Identification and classification of p53-regulated genes

Sequence-specific transactivation by p53 is essential to its role as a tumor suppressor. A modified tetracycline-inducible system was established to search for transcripts that were activated soon after p53 induction. Among 9,954 unique transcripts identified by serial analysis of gene expression, 34 were increased more than 10-fold; 31 of these had not previously been known to be regulated by p53. The transcription patterns of these genes, as well as previously described p53-regulated genes, were evaluated and classified in a panel of widely studied colorectal cancer cell lines. “Class I” genes were uniformly induced by p53 in all cell lines; “class II” genes were induced in a subset of the lines; and “class III” genes were not induced in any of the lines. These genes were also distinguished by the timing of their induction, their induction by clinically relevant chemotherapeutic agents, the absolute requirement for p53 in this induction, and their inducibility by p73, a p53 homolog. The results revealed substantial heterogeneity in the transcriptional responses to p53, even in cells derived from a single epithelial cell type, and pave the way to a deeper understanding of p53 tumor suppressor action.

p53的序列特异性反式激活作用，对于其作为肿瘤抑制因子的功能至关重要。本研究构建了改良型四环素诱导表达系统，用于筛选p53诱导后快速激活的转录本。通过基因表达系列分析（serial analysis of gene expression, SAGE）鉴定得到的9954个独特转录本中，有34个的表达水平上调超过10倍；其中31个此前未被发现受p53调控。研究人员针对一组经广泛研究的结直肠癌细胞系，对上述基因以及此前已报道的p53调控基因的转录模式展开评估与分类。根据p53诱导情况可将这些基因分为三类：Ⅰ类基因在所有受试细胞系中均被p53诱导激活；Ⅱ类基因仅在部分细胞系中被诱导激活；Ⅲ类基因则在所有细胞系中均未被p53诱导激活。此外，这些基因还可通过以下特征进行区分：激活时序、临床相关化疗药物的诱导效应、该诱导过程对p53的绝对依赖性，以及p53同源蛋白p73的诱导能力。本研究结果表明，即便源自同一上皮细胞类型的细胞，其对p53的转录应答也存在显著异质性，该发现为深入解析p53作为肿瘤抑制因子的作用机制奠定了重要基础。