Tolbert Dawn, Lu Xiangdong, Yin Chaoying, Tantama Mathew, Van Dyke Terry
Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Mol Cell Biol. 2002 Jan;22(1):370-7. doi: 10.1128/MCB.22.1.370-377.2002.
Recent studies have shown the p19(ARF) tumor suppressor to be involved in the response to oncogenic stress by regulating the activity of p53. This response is mediated by antagonizing the function of Mdm2, a negative regulator of p53, indicating a pathway for tumor suppression that involves numerous genes altered in human tumors. We previously described a transgenic mouse brain tumor model in which oncogenic stress, provided by cell-specific inactivation of the pRb pathway, triggers a p53-dependent apoptotic response. This response suppresses the growth of developing tumors and thus represents a bona fide in vivo tumor suppressor activity. We further showed that E2F1, a transcription factor known to induce p19(ARF) expression, was required for the response. Here, we use a genetic approach to test whether p19(ARF) functions to transduce the signal from E2F1 to p53 in this tumor suppression pathway. Contrary to the currently accepted hypothesis, we show that a deficiency in p19(ARF) has no impact on p53-mediated apoptosis or tumor suppression in this system. All measures of p53 function, including the level of apoptosis induced by pRb inactivation, the expression of p21 (a p53-responsive gene), and the rate of tumor growth, were comparable in mice with and without a functional p19(ARF) gene. Thus, although p19(ARF) is required in some cell types to transmit an oncogenic response signal to p53, it is dispensable for this function in an in vivo epithelial system. These results underscore the complexity of p53 tumor suppression and further indicate the existence of distinct cell-specific pathways that respond to similar stimuli.
最近的研究表明，p19(ARF)肿瘤抑制因子通过调节p53的活性参与对致癌应激的反应。这种反应是通过拮抗Mdm2（p53的负调节因子）的功能介导的，这表明了一种肿瘤抑制途径，该途径涉及在人类肿瘤中改变的众多基因。我们之前描述了一种转基因小鼠脑肿瘤模型，其中由pRb途径的细胞特异性失活提供的致癌应激触发了p53依赖性凋亡反应。这种反应抑制了发育中肿瘤的生长，因此代表了一种真正的体内肿瘤抑制活性。我们进一步表明，E2F1（一种已知可诱导p19(ARF)表达的转录因子）是该反应所必需的。在这里，我们使用遗传学方法来测试p19(ARF)是否在这个肿瘤抑制途径中发挥作用，将信号从E2F1传递到p53。与目前公认的假设相反，我们表明p19(ARF)的缺陷对该系统中p53介导的凋亡或肿瘤抑制没有影响。p53功能的所有指标，包括pRb失活诱导的凋亡水平、p21（一个p53反应基因）的表达以及肿瘤生长速率，在有和没有功能性p19(ARF)基因的小鼠中是可比的。因此，尽管在某些细胞类型中p19(ARF)是将致癌反应信号传递给p53所必需的，但在体内上皮系统中该功能是可有可无的。这些结果强调了p53肿瘤抑制的复杂性，并进一步表明存在对相似刺激做出反应的不同细胞特异性途径。
