G-PROTEIN EFFECTORS AS TARGETS FOR ANTINEOPLASTIC THERAPIES

以前的研究表明，乳霜多糖（MP），一种肽衍生物， 具有两亲性的黄蜂毒液，可能会刺激 G蛋白介导的信号传导。我们也知道MP可以破坏 膜结构和改变某些磷脂酶的活性。到 确定膜破裂的结构要求， 改变G蛋白的功能，我们构建了几个类似物， 肽并使用Swiss 3 T3细胞膜对其进行表征。的影响 i）G-蛋白介导的刺激， 磷脂酶-C活性通过GTP γ和蛙皮素和ii）膜 Ca ~（2+）激活的磷脂酶-C和Na，K-ATP酶活性。MP 强烈抑制上述活性，并引起膜 透化作用用Gly取代一个Lys残基， 或C-末端产生肽， 抑制G蛋白刺激的磷脂酶-C，无或轻微膜- 扰动效应。将额外的Lys残基引入MP导致 相反的效果。因此，G蛋白调节和膜破坏 MP的行动似乎不一定是联系在一起的，也可能是分开的。

Previous studies had demonstrated that mastoparan(MP), a peptide derived from wasp venom with amphipathic properties, could potentially stimulate G-protein mediated signalling. It was also known that MP could disrupt membrane structure and alter the activity of certain phospholipases. To determine the structural requirements for disruption of membranes and for alteration of G-protein function, we constructed several analogs of the peptide and characterized them using Swiss 3T3 cell membranes. The effects of these peptides were measured on i) G-protein-mediated stimulation of phospholipase-C activity by GTPgamma and bombesin and ii) the membrane enzyme activities Ca2+-activated phospholipase-C and Na,K-ATPase. MP strongly inhibited all the above activities and caused membrane permeabilization. Substitution of one Lys residue by Gly at either the N- or C- terminal of the MP molecule resulted in peptides which selectively inhibited G-protein-stimulated phospholipase-C with no or slight membrane- perturbing effects. Introduction af additional Lys residues to MP led to the opposite effect. Thus, G-protein modulating and membrane-disrupting actions of MP appear to be not necessarily linked, and may be separated.