The differential impact of p16INK4a or p19ARF deficiency on cell growth and tumorigenesis
The differential impact of p16INK4a or p19ARF deficiency on cell growth and tumorigenesis
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DOI：
10.1038/sj.onc.1207074
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发表时间：
2004-01-15
期刊：
影响因子：
8
通讯作者：
DePinho, RA
中科院分区：
文献类型：
--
作者：
Sharpless, NE;Ramsey, MR;DePinho, RA
越来越多的遗传证据表明，Ink 4/Arf基因座的每种产物p16（INK 4a）和p19（ARF）具有肿瘤抑制活性（Kamijo et al.，1997; Krimpenfort等人，2001; Sharpless等人，2001年a）。我们报告了p19（ARF）特异性敲除等位基因（p19（ARF）-/-）的产生和表征，并与p16（INK 4a）、p16（INK 4a）和p19（ARF）以及p53缺陷的小鼠和衍生细胞进行了直接比较。与Ink 4/Arf-/-鼠胚胎成纤维细胞（MEFs）一样，p19（ARF）-/- MEFs对致癌转化高度敏感，在低密度下表现出增强的亚克隆效率，并抵抗RAS和培养诱导的生长停滞。相比之下，在这些测定中p16（INK 4a）-/- MEFs的生物学特征更接近于野生型细胞的生物学特征。然而，在体内，p19（ARF）-/-和p16（INK 4a）-/-动物都比野生型动物明显更容易发生肿瘤，但每一种都比p53-/-或Ink 4/Arf-/-动物少，并且具有不同的肿瘤谱。这些数据证实了p19（ARF）在基于细胞培养的MEFs检测中相对于p16（INK 4a）的主要作用，但也强调了在生物体内许多细胞类型中分析肿瘤抑制因子的重要性。p16（INK 4a）或p19（ARF）单一缺陷小鼠的癌症易感条件与来自人类癌症遗传学的数据一致，并加强了这两种基因产物在抑制体内恶性转化中发挥重要而非冗余作用的观点。
Mounting genetic evidence suggests that each product of the Ink4/Arf locus, p16(INK4a) and p19(ARF), possesses tumor-suppressor activity (Kamijo et al., 1997; Krimpenfort et al., 2001; Sharpless et al., 2001a). We report the generation and characterization of a p19(ARF)-specific knockout allele (p19(ARF)-/-) and direct comparison with mice and derivative cells deficient for p16(INK4a), both p16(INK4a) and p19(ARF), and p53. Like Ink4/Arf-/- murine embryo fibroblasts (MEFs), p19(ARF)-/- MEFs were highly susceptible to oncogenic transformation, exhibited enhanced subcloning efficiency at low density, and resisted both RAS- and culture-induced growth arrest. In contrast, the biological profile of p16(INK4a)-/- MEFs in these assays more closely resembled that of wild-type cells. In vivo, however, both p19(ARF)-/- and p16(INK4a)-/- animals were significantly more tumor prone than wild-type animals, but each less so than p53-/- or Ink4/Arf-/- animals, and with differing tumor spectra. These data confirm the predominant role of p19(ARF) over p16(INK4a) in cell culture-based assays of MEFs, yet also underscore the importance of the analysis of tumor suppressors across many cell types within the organism. The cancer-prone conditions of mice singly deficient for either p16(INK4a) or p19(ARF) agree with data derived from human cancer genetics, and reinforce the view that both gene products play significant and nonredundant roles in suppressing malignant transformation in vivo.