p53轉(zhuǎn)錄因子既是一個腫瘤抑制因子（在幾乎所有癌癥中都失去活性），又是一個防止腺病毒復制的防衛(wèi)因子,。腺病毒E1B-55K以p53為降解目標,，被認為在腺病毒復制過程中是p53失活的關(guān)鍵。的確,，缺失E1B-55K的突變體病毒已被作為對p53-陽性腫瘤有選擇性的病毒癌癥治療藥物進行了測試?，F(xiàn)在，Soria等人發(fā)現(xiàn)，另一種腺病毒蛋白E4-ORF3,，可以通過一個阻止p53接觸其DNA的染色質(zhì)沉寂機制來獨立于E1B-55K使p53失去活性,。這項工作表明，在腺病毒感染中的p53失活是一個比以前所認為的更為復雜的過程,，并且也許還有可能在這一體系被更全面了解之后來開發(fā)真正的p53選擇性抗腫瘤病毒療法,。（生物谷Bioon.com）
生物谷推薦原文出處：
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.
