Coordinate Regulation of p53 and c-MYC in an HTLV-1 Model of Carcinogenesis

HTLV-1 致癌模型中 p53 和 c-MYC 的协调调节

• 批准号: 8232612
• 负责人: ROBERT L HARROD
• 金额: $ 43.57万
• 依托单位: SOUTHERN METHODIST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8232612
• 关键词: Acetylation; Acetyltransferase; Address; Adult; Affect; Alanine; Apoptosis; Apoptotic; Area; Base Sequence; Binding; Binding Proteins; Biochemical; Biological Assay; CD4 Positive T Lymphocytes; Cell Death; Cell Proliferation; Cells; Clinical; Complex; Cytomegalovirus; DNA Binding; Data; Disease; Dominant-Negative Mutation; Event; Figs - dietary; Future; Gene Expression; Genes; Genetic Transcription; Genome; Growth; HIV; HTATIP gene; Hematologic Neoplasms; Human T-lymphotropic virus 1; In Vitro; Laboratories; Lentivirus Vector; Leukemic Lymphocyte; Lymphocyte; Lysine; MYC gene; Malignant - descriptor; Malignant Neoplasms; Maps; Masks; Mediating; Methylation; Modality; Modeling; Molecular; Mutation; Nonstructural Protein; Oncogene Activation; Oncogene Proteins; Oncogenic; Patients; Phenotype; Physiological; Positioning Attribute; Post-Translational Protein Processing; Protein p53; Proteins; Puma; Regulation; Research; Research Project Grants; Research Training; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Role; Science; Signal Pathway; Signal Transduction; Surface; T-Cell Leukemia; T-Cell Transformation; T-Lymphocyte; Taxes; Testing; Time; Trans-Activators; Transactivation; Tumor Suppressor Proteins; Viral; Virus; anticancer research; base; c-myc Genes; cancer therapy; carcinogenesis; career; cell growth; cellular transduction; cofactor; expression vector; genetic regulatory protein; graduate student; leukemia/lymphoma; leukemogenesis; metaplastic cell transformation; multicatalytic endopeptidase complex; mutant; neoplastic; neoplastic cell; novel; oncology; prevent; protein degradation; transforming virus; tumorigenesis; viral carcinogenesis

