Role of the DREAM Complex in Head and Neck Preneoplasia

DREAM 复合物在头颈部肿瘤前期的作用

• 批准号: 10042333
• 负责人: Larisa Litovchick
• 金额: $ 23.29万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10042333
• 关键词: Abnormal Cell; Affinity; Animals; Binding; Binding Proteins; Carcinogens; Cell Cycle; Cell Cycle Progression; Cell Cycle Stage; Cell Proliferation; Cells; Clinical; Clinical Markers; Complex; DNA Repair; DNA damage checkpoint; Diagnosis; Diet; Dimerization; Disease; Epithelial; Epithelium; Evaluation; Family; Future; Gene Expression; Genes; Genetic Models; Goals; Growth; HPV E7; Head and Neck Cancer; Head and neck structure; Human Papillomavirus; Human papillomavirus 16; Hyperplasia; Incidence; Knock-in Mouse; Knowledge; Lead; Malignant Neoplasms; Mediating; Modeling; Molecular; Molecular Carcinogenesis; Mouth Neoplasms; Multiprotein Complexes; Mus; Mutation; Oncogenes; Oncogenic; Oncogenic Viruses; Oral Stage; Oral cavity; Oral mucous membrane structure; Oropharyngeal Squamous Cell Carcinoma; Pathogenesis; Phosphorylation; Phosphorylation Site; Play; Population; Prevention; Preventive vaccine; Protein Family; Proteins; Repression; Repressor Proteins; Resistance; Retinoblastoma; Retinoblastoma Protein; Role; S Phase; Serine; Therapeutic; Tissue Sample; Transcription Repressor; Transgenic Mice; Tumor Suppressor Proteins; United States; Viral Pathogenesis; cancer cell; cancer risk; cancer subtypes; cancer therapy; candidate marker; carcinogenesis; gene therapy; high risk; improved; malignant mouth neoplasm; malignant oropharynx neoplasm; mouse genetics; mouse model; mutant; neoplastic; neoplastic cell; oral HPV; oral cancer prevention; oral carcinogenesis; oral tumorigenesis; promoter; recruit; retinoblastoma tumor suppressor; transcriptome; transcriptome sequencing; tumor; tumor progression; tumorigenesis

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.

抽象的 HPV16在90％的HPV+口咽癌中是病因，现在最多代表所有癌症的70％ 口咽癌。重要的是，HPV+口服癌的发病率在全球范围内稳步提高 在美国。虽然预防性疫苗将来会遏制HPV癌的发病率，但有一个 迫切需要研究HPV16癌症发病机理，以降低已经感染的人群的癌症风险 与HPV。为了改善这种疾病的预防和治疗，我们必须更好地了解 HPV肿瘤发病机理的早期步骤。当前的知识将HPV E7癌纳入 通过靶向视网膜细胞瘤（RB）家族的宿主细胞肿瘤抑制剂的早期癌变的早期阶段 包括PRB，P107和P130的蛋白质。 HPV16 E7通过其LXCXE基序直接结合RB蛋白，并且 灭活他们维护G0/G1检查点的能力。重要的是，有令人信服的证据表明 RB家族的失活对于口服癌变的早期步骤至关重要，但分子机制 E7的这种影响尚未完全理解。 最近的研究表明，E7破坏了梦想，这是一个转录的阻遏物综合体，其中可能包括 p130或p107，但没有PRB。 Dream（Dimerization伙伴，类似RB的E2F和MUVB）在G0/G1中组装 当P130结合由LIN9，LIN9，LIN52，LIN54和RBBP4组成的MUVB芯时，细胞周期的阶段 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 分解，MUVB核心由B-MYB招募，以形成MMB（MYB-MUVB）复合物所需 G2/m基因表达。 MUVB Core Lin52蛋白直接与P130和B-MYB结合，并用作 MUVB核心招聘的适配器。 LIN52 N末端中的E7样LXSXE基序介导了其相互作用 使用P130，而其C末端则介导B-MYB结合。在Lin52中替换LXSXE序列 使用LXCXE导致LIN52S20C突变体与E7竞争P130绑定并恢复梦想 HPV+癌细胞，导致生长抑制。相反，Lin52中S28磷酸化位点的突变 （LIN52S28A突变体）完全消除了梦想形成，从而增加了细胞增殖。损失 对细胞周期依赖基因的梦想抑制对于异常细胞增殖可能是必不可少的 增生，然后是癌症。但是，尚不清楚这种机制是否可以在早期发挥作用 HPV口腔肿瘤发生的阶段。我们提出的研究旨在通过应用来解决知识的差距 我们的新发现和小鼠遗传模型，用于理解HPV+口服癌的发病机理。