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首页> 外文期刊>Biochemistry >Antiapoptotic cdc42 mutants are potent activators of cellular transformation.
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Antiapoptotic cdc42 mutants are potent activators of cellular transformation.

机译：抗曝气剂CDC42突变体是细胞转化的有效活化剂。

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Cdc42 is a small GTP-binding protein which has been implicated in a number of cellular activities, including cell morphology, motility, cell-cycle progression, and malignant transformation. While GTPase-defective forms of Cdc42 inhibit cell growth, a mutation [Cdc42(F28L)] that allows the constitutive exchange of GDP for GTP and is GTPase-competent induces cellular transformation. These results suggest that Cdc42 must cycle between its GTP- and GDP-bound states to stimulate cell growth. In attempting to design Cdc42 molecules with more potent transforming activity, we set out to generate other types of Cdc42 mutants capable of constitutive GDP-GTP exchange. Here, we describe one such mutant, generated by changing a conserved aspartic acid residue at position 118 to an asparagine. The Cdc42(D118N) protein exchanges GDP for GTP more rapidly than wild-type Cdc42, but significantly more slowly than the Cdc42(F28L) mutant. Despite its slower rate of activation, the Cdc42(D118N) mutant is more potent at inducing cellular transformation than the Cdc42(F28L) protein, and causes a significant loss in actin stress fibers, reminiscent of what is observed with fibroblasts transformed by oncogenic Ras mutants. Effector-loop mutations made within the D118N background inhibit Cdc42-induced transformation and Cdc42-mediated antiapoptotic (survival) activity to similar extents. In addition, mutating aspartic acid 121 (to asparagine), which forms part of a caspase cleavage site (DLRD, residues 118-121 of Cdc42), in combination with the F28L mutation generates a Cdc42 molecule [Cdc42(F28L/D121N)] with transforming activity significantly stronger than that of Cdc42(F28L). Thus, mutations that combine some capacity for cycling between the GTP- and GDP-bound states with increased survival against apoptotic signals yield Cdc42 molecules with the maximum capability for inducing cellular transformation.
机译：CDC42是一种小GTP结合蛋白，其涉及多种细胞活性，包括细胞形态，运动，细胞周期进展和恶性转化。虽然GTPase缺陷的CDC42抑制细胞生长，但突变[CDC42（F28L）]，其允许GDP的组成型GDP和GTP酶致力诱导细胞转化。这些结果表明，CDC42必须在其GTP和GDP绑定状态之间循环以刺激细胞生长。在尝试设计具有更有效的转化活动的CDC42分子时，我们开始产生能够组成的GDP-GTP交换的其他类型的CDC42突变体。在这里，我们描述一种这样的突变体，通过在118位至天冬酰胺的位置改变保守的天冬氨酸残基而产生。 CDC42（D118N）蛋白质比野生型CDC42更快地将GDP交换GDP，但显着比CDC42（F28L）突变体更缓慢。尽管活化速度较慢，CDC42（D118N）突变体在诱导细胞转化时比CDC42（F28L）蛋白更有效，并且在肌动蛋白应激纤维中造成显着的损失，使用致癌RAS突变体转化的成纤维细胞观察到的内容。在D118N背景中提出的效应环突变抑制CDC42诱导的转化和CDC42介导的抗曝光（存活）活性与相似的范围。另外，与F28L突变组合形成胱天冬烷酸121（浅冬酰胺），其形成半胱天冬酶切割位点（DLRD，CDC42的残基118-121）的一部分，产生CDC42分子[CDC42（F28L / D121N）]转化活性明显强于CDC42（F28L）。因此，将一些能力组合在GTP和GDP结合状态之间循环的突变，随着凋亡信号的增加而增加，产生CDC42分子，具有诱导细胞转化的最大能力。

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