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皮肤乳头瘤病毒 E6 癌蛋白与 MAML1 结合，抑制反式激活和 NOTCH 信号传导。

Cutaneous papillomavirus E6 oncoproteins associate with MAML1 to repress transactivation and NOTCH signaling.

机构信息

Department of Pathology, University of Virginia, Charlottesville, VA 22908-0904, USA.

出版信息

Oncogene. 2012 Oct 25;31(43):4639-46. doi: 10.1038/onc.2011.589. Epub 2012 Jan 16.

DOI:10.1038/onc.2011.589
PMID:22249263
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3330202/
Abstract

Papillomavirus E6 oncoproteins associate with LXXLL motifs on target cellular proteins to alter their function. Using a proteomic approach, we found the E6 oncoproteins of cutaneous papillomaviruses Bovine Papillomavirus Type 1 (BPV-1) E6 and human papillomavirus (HPV) types 1 and 8 (1E6 and 8E6) associated with the MAML1 transcriptional co-activator. All three E6 proteins bind to an acidic LXXLL motif at the carboxy-terminus of MAML1 and repress transactivation by MAML1. MAML1 is best known as the co-activator and effector of NOTCH-induced transcription, and BPV-1 E6 represses synthetic NOTCH-responsive promoters, endogenous NOTCH-responsive promoters, and is found in a complex with MAML1 in stably transformed cells. BPV-1-induced papillomas show characteristics of repressed NOTCH signal transduction, including suprabasal expression of integrins, talin and basal type keratins, and delayed expression of the NOTCH-dependent HES1 transcription factor. These observations give rise to a model whereby papillomavirus oncoproteins, including BPV-1 E6, and the cancer-associated HPV-8 E6 repress NOTCH-induced transcription, thereby delaying keratinocyte differentiation.

摘要

乳头瘤病毒 E6 癌蛋白与靶细胞蛋白上的 LXXLL 基序结合，改变其功能。我们使用蛋白质组学方法发现，皮肤乳头瘤病毒牛乳头瘤病毒 1 型（BPV-1）E6 和人乳头瘤病毒（HPV）1 型和 8 型（1E6 和 8E6）的 E6 癌蛋白与 MAML1 转录共激活因子相关。这三种 E6 蛋白都与 MAML1 羧基末端的酸性 LXXLL 基序结合，并抑制 MAML1 的转录激活。MAML1 最著名的是 NOTCH 诱导转录的共激活因子和效应子，BPV-1 E6 抑制合成的 NOTCH 反应性启动子、内源性 NOTCH 反应性启动子，并与稳定转化细胞中的 MAML1 形成复合物。BPV-1 诱导的乳头瘤表现出受抑制的 NOTCH 信号转导的特征，包括整合素、talin 和基底型角蛋白的超基底层表达，以及 NOTCH 依赖性 HES1 转录因子的延迟表达。这些观察结果提出了一种模型，即乳头瘤病毒癌蛋白，包括 BPV-1 E6 和与癌症相关的 HPV-8 E6，抑制 NOTCH 诱导的转录，从而延迟角质形成细胞分化。

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