Moore Lynette, Venkatachalam Sundaresan, Vogel Hannes, Watt Julie C, Wu Chao-Ling, Steinman Heather, Jones Stephen N, Donehower Lawrence A
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Oncogene. 2003 Oct 30;22(49):7831-7. doi: 10.1038/sj.onc.1206985.
The p19ARF gene product responds to oncogenic stresses by interfering with the inhibitory effects of Mdm2 on p53, thus enhancing p53 activity and its antiproliferative functions. The absence of p19ARF in the mouse leads to early tumor susceptibility, presumably in part due to decreased p53 activity. To examine the tumorigenic cooperativity of p19ARF, Mdm2, and p53 in vivo, p19ARF-deficient mice were crossed first to p53-deficient mice and then to Mdm2 transgenic mice. The progeny were monitored for tumors. Cooperativity between p19ARF and p53 deficiencies in accelerating tumor formation was observed for most genotypes except p53-/- p19ARF-/- mice. p53-/- p19ARF-/- mice had a tumor incidence similar to p53-/- mice. In this context, tumor suppression by ARF appears to be primarily p53 dependent. The majority of the p19ARF+/- tumors deleted the wildtype p19ARF allele, in agreement with the previous studies, suggesting that p19ARF is a classic 'two hit' tumor suppressor. In a p53+/- background, however, all p19ARF+/- tumors retained a wildtype ARF allele and most also retained wildtype p53. In the second cross between p19ARF-deficient and Mdm2 transgenic mice, cooperativity in tumor incidence between Mdm2 overexpression and ARF deficiency was observed, consistent with the role of p19ARF in negatively regulating Mdm2 activity. These experiments further demonstrate in vivo the inter-relationships of the p19ARF-Mdm2-p53 signaling axis in tumor suppression.
p19ARF基因产物通过干扰Mdm2对p53的抑制作用来应对致癌应激，从而增强p53活性及其抗增殖功能。小鼠中p19ARF的缺失导致早期肿瘤易感性，推测部分原因是p53活性降低。为了在体内检测p19ARF、Mdm2和p53的致瘤协同作用，首先将p19ARF缺陷小鼠与p53缺陷小鼠杂交，然后与Mdm2转基因小鼠杂交。对后代进行肿瘤监测。除了p53-/- p19ARF-/-小鼠外，大多数基因型在加速肿瘤形成方面观察到p19ARF和p53缺陷之间的协同作用。p53-/- p19ARF-/-小鼠的肿瘤发生率与p53-/-小鼠相似。在这种情况下，ARF的肿瘤抑制作用似乎主要依赖于p53。与先前的研究一致，大多数p19ARF+/-肿瘤缺失了野生型p19ARF等位基因，这表明p19ARF是一种典型的“双打击”肿瘤抑制因子。然而，在p53+/-背景下，所有p19ARF+/-肿瘤都保留了野生型ARF等位基因，并且大多数还保留了野生型p53。在p19ARF缺陷小鼠与Mdm2转基因小鼠的第二次杂交中，观察到Mdm2过表达与ARF缺陷之间在肿瘤发生率方面的协同作用，这与p19ARF对Mdm2活性的负调节作用一致。这些实验进一步在体内证明了p19ARF-Mdm2-p53信号轴在肿瘤抑制中的相互关系。
