ALTERED GS AND ADENYLATE-CYCLASE ACTIVITY IN HUMAN GH-SECRETING PITUITARY-ADENOMAS
ALTERED GS AND ADENYLATE-CYCLASE ACTIVITY IN HUMAN GH-SECRETING PITUITARY-ADENOMAS
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DOI：
10.1038/330566a0
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发表时间：
1987-12-10
期刊：
影响因子：
64.8
通讯作者：
GIANNATTASIO, G
中科院分区：
文献类型：
--
作者：
VALLAR, L;SPADA, A;GIANNATTASIO, G
G和Giare鸟嘌呤核苷酸结合异源三聚体蛋白，调节腺苷酸环化酶的活性，并分别负责将刺激性和抑制性激素信号从细胞表面受体转移到酶催化单元1 -3。这些蛋白质可以直接激活剂，如GTP和类似物，氟化物和镁2，4，5。已经描述了Gs和Gi的量的减少，甚至Gs的缺乏6 -9，而在培养的细胞系中已经报道了改变的Gs（S49淋巴瘤细胞的突变体10），但是在人类疾病状态中从未观察到。我们在一组人生长激素分泌型垂体腺瘤中发现了一种发生了深刻改变的G蛋白，其特征是高分泌活性和细胞内环AMP水平。在这些肿瘤的膜中，没有观察到生长激素释放激素、GTP或氟化物对腺苷酸环化酶活性的刺激。事实上，最后两种药物引起抑制，可能是由Gi介导的。相比之下，腺苷酸环化酶的刺激镁离子大大增加。当肿瘤细胞膜的胆酸盐提取物（含有G蛋白）与不含GS的cyc−S49细胞膜重组时，腺苷酸环化酶调节的模式发生了改变。由于已知促生长细胞的分泌是cAMP依赖性的功能，因此G的改变可能是肿瘤高分泌活性的直接原因。
Gsand Giare guanine nucleotide-binding, heterotrimer proteins that regulate the activity of adenylate cyclase, and are responsible for transferring stimulatory and inhibitory hormonal signals, respectively, from cell surface receptors to the enzyme catalytic unit1–3. These proteins can be directly activated by agents such as GTP and analogues, fluoride and magnesium2,4,5. Decreased amounts of Gsand Giand even the absence of Gs, have been described6–9, whereas an altered Gshas been reported in a cultured cell line (UNC variant of S49 lymphoma cells10), but has never been observed in human disease states. We have found a profoundly altered Gsprotein in a group of human growth hormone-secreting pituitary adenomas, characterized by high secretory activity and intracellular cyclic AMP levels. In the membranes from these tumours no stimulation of adenylate cyclase activity by growth hormone-releasing hormone, by GTP or by fluoride was observed. Indeed, the last two agents caused an inhibition, probably mediated by Gi. In contrast, adenylate cyclase stimulation by Mg2+was enormously increased. This altered pattern of adenylate cyclase regulation was reproduced when a cholate extract of the tumour membranes (which contains G proteins) was reconstituted with Gs-free,cyc−S49 cell membranes. Inasmuch as secretion from somatotrophic cells is known to be a cAMP-dependent function11, the alteration of Gscould be the direct cause of the high secretory activity of the tumours in which it occurs.