Kichina J V, Zeremski M, Aris L, Gurova K V, Walker E, Franks R, Nikitin A Y, Kiyokawa H, Gudkov A V
Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
Oncogene. 2006 Feb 9;25(6):857-66. doi: 10.1038/sj.onc.1209118.
Ing1 belongs to the family of evolutionary conserved genes encoding nuclear PHD finger-containing proteins implicated in a variety of processes, including tumorigenesis, replicative senescence, excision repair and response to genotoxic stress. We have generated mice deficient in all the isoforms of Ing1 by targeted disruption of the exon that is common for all ing1 transcripts. Embryonic fibroblasts from ing1-knockout mice were similar to the wild-type cells in their growth characteristics, replicative lifespan in culture, p53 induction and sensitivity to various cytotoxic treatments with minor alterations in cell cycle distribution in response to genotoxic stress. ing1-deficient animals are characterized by reduced size with no obvious morphological, physiological or behavioral abnormalities, indicating that ing1 function is dispensable for the viability of mice under normal physiological conditions. Loss of ing1 was associated with earlier onset and higher incidence of lymphomas. Consistent with the possible involvement of Ing1 in DNA repair, ing1-deficient mice were more sensitive to total body gamma radiation. Our observations are well in line with the suggested role of ing1 as a candidate tumor suppressor gene involved in control of DNA damage response.
Ing1属于进化保守基因家族，该家族编码含核PHD结构域的蛋白质，这些蛋白质参与多种过程，包括肿瘤发生、复制性衰老、切除修复以及对基因毒性应激的反应。我们通过靶向破坏所有Ing1转录本共有的外显子，培育出了缺失所有Ing1异构体的小鼠。Ing1基因敲除小鼠的胚胎成纤维细胞在生长特性、培养中的复制寿命、p53诱导以及对各种细胞毒性处理的敏感性方面与野生型细胞相似，只是在对基因毒性应激的反应中细胞周期分布有轻微改变。Ing1基因缺陷的动物体型较小，但无明显的形态、生理或行为异常，这表明在正常生理条件下，Ing1功能对于小鼠的生存并非必需。Ing1缺失与淋巴瘤的发病提前和发病率升高有关。与Ing1可能参与DNA修复一致，Ing1基因缺陷的小鼠对全身γ辐射更敏感。我们的观察结果与Ing1作为参与控制DNA损伤反应的候选肿瘤抑制基因的推测作用高度相符。
