Multihormonal Regulation of Milk Protein Gene Expression
Multihormonal Regulation of Milk Protein Gene Expression
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DOI：
10.1111/j.1749-6632.1986.tb15521.x
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发表时间：
1986-10
影响因子：
5.2
通讯作者：
J. Rosen;J. Rodgers;C. H. Couch;C. A. Bisbee;Y. David-Inouye;S. Campbell;L. Yu-Lee
中科院分区：
文献类型：
--
作者：
J. Rosen;J. Rodgers;C. H. Couch;C. A. Bisbee;Y. David-Inouye;S. Campbell;L. Yu-Lee
乳蛋白基因在乳腺上皮细胞中的表达受多种肽和类固醇激素在转录和转录后水平上的复杂相互作用的调节。影响细胞-细胞和细胞-基质相互作用的发育过程也在这些激素调节基因的表达中发挥关键作用。所描述的研究的总体目标是阐明调节乳蛋白基因表达的发育和多激素控制的机制。采用的一般方法是首先通过DNA介导的基因转移来确定通过阶段和组织特异性的可诱导的反式作用因子控制乳蛋白基因表达所需的顺式作用调控序列。一旦野生型和“突变型”基因都被鉴定出来，就有可能鉴定出这些特定的调控分子。我们实验室遇到的主要问题不是重组DNA技术的局限性，而是细胞生物学的局限性;即，细胞-细胞和细胞-基质相互作用以及细胞形状是调节乳蛋白基因表达的关键因素。与本次会议上讨论的大多数参与代谢调节的其他系统相反，我们实验室将要描述的研究将关注编码具有非酶功能的蛋白质的基因的调节。酪蛋白是主要的乳蛋白，是丰富的膳食蛋白质，对于提供必需氨基酸和将过饱和浓度的钙和磷酸盐转运到乳中是重要的。因此，需要慢性调节导致这些蛋白质的持续高水平合成和分泌，而不是酶活性的急性调节。在乳腺上皮细胞中，这种调节主要是转录后的，是初级转录物稳定的结果，而不是通过调节转录速率。与急性调节基因一样，如磷酸烯醇丙酮酸羧激酶（PEPCK）基因，不需要强启动子。相反，一个中等活性的启动子产生非常稳定的mRNA，导致高水平的乳蛋白mRNA的积累在哺乳期。这些效应的结果是，单独的5'侧翼DNA序列似乎不足以引起激素调节。
Milk protein gene expression in mammary epithelial cells is regulated by the complex interplay of several peptide and steriod hormones at both the transcriptional and posttranscriptional levels.’ Developmental processes that affect both cell-cell and cell-substratum interactions also play a critical role in the expression of these horrnonally regulated genes.* The overall objective of the studies to be described is to elucidate the mechanisms regulating the developmental and multihormonal control of milk protein gene expression. The general approach employed is first to define by DNA-mediated gene transfer cis-acting regulatory sequences required for the control of milk protein gene expression by stageand tissue-specific hormone-inducible transacting factors. Once both wild-type and “mutant” genes have been characterized it may then be possible to identify these specific regulatory molecules. The principal problems encountered in our laboratory are not the result of limitations of recombinant DNA technology, but rather those of cell biology; that is, cell-cell and cell-substratum interactions as well as cell shape are critical factors regulating milk protein gene expression. In contrast to most of the other systems involved in metabolic regulation discussed at this conference, the studies to be described from our laboratory will be concerned with the regulation of genes encoding proteins with nonenzymatic functions. Caseins, the principal milk proteins, are abundant dietary proteins important for the provision of essential amino acids and the transport of supersaturating concentrations of calcium and phosphate into milk. Therefore, there is a need for chronic regulation leading to a sustained high level of synthesis and secretion of these proteins, rather than an acute modulation of enzyme activity. In mammary epithelial cells this regulation is primarily posttranscriptional as a result of stabilization of the primary transcripts rather than by modulation of the rates of transcription. As with acutely regulated genes, such as the phosphoenolpyruvate carboxykinase (PEPCK) gene, there is no need for a strong promoter. Instead, a moderately active promoter generating extremely stable mRNAs leads to the accumulation of high levels of the milk protein mRNAs during lactation. The consequence of these effects is that 5’ flanking DNA sequences alone appear to be insufficient to elicit hormonal regulation.