Department of Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas, United States of America.
PLoS One. 2009 Nov 10;4(11):e7775. doi: 10.1371/journal.pone.0007775.
WWOX, the gene that spans the second most common human chromosomal fragile site, FRA16D, is inactivated in multiple human cancers and behaves as a suppressor of tumor growth. Since we are interested in understanding WWOX function in both normal and cancer tissues we generated mice harboring a conditional Wwox allele by flanking Exon 1 of the Wwox gene with LoxP sites. Wwox knockout (KO) mice were developed by breeding with transgenic mice carrying the Cre-recombinase gene under the control of the adenovirus EIIA promoter. We found that Wwox KO mice suffered from severe metabolic defect(s) resulting in growth retardation and all mice died by 3 wk of age. All Wwox KO mice displayed significant hypocapnia suggesting a state of metabolic acidosis. This finding and the known high expression of Wwox in kidney tubules suggest a role for Wwox in acid/base balance. Importantly, Wwox KO mice displayed histopathological and hematological signs of impaired hematopoiesis, leukopenia, and splenic atrophy. Impaired hematopoiesis can also be a contributing factor to metabolic acidosis and death. Hypoglycemia and hypocalcemia was also observed affecting the KO mice. In addition, bone metabolic defects were evident in Wwox KO mice. Bones were smaller and thinner having reduced bone volume as a consequence of a defect in mineralization. No evidence of spontaneous neoplasia was observed in Wwox KO mice. We have generated a new mouse model to inactivate the Wwox tumor suppressor gene conditionally. This will greatly facilitate the functional analysis of Wwox in adult mice and will allow investigating neoplastic transformation in specific target tissues.
WWOX 基因跨越了人类第二大常见染色体脆性位点 FRA16D，在多种人类癌症中失活，并表现出抑制肿瘤生长的作用。由于我们有兴趣了解 WWOX 在正常组织和癌症组织中的功能，我们通过在 Wwox 基因的外显子 1 侧翼用 LoxP 位点生成了携带条件性 Wwox 等位基因的小鼠。通过与携带腺病毒 EIIA 启动子控制的 Cre 重组酶基因的转基因小鼠杂交，开发了 Wwox 敲除（KO）小鼠。我们发现 Wwox KO 小鼠患有严重的代谢缺陷，导致生长迟缓，所有小鼠在 3 周龄时死亡。所有 Wwox KO 小鼠均表现出明显的低碳酸血症，表明存在代谢性酸中毒状态。这一发现以及已知的 Wwox 在肾小管中的高表达表明 Wwox 在酸碱平衡中发挥作用。重要的是，Wwox KO 小鼠表现出造血功能受损、白细胞减少和脾脏萎缩的组织病理学和血液学迹象。造血功能受损也可能是代谢性酸中毒和死亡的一个促成因素。KO 小鼠还出现了低血糖和低钙血症。此外，在 Wwox KO 小鼠中还观察到骨代谢缺陷。由于矿化缺陷，骨骼更小、更薄，骨量减少。在 Wwox KO 小鼠中未观察到自发肿瘤的证据。我们已经生成了一种新的小鼠模型，可条件性地使 Wwox 肿瘤抑制基因失活。这将极大地促进成年小鼠中 Wwox 的功能分析，并允许在特定靶组织中研究肿瘤转化。
