Whitman M, Melton D A
Department of Biochemistry and Molecular Biology, Cambridge, Massachusetts.
Nature. 1992 May 21;357(6375):252-4. doi: 10.1038/357252a0.
During early vertebrate embryogenesis, mesoderm is specified by a signal emanating from prospective endoderm. This signal can respecify Xenopus prospective ectoderm as mesoderm, and can be mimicked by members of the fibroblast growth factor and transforming growth factor-beta families. In other systems, the p21c-ras proto-oncogene product has been implicated in signal transduction for various polypeptide growth factors. We report here that a dominant inhibitory ras mutant blocks the mesoderm-inducing activity of fibroblast growth factor and activin, as well as the endogenous inducing activity of prospective endoderm. A constitutively active ras mutant partially mimics these activities. These results indicate that p21ras may have a central role in the transduction of the mesoderm inductive signal. Basic fibroblast growth factor and activin have emerged as candidates for endogenous mesoderm-inducing molecules. The character of the mesoderm induced by these two factors is overlapping but distinct when assessed both by histological and molecular criteria. The signal transduction pathways used during induction by these factors are unknown. We used messenger RNA microinjection of Xenopus eggs to express a dominant inhibitory mutant ras, p21(Asn 17)Ha-ras, in cells competent to respond to inducing factors to examine the role of p21ras in this response. This mutant, which has a reduced affinity for GTP relative to GDP, blocks a variety of mitogenic signals in 3T3 fibroblasts as well as the differentiation of pheochromocytoma cells in response to nerve growth factor.
在早期脊椎动物胚胎发生过程中，中胚层由来自预期内胚层的信号所指定。该信号可将非洲爪蟾的预期外胚层重新指定为中胚层，并且可被成纤维细胞生长因子家族和转化生长因子-β家族的成员模拟。在其他系统中，p21c-ras原癌基因产物已被牵涉到各种多肽生长因子的信号转导中。我们在此报告，一个显性抑制性ras突变体阻断了成纤维细胞生长因子和激活素的中胚层诱导活性，以及预期内胚层的内源性诱导活性。一个组成型激活的ras突变体部分模拟了这些活性。这些结果表明，p21ras可能在中胚层诱导信号的转导中起核心作用。碱性成纤维细胞生长因子和激活素已成为内源性中胚层诱导分子的候选者。当通过组织学和分子标准评估时，由这两种因子诱导的中胚层的特征是重叠但又不同的。这些因子诱导过程中所使用的信号转导途径尚不清楚。我们通过对非洲爪蟾卵进行信使核糖核酸显微注射，在能够对诱导因子作出反应的细胞中表达一个显性抑制性突变体ras，即p21(Asn 17)Ha-ras，以研究p21ras在这种反应中的作用。相对于GDP，该突变体对GTP的亲和力降低，它阻断了3T3成纤维细胞中的多种促有丝分裂信号，以及嗜铬细胞瘤细胞对神经生长因子的分化反应。
