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首页> 外文期刊>Oncogene >An unusual H-Ras mutant isolated from a human multiple myeloma line leads to transformation and factor-independent cell growth
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An unusual H-Ras mutant isolated from a human multiple myeloma line leads to transformation and factor-independent cell growth

机译：从人类多发性骨髓瘤细胞系分离出的不寻常的H-Ras突变体导致转化和因子独立的细胞生长

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Multiple myeloma (MM) is an incurable plasma cell malignancy. To investigate biochemical lesions associated with MM, we constructed an expression cDNA library from the OPM-2 human myeloma line. A highly transforming H-Ras mutant was identified by transfection analysis using NIH 3T3 cells. DNA sequencing demonstrated a single-point mutation at position 117 located in the guanine nucleotide-binding site resulting in a lysine-to-glutamic acid substitution. This mutant, H-Ras (K117E), was found to be constitutively activated in terms of GTP binding. We compared the biological effects of H-Ras (K117E) and H-Ras (G12V) in 32D murine hematopoietic progenitor cells. Whereas both Ras proteins are constitutively activated, 32D cells expressing H-Ras (G12V) are still dependent on IL-3 for survival and proliferation while cells carrying H-Ras (K117E) become IL-3 independent. Similar experiments conducted with the B9 line, an IL-6-dependent hybridoma, also demonstrated that B9/H-Ras (K117E) became IL-6-independent. Expression of H-Ras (K117E) in the human IL-6-dependent ANBL-6 myeloma line resulted in enhanced proliferation at suboptimal concentrations of IL-6. These observations suggest that H-Ras mutations at the binding site for the GTP nucleotide ring structure may also represent activating lesions and have additional biological effects when compared to previously described Ras mutants.
机译：多发性骨髓瘤（MM）是无法治愈的浆细胞恶性肿瘤。为了调查与MM相关的生化病变，我们从OPM-2人骨髓瘤细胞系构建了一个表达cDNA文库。通过使用NIH 3T3细胞进行转染分析，鉴定了高度转化的H-Ras突变体。 DNA测序表明位于鸟嘌呤核苷酸结合位点117处的单点突变导致赖氨酸-谷氨酸取代。发现该突变体H-Ras（K117E）就GTP结合而言被组成性激活。我们比较了H-Ras（K117E）和H-Ras（G12V）在32D小鼠造血祖细胞中的生物学作用。尽管两种Ras蛋白都被组成性激活，但表达H-Ras（G12V）的32D细胞的存活和增殖仍然依赖IL-3，而带有H-Ras（K117E）的细胞变得独立于IL-3。用B9系（一种依赖IL-6的杂交瘤）进行的类似实验也证明B9 / H-Ras（K117E）变得不依赖IL-6。 H-Ras（K117E）在人类依赖IL-6的ANBL-6骨髓瘤细胞系中的表达导致在次适浓度的IL-6下增殖增强。这些观察结果表明，与先前描述的Ras突变体相比，在GTP核苷酸环结构的结合位点处的H-Ras突变也可能代表活化损伤并且具有额外的生物学效应。

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