Role of the DREAM Complex in Head and Neck Preneoplasia

摘要 HPV 16是90%的HPV+口咽癌的病因，现在占所有口咽癌的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， 迫切需要研究HPV 16癌症发病机制，以降低已感染人群的癌症风险 关于HPV为了更好地预防和治疗这种疾病，我们必须更好地了解 口腔中HPV肿瘤发病的早期步骤。目前的知识暗示HPV E7癌基因 通过靶向视网膜母细胞瘤（RB）家族的宿主细胞肿瘤抑制因子来研究口腔癌发生的早期阶段 pRb、p107和p130蛋白。HPV 16 E7通过其LxCxE基序直接结合RB蛋白， 使其无法维持G 0/G1检查点。重要的是，有令人信服的证据表明， RB家族的失活对于口腔癌发生的早期步骤是必不可少的，但是RB家族的失活的分子机制还不清楚。 E7的这种效果还没有完全理解。 最近的研究表明，E7破坏DREAM，这是一种转录抑制复合物，可以包括 p130或p107，而不是pRb。DREAM（二聚化伴侣、RB样、E2 F和MuvB）在G 0/G1中组装 当p130结合由LIN 9、LIN 37、LIN 52、LIN 54和RBBP 4组成的MuvB核心时的细胞周期阶段 蛋白质，并抑制细胞周期进程和DNA修复所需的基因。在S阶段，梦想 MuvB核心被B-Myb招募，形成MMB（Myb-MuvB）复合物， G2/M基因表达。MuvB核心LIN 52蛋白直接结合p130和B-Myb，并作为一种免疫调节剂。 MuvB核心招募适配器。LIN 52 N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。LIN 52中LxSxE序列的替换 LxCxE导致LIN 52 S20 C突变体与E7竞争p130结合并恢复DREAM。 HPV+癌细胞，导致生长抑制。相反，LIN 52中S28磷酸化位点的突变 （LIN 52 S28 A突变体）完全消除DREAM形成，导致细胞增殖增加。损失 DREAM对细胞周期依赖性基因的抑制可能是导致细胞增殖异常的关键。 增生然后是癌症然而，目前尚不清楚这种机制是否能在早期发挥作用。 HPV口腔肿瘤发生的阶段。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用于了解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.