p53转录因子既是一个肿瘤抑制因子（在几乎所有癌症中都失去活性），又是一个防止腺病毒复制的防卫因子。腺病毒E1B-55K以p53为降解目标，被认为在腺病毒复制过程中是p53失活的关键。的确，缺失E1B-55K的突变体病毒已被作为对p53-阳性肿瘤有选择性的病毒癌症治疗药物进行了测试。现在，Soria等人发现，另一种腺病毒蛋白E4-ORF3，可以通过一个阻止p53接触其DNA的染色质沉寂机制来独立于E1B-55K使p53失去活性。这项工作表明，在腺病毒感染中的p53失活是一个比以前所认为的更为复杂的过程，并且也许还有可能在这一体系被更全面了解之后来开发真正的p53选择性抗肿瘤病毒疗法。（生物谷Bioon.com）
生物谷推荐原文出处：
Nature doi:10.1038/nature09307
Heterochromatin silencing of p53 target genes by a small viral protein
Conrado Soria,Fanny E. Estermann,Kristen C. Espantman& Clodagh C. O’Shea
The transcription factor p53 (also known as TP53) guards against tumour and virus replication and is inactivated in almost all cancers. p53-activated transcription of target genes is thought to be synonymous with the stabilization of p53 in response to oncogenes and DNA damage. During adenovirus replication, the degradation of p53 by E1B-55k is considered essential for p53 inactivation, and is the basis for p53-selective viral cancer therapies. Here we reveal a dominant epigenetic mechanism that silences p53-activated transcription, irrespective of p53 phosphorylation and stabilization. We show that another adenoviral protein, E4-ORF3, inactivates p53 independently of E1B-55k by forming a nuclear structure that induces de novo H3K9me3 heterochromatin formation at p53 target promoters, preventing p53–DNA binding. This suppressive nuclear web is highly selective in silencing p53 promoters and operates in the backdrop of global transcriptional changes that drive oncogenic replication. These findings are important for understanding how high levels of wild-type p53 might also be inactivated in cancer as well as the mechanisms that induce aberrant epigenetic silencing of tumour-suppressor loci. Our study changes the longstanding definition of how p53 is inactivated in adenovirus infection and provides key insights that could enable the development of true p53-selective oncolytic viral therapies.
