Role of the DREAM Complex in Head and Neck Preneoplasia

摘要 HPV16在90%的HPV阳性口咽癌中是致病因素，现在占所有癌症的70% 口咽癌。重要的是，HPV+口腔癌的发病率在全球范围内稳步上升。 在美国也是如此。虽然预防性疫苗将在未来遏制HPV癌症的发病率，但有一个 迫切需要研究HPV16癌症发病机制，以降低已经感染的人群患癌症的风险 感染了人乳头瘤病毒。为了更好地预防和治疗这种疾病，我们必须更好地了解 口腔HPV肿瘤发病机制的早期步骤。目前的知识表明HPV E7癌基因与 靶向视网膜母细胞瘤(RB)家族宿主细胞肿瘤抑制因子在口腔癌变早期的作用 包括pRb、p107和p130的蛋白质。HPV16 E7通过其LxCxE基序直接与Rb蛋白结合，并 停用他们维护G0/G1检查点的能力。重要的是，有令人信服的证据表明 Rb家族失活在口腔癌发生的早期过程中是必不可少的，但其分子机制 对E7的这种影响还没有完全了解。 最近的研究表明，E7可以扰乱梦，这是一种转录抑制复合体，可以包括 P130或p107，但不是pRb。Dream(二聚化伙伴，类似RB，E2F和MuvB)在G0/G1中组装 当p130结合由LIN9、LIN37、LIN52、LIN54和RBBP4组成的MuvB核心时，细胞周期的不同阶段 蛋白质，抑制细胞周期进程和DNA修复所需的基因。在S阶段，梦想 分解，MuvB核心被B-Myb招募形成所需的MMB(Myb-MuvB)复合体 G2/M基因表达。MuvB核心LIN52蛋白直接与p130和B-Myb结合，并作为一种 MuvB核心招聘适配器。LIN52 N末端的E7样LxSxE基序介导其相互作用 与p130结合，而其C末端介导B-Myb结合。LIN52中LxSxE序列的替换 LxCxE导致LIN52S20C突变体与E7竞争p130结合并恢复梦想 HPV+癌细胞，造成生长抑制。相反，LIN52中S28磷酸化位点的突变 (LIN52S28A突变体)完全消除梦境的形成，导致细胞增殖增加。损失 细胞周期依赖基因的梦境抑制可能是导致细胞异常增殖的关键因素 增生，然后是癌症。然而，这一机制是否能在早期发挥作用尚不清楚。 HPV口腔肿瘤发生的分期。我们提出的研究旨在通过应用 我们的新发现和小鼠遗传模型有助于理解HPV+口腔癌的发病机制。

ABSTRACT HPV16 is causative in 90% of HPV+ oropharyngeal cancers, which now represent up to 70% of all oropharyngeal cancers. Importantly, the incidence rate of HPV+ oral cancers is steadily increasing worldwide and in the United States. While prophylactic vaccines will curb HPV cancer incidence in the future, there is an urgent need to study HPV16 cancer pathogenesis to reduce the risk of cancer for populations already infected with HPV. In order to improve the prevention and treatment of this disease, we must better understand the early steps of HPV tumor pathogenesis in the oral cavity. Current knowledge implicates HPV E7 oncogene into early stages of oral carcinogenesis by targeting the host-cell tumor suppressors of retinoblastoma (RB) family proteins that includes pRb, p107 and p130. HPV16 E7 binds RB proteins directly through its LxCxE motif, and inactivates their ability to maintain G0/G1 checkpoint. Importantly, there is compelling evidence showing that inactivation of the RB family is essential for early steps of oral carcinogenesis but the molecular mechanisms of this effect of E7 are not fully understood. Recent studies show that E7 disrupts DREAM, a transcriptional repressor complex that can include p130 or p107, but not pRb. DREAM (Dimerization partner, RB-like, E2F And MuvB) assembles in the G0/G1 stages of the cell cycle when p130 binds the MuvB core consisting of LIN9, LIN37, LIN52, LIN54 and RBBP4 proteins, and represses genes required for cell cycle progression and DNA repair. In S-phase, DREAM disassembles, and the MuvB core is recruited by B-Myb to form the MMB (Myb-MuvB) complex required for G2/M gene expression. MuvB core LIN52 protein binds directly to both p130 and B-Myb, and serves as an adaptor for MuvB core recruitment. An E7-like LxSxE motif in the LIN52 N-terminus mediates its interaction with p130, whereas its C-terminus mediates the B-Myb binding. Replacement of the LxSxE sequence in LIN52 with LxCxE results in the LIN52S20C mutant that competes with E7 for p130 binding and restores DREAM in HPV+ cancer cells, causing growth suppression. Conversely, mutation of the S28 phosphorylation site in LIN52 (LIN52S28A mutant) completely abolishes DREAM formation, resulting in increased cell proliferation. Loss of DREAM repression of cell cycle dependent genes could be essential for aberrant cell proliferation leading to hyperplasia and then cancer. However, it is not known whether this mechanism could play a role in early stages of HPV oral tumorigenesis. Our proposed study is aimed at closing this gap in knowledge by applying our new findings and mouse genetic models for understanding the pathogenesis of HPV+ oral cancers.