POSTTRANSCRIPTIONAL REGULATION OF TRANSFORMING GROWTH FACTOR-BETA 1

在许多细胞类型中，测量到的 转化生长因子-β1的mRNA和蛋白水平。此外，该委员会的许多成员 类固醇激素超家族，包括具有临床意义的 抗雌激素和某些新的合成孕激素似乎增加了 转化生长因子-β1蛋白的产生而不伴随任何mRNA的变化 级别。这表明翻译或翻译后机制 可能在调节转化生长因子-β1的产生中起重要作用。我们 对许多细胞类型进行了多聚体分析，并展示了 无论是最初的招聘还是随后的翻译-- β1基因可能是低效的。在某些细胞中，如乳房 腺癌株MCF-7有证据表明低丰度的小 转化生长因子-β1m RNA转录本可能优先翻译。至 对这些现象进行了进一步的研究，构建了表达载体 其中转化生长因子-β1基因的5‘和3’端非编码区的不同部分 已被删除。这些结构正被用于体外实验 转录/翻译以及在产生稳定的转化子时， 为了确定与转化生长因子-β1mRNA相关的区域 对于翻译调节，特别是对类固醇的反应 荷尔蒙超家族成员。初步实验表明，3‘ 非编码区可能是高效的信使核糖核酸翻译的关键。产品的生产 转化生长因子-β1对体外培养的细胞株对类固醇激素的反应不同 戏剧性地与培养条件相联系。方法论正在开发中。 测定人血浆中循环转化生长因子-β的方法 乳腺癌患者治疗前和治疗后 抗雌激素他莫昔芬和一种合成的维甲酸，以确定转化生长因子- 无论是在体内还是在体外，这些药物都能诱导出Beta。一个 对类固醇及相关化合物作用机制的认识 调节转化生长因子-β家族生长抑制物的生产可能 允许合理设计更有效的药理药剂用于 癌症的化学预防或化学治疗。

In many cell types there is a large discrepancy between the measured levels of TGF-Beta 1 mRNA and protein. Furthermore, many members of the steroid hormone superfamily, including the clinically significant antiestrogens and certain novel synthetic progestins, appear to increase TGF-Beta 1 protein production without any concomitant change in mRNA levels. This suggests that translational or post-translational mechanisms may play an important role in the regulation of TGF-Beta 1 production. We have performed polysome analyses on a number of cell types and have shown that both the initial recruitment and subsequent translation of the TGF- Beta 1 mRNA may be inefficient. In certain cells such as the breast adenocarcinoma line MCF-7, there is evidence that a low abundance of small TGF-Beta 1 mRNA transcript may be preferentially translated. To investigate these phenomena further, expression constructs have been made in which various portions of the 5' and 3' UTRs of the TGF-Beta 1 cDNA have been deleted. These constructs are being used for in vitro transcription/translation and in the generation of stable trans- fectants, in order to identify regions of the TGF-Beta 1 mRNA that are responsible for the translational regulation, particularly in response to steroid hormone superfamily members. Preliminary experiments indicate that the 3' UTR may be critical for efficient mRNA translation. The production of TGF-Beta 1 by cell lines in vitro in response to steroid hormones varies dramatically with culture conditions. The methodology is being developed to allow measurement of circulating TGF-Betas in the plasma of human subjects with breast cancer, before and after treatment with the antiestrogen tamoxifen and a synthetic retinoid, to determine whether TGF- Betas are induced by these agents in vivo as well as in vitro. An understanding of the mechanisms whereby steroids and related compounds regulate the production of the TGF-Beta family of growth inhibitors may allow the rational design of more potent pharmacological agents for use in chemoprevention or chemotherapy of cancer.