G-PROTEIN-COUPLED RECEPTOR GENES AS PROTOONCOGENES - CONSTITUTIVELY ACTIVATING MUTATION OF THE ALPHA-1B-ADRENERGIC RECEPTOR ENHANCES MITOGENESIS AND TUMORIGENICITY
G-PROTEIN-COUPLED RECEPTOR GENES AS PROTOONCOGENES - CONSTITUTIVELY ACTIVATING MUTATION OF THE ALPHA-1B-ADRENERGIC RECEPTOR ENHANCES MITOGENESIS AND TUMORIGENICITY
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DOI：
10.1073/pnas.88.24.11354
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发表时间：
1991-12-01
影响因子：
11.1
通讯作者：
COTECCHIA, S
中科院分区：
文献类型：
--
作者：
ALLEN, LF;LEFKOWITZ, RJ;COTECCHIA, S
α - 1b肾上腺素能受体（α - 1b -adr）是跨膜受体g蛋白偶联家族的一员。当转染到大鼠-1和NIH 3T3成纤维细胞时，该受体以激动剂依赖的方式诱导病灶形成。病灶衍生的转化成纤维细胞表现出高水平的功能性α - 1b - adr表达，显示出儿茶酚胺诱导的细胞增殖速度的增强，并且当注射到裸鼠中时具有致瘤性。因此，α - 1b - adr诱导肿瘤转化，将这种正常细胞基因确定为原癌基因。该受体的突变改变可导致该原癌基因的激活，从而增强激动剂诱导灶形成的能力，减少潜伏时间，增加转化灶的数量。与表达野生型α - 1b - adr的细胞相比，在表达“癌变”的细胞系中，灶的形成似乎随着未受刺激细胞中灶的产生而构成性地激活。此外，即使在没有补充儿茶酚胺的情况下，这些细胞系也表现出接近最大的增殖率。与表达野生型受体的细胞相比，它们在裸小鼠中产生肿瘤的能力增强，潜伏期缩短。因此，α - 1b - adr基因在过度表达和激活时，可以作为致癌基因诱导肿瘤转化。该受体基因的突变改变可导致该原癌基因的激活，增强其致癌潜能。这些发现表明，这类受体蛋白类似的自发突变可能在肿瘤转化和动脉粥样硬化的诱导或进展中发挥关键作用。
The alpha-1B-adrenergic receptor (alpha-1B-ADR) is a member of the G-protein-coupled family of transmembrane receptors. When transfected into Rat-1 and NIH 3T3 fibroblasts, this receptor induces focus formation in an agonist-dependent manner. Focus-derived, transformed fibroblasts exhibit high levels of functional alpha-1B-ADR expression, demonstrate a catecholamine-induced enhancement in the rate of cellular proliferation, and are tumorigenic when injected into nude mice. Induction of neoplastic transformation by the alpha-1B-ADR, therefore, identifies this normal cellular gene as a protooncogene. Mutational alteration of this receptor can lead to activation of this protooncogene, resulting in an enhanced ability of agonist to induce focus formation with a decreased latency and quantitative increase in transformed foci. In contrast to cells expressing the wild-type alpha-1B-ADR, focus formation in "oncomutant"-expressing cell lines appears constitutively activated with the generation of foci in unstimulated cells. Further, these cell lines exhibit near-maximal rates of proliferation even in the absence of catecholamine supplementation. They also demonstrate an enhanced ability for tumor generation in nude mice with a decreased period of latency compared with cells expressing the wild-type receptor. Thus, the alpha-1B-ADR gene can, when overexpressed and activated, function as an oncogene inducing neoplastic transformation. Mutational alteration of this receptor gene can result in the activation of this protooncogene, enhancing its oncogenic potential. These findings suggest that analogous spontaneously occurring mutations in this class of receptor proteins could play a key role in the induction or progression of neoplastic transformation and atherosclerosis.