高血糖素的8-溴-cAMP和蛋白激酶A（PKA）的转录反应仓鼠胰岛细胞系（InR1G9）。通过几种不同的DNA-蛋白质结合测定，我们表明转录因子CREB与CRE八聚体结合，另外的核蛋白与与CRE相邻的序列结合。在瞬时转染实验中，Glu-CRE八聚体的突变既减弱了CREB的结合，又减弱了cAMP依赖性PKA刺激的转录活性，但不影响相邻CREB相关蛋白的结合。位于Glu-CRE侧翼的序列的进行性缺失和聚类点突变可识别位于与几个蛋白结合的核心CRE八聚体的5'和3'的序列（5'-TCATT-3'）。分子量为80和100 kDa的两种蛋白质分别与5'和3'TCATT位点结合。包含45kDa和20kDa蛋白质的其他蛋白质-DNA复合物的形成取决于两个TCATT序列的完整性。位于CRE八聚体3'侧的TCATT基序的缺失或点突变导致对PKA的转录反应增强，表明CREB相关蛋白降低了CREB介导PKA刺激的转录的能力。这些研究的结果表明，位于核心CRE八聚体侧翼的核苷酸可以通过充当调节CREB功能的蛋白质的结合位点来影响CRE的活性，并提出了一种机制来解释为什么某些共识回教CRE对cAMP刺激的反应比其他。

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