Gastric hyperplasia in mice lacking the putative Cdc42 effector IQGAP1
Gastric hyperplasia in mice lacking the putative Cdc42 effector IQGAP1
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DOI：
10.1128/mcb.20.2.697-701.2000
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发表时间：
2000-01-01
影响因子：
5.3
通讯作者：
Bernards, A
中科院分区：
文献类型：
--
作者：
Li, SH;Wang, QJ;Bernards, A
人类 IQGAP1 是一种广泛表达的 190 kDa Cdc42、Rac1 和钙调蛋白结合蛋白，可在体内与 F-肌动蛋白相互作用，并可在体外交联 F-肌动蛋白微丝。最近的结果表明 IQGAP1 是 Cdc42 或 Rad 调节基于钙粘蛋白的细胞粘附的途径的一个组成部分 (S, Kuroda 等人, Science 281:832-835, 1998)，而酵母 IQGAP 相关蛋白已被发现在胞质分裂过程中发挥重要作用。为了确定 IQGAP1 的关键体内功能，我们通过基因靶向产生了缺陷小鼠。我们证明 IQGAP1 无效突变体以正常频率出现，并且在发育期间或成年后的大部分时间没有表现出明显的缺陷。 IQGAP1的缺失也不会影响肿瘤的发生或进展，但相对于相同遗传背景的野生型动物，突变小鼠表现出迟发性胃增生显着增加（P < 0.0001）。虽然我们不能排除 IQGAP2 的功能冗余导致发育表型缺乏，但 IQGAP2 的限制表达模式在成年 IQGAP1 突变小鼠中没有明显改变。因此，IQGAP1 在小鼠发育过程中不发挥任何重要的非冗余功能，但可能有助于维持老年动物胃粘膜的完整性。
Human IQGAP1 is a widely expressed 190-kDa Cdc42-, Rac1-, and calmodulin-binding protein that interacts with F-actin in vivo and that can cross-link F-actin microfilaments in vitro. Recent results have implicated IQGAP1 as a component of pathways via which Cdc42 or Rad modulates cadherin-based cell adhesion (S, Kuroda et al,, Science 281:832-835, 1998), whereas yeast IQGAP-related proteins have been found to play essential roles during cytokinesis. To identify critical in vivo functions of IQGAP1, we generated deficient mice by gene targeting. We demonstrate that IQGAP1 null mutants arise at normal frequency and show no obvious defects during development or for most of their adult life. Loss of IQGAP1 also does not affect tumor development or tumor progression, but mutant mice exhibit a significant (P < 0.0001) increase in late-onset gastric hyperplasia relative to wild-type animals of the same genetic background. While we cannot exclude that functional redundancy with IQGAP2 contributes to the Lack of developmental phenotypes, the restricted expression pattern of IQGAP2 is not obviously altered in adult IQGAP1 mutant mice. Thus, IQGAP1 does not serve any essential nonredundant functions during murine development but may serve to maintain the integrity of the gastric mucosa in older animals.