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Action of the SV40 T Antigen Chaperone Machine on Tumor Suppressors

SV40 T 抗原伴侣机对肿瘤抑制剂的作用

基本信息

批准号：
8110978
负责人：
JAMES M PIPAS
金额：
$ 5.2万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-14 至 2012-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8110978
关键词：
ATP Hydrolysis ATP phosphohydrolase Adopted Amino Acids Apoptosis Binding Biochemical Biological Cell Cycle Regulation Cell Proliferation Cell physiology Chemicals Chromatin Complex Crystallization Crystallography DNA biosynthesis Data Development Discrimination Disease E2F transcription factors Family Family member Gene Mutation Genes Genetic Genetic Transcription Goals Growth Homeostasis Homologous Gene Host Defense In Vitro Infection Location Malignant Neoplasms Mediating Modeling Molecular Molecular Chaperones Molecular Conformation Oncogene Proteins Participant Phosphorylation Play Production Protein Binding Proteins RBL2 gene Reaction Recruitment Activity Regulation Relaxation Resolution Rest Retinoblastoma Retinoblastoma Protein Role Signal Transduction Simian virus 40 Staging System Testing Tissues Transcriptional Activation Transcriptional Regulation Tumor Antigens Tumor Suppressor Proteins Viral Viral Tumor Antigens Virion Virus Virus Diseases Work X-Ray Crystallography antigen binding base flexibility genetic regulatory protein in vivo interest member metaplastic cell transformation mutant promoter research study sialosyl-T antigen three dimensional structure transcription factor viral DNA

项目摘要

Tumor suppressors are regulatory proteins that receive and integrate diverse signals and function to exert control over key cellular processes such as cell proliferation, differentiation, and apoptosis. Because loss or perturbation of their activity often results in cancer or other diseases, and because of their central role in governing organismal development and tissue homeostasis, these proteins are of great interest. The retinoblastoma protein (pRb) is a well characterized tumor suppressor that, in concert with two related proteins, p130and p107,control cell cycle entry and exit, in part, by regulating the activity of the E2F family of transcription factors. Many viruses, including Simian virus 40 (SV40) encode oncoproteins that bind Rb-family members and interfere with their ability to regulate E2Fs. The large tumor antigen (T antigen) encoded by SV40 binds to pRb, p107, and p130via an LXCXE motif and blocks the ability of these proteins to inhibit E2F-dependent transcription and to induce growth arrest. The retinoblastoma family has been studied intensively, yet little is known about the molecular basis by which viruses, such as SV40, block their action. In fact, interaction with T antigen has different consequences for each Rb protein. For example, p130 is degraded following SV40 infection or transformation, while the levels of pRb remain unchanged. Thus, T antigen appears to be able to distinguish different Rb-E2F complexes, but the basis for this discrimination is unknown. Like many regulatory proteins pRb and E2F transcription factors do not exist in isolation. Rather they function as part of large multiprotein assemblages that include chromatin modifiers, the basal transcription apparatus, as well as other factors, and the dynamic assembly and disassembly of these complexes is critical to their regulation. T antigen has a J domain and has been shown to function as a DnaJ molecular chaperone. The J domain is required for a vital DNA replication, transcriptional control, and virion assembly. Importantly, the J domain is required for T antigen to block the function of Rb proteins and thus to activate E2F-dependent transcription. This application seeks to understand the mechanistic and structural basis for the action of T antigen's recognition and disruption of Rb-E2F complexes.' First, biochemical studies will explore the ability of the T antigen chaperone machine to distinguish and act upon p130-E2F4-DP1, pRb- E2F4-DP1, and pRb-E2F1-DP1 complexes. Second, the role of J domain orientation and flexibility will be examined using a combination of NMR and X-ray crystallography. Finally, a combined genetic and biochemical approach will be used to identify additional protein participants in the chaperone reaction. These studies will enhance our understanding of how these tumor suppressors govern cell proliferation and survival, and how subversion of these mechanisms by viruses or genetic mutation, contribute to cancer.

肿瘤抑制因子是一种接受和整合多种信号和功能的调节蛋白