p53 must be competent for transcriptional regulation to suppress tumor formation
p53 must be competent for transcriptional regulation to suppress tumor formation
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DOI：
10.1038/sj.onc.1208354
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发表时间：
2005-05-19
期刊：
影响因子：
8
通讯作者：
Wahl, GM
中科院分区：
文献类型：
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作者：
Nistér, M;Tang, MJ;Wahl, GM
体外研究表明，p53的有效肿瘤抑制需要多个结构域来执行转录依赖性和转录非依赖性功能。我们在小鼠中产生了突变的p53等位基因，p53（W25 QL 26 S）（p53（QS）），含有一个无活性的反式激活结构域，以评估反式激活对p53介导的肿瘤抑制的重要性。最近，我们发现该等位基因在密码子135处也包含丙氨酸的缬氨酸取代，该密码子与DNA结合结构域相邻。我们发现，p53（QSval 135）结合染色质，虽然不如p53（QSala 135），但两者都同样缺乏转录调控，凋亡诱导小鼠胚胎成纤维细胞（MEFs），并抑制肿瘤形成的E1 A，Ha-Ras转化的MEFs。当在纯合子和杂合子配置中测试时，p53（QSval 135）小鼠和p53缺失小鼠在自发和癌基因启动的致瘤性测定中表现出相同的肿瘤发展动力学和光谱。p53（QSval 135）等位基因不具有显性负功能，表现为无效等位基因。总之，这些数据表明，有效的肿瘤抑制需要p53的转录调控功能，他们建议，反式激活的p53的独立功能不太可能有助于显着的肿瘤抑制在体内。
In vitro studies suggest that effective tumor suppression by p53 requires multiple domains to execute transcription-dependent and transcription-independent functions. We generated a mutant p53 allele in mice, p53(W25QL26S) (p53(QS)), containing an inactive transactivation domain to evaluate the importance of transactivation for p53-mediated tumor suppression. Recently, we discovered that the allele also contains a valine substitution for alanine at codon 135, which borders the DNA-binding domain. We found that p53(QSval135) bound to chromatin albeit less well than p53(QSala135), but both were equally deficient in transcriptional regulation, apoptosis induction in mouse embryo fibroblasts (MEFs), and suppression of tumor formation by E1A, Ha-Ras transformed MEFs. p53(QSval135) mice and p53-null mice exhibited identical tumor development kinetics and spectra in spontaneous and oncogene-initiated tumorigenicity assays, when tested in a homo- and heterozygous configuration. The p53(QSval135) allele did not have dominant negative functions and behaved as a null allele. Taken together, these data indicate that effective tumor suppression requires the transcriptional regulation function of p53, and they suggest that transactivation independent functions of p53 are unlikely to contribute significantly to tumor suppression in vivo.