DESCRIPTION (provided by applicant): The human T-cell leukemia virus type-1 (HTLV-1) infects and transforms CD4+ Th-lymphocytes and is the etiological agent of adult T-cell leukemia/lymphoma (ATL), an aggressive hematological malignancy that is resistant to most anticancer modalities. Importantly, the molecular events that contribute to oncogenic cellular transformation and T-cell leukemogenesis remain to be completely defined. Several nonstructural and regulatory proteins (Tax, Rex, p30II, p13II, p12I, p8I, Hbz) encoded by a conserved 3' nucleotide sequence, known as pX, in the HTLV-1 genome deregulate cellular signaling pathways and promote neoplastic T-cell transformation. While the retroviral transactivator, Tax, is considered to be the major oncoprotein of HTLV-1, the roles of the other pX factors in tumorigenesis and the progression of malignant disease have not been extensively studied. We have made significant progress in this area and provided the first evidence that the HTLV-1 p30II protein interacts with the c-MYC oncoprotein and augments c-MYC-dependent transactivation and oncogenic potential, dependent upon recruitment of the TIP60 acetyltransferase to p30II/c-MYC transcription complexes. A dominant-negative TIP60Q377E/G380E mutant inhibits cooperation between p30II and c-MYC and abrogates oncogenic foci- formation in vitro. The TIP60-interacting domain of p30II has been mapped in biochemical protein- interaction studies to aa residues 99-154, which reside on an exposed surface of the p30II protein. The TIP60 acetyltransferase is a transcriptional cofactor for both c-MYC and the p53 tumor suppressor. Our preliminary data further demonstrate that p30II induces and interacts with p53 and transactivates the G2/M anti-apoptotic gene, 14-3-3s. Surprisingly, wildtype p53 enhances oncogenic transformation induced by p30II/c-MYC. A p53 DNA-binding mutant, p53-R175H, inhibited p30II/c-MYC oncogenic activity. TIP60 acetylates lysine residue K120 of p53 and differentially regulates the expression of cellular growth-arrest/survival and pro-apoptotic signals. As c-myc oncogene activation induces p53- dependent apoptosis, we hypothesize that p30II coordinately regulates p53 survival genes (e.g., 14-3- 3s, p21Waf1/Cip1, p53R2, gadd45, tigar) and c-MYC to prevent c-MYC-induced cell-death and promote aberrant lymphoproliferation in HTLV-1-infected cells. The proposed research will build upon our preliminary studies by addressing the following Specific Aims: (1) to determine how HTLV-1 p30II-TIP60 and p30II-p53 biochemical interactions modulate c-MYC and p53 functions. (2) To determine how p53 enhances the cooperation between p30II and c-MYC to promote oncogenic transformation. Our findings allude to a novel paradigm for the deregulation of c-MYC and p53 by transforming viruses through interactions with the common transcriptional cofactor, TIP60. The proposed studies will advance our fundamental understanding of the roles of oncoproteins and tumor suppressors in viral carcinogenesis. PUBLIC HEALTH RELEVANCE: Many cancer-inducing viruses promote aberrant cellular growth and proliferation through interactions with oncoproteins and tumor suppressors. We have demonstrated that the HTLV-1 p30II protein interacts with a common transcriptional cofactor of c-MYC and p53 and coordinately regulates c-MYC oncogenic activity and p53 anti-apoptotic functions. The proposed research will advance our understanding of the molecular events involved in retroviral carcinogenesis and may elucidate new targets for anticancer therapy. This R15 AREA project will provide excellent cancer research training opportunities for undergraduates and graduate students to better prepare them for future careers in the basic or clinical oncological sciences.

描述（由申请人提供）：人类T细胞白血病病毒类型1（HTLV-1）感染并转化CD4+ TH淋巴细胞，是成人T细胞白血病/淋巴瘤（ATL）的病因，一种积极的血液学恶性肿瘤对大多数抗癌药物的抵抗力。重要的是，有助于致癌细胞转化和T细胞白血病发生的分子事件尚待完全定义。在HTLV-1基因组中，由保守的3'核苷酸序列（称为PX）编码的几种非结构性和调节蛋白（REX，REX，REX，P3II，P13II，P13II，P12I，P8I，HBZ）编码。虽然逆转录病毒式税收税被认为是HTLV-1的主要癌蛋白，但其他PX因子在肿瘤发生中的作用和恶性疾病的进展尚未得到广泛的研究。我们在这一领域取得了重大进展，并提供了第一个证据，表明HTLV-1 P30II蛋白与C-Myc癌蛋白相互作用，并增强C-MYC依赖性反式激活和致癌潜力，取决于TIP60乙酰基转移酶募集到P30II/C-MYC转录复合物。显性阴性的TIP60Q377E/G380E突变体抑制P30II和C-MYC之间的合作，并在体外消除了致癌的焦点。 P30II的TIP60相互作用结构域已在生化蛋白相互作用研究中映射到AA残基99-154，该研究位于P30II蛋白的暴露表面上。 TIP60乙酰转移酶是C-MYC和p53肿瘤抑制剂的转录辅助因子。我们的初步数据进一步表明，P30II诱导并与p53相互作用，并将G2/M抗凋亡基因（14-3-3s）进行反式激活。令人惊讶的是，野生型P53增强了P30II/C-MYC诱导的致癌转化。 p53 DNA结合突变体P53-R175H抑制了P30II/C-MYC致癌活性。 p53的TIP60乙酰酸酯赖氨酸残基K120，并差异调节细胞生长避孕/生存和促凋亡信号的表达。 As c-myc oncogene activation induces p53- dependent apoptosis, we hypothesize that p30II coordinately regulates p53 survival genes (e.g., 14-3- 3s, p21Waf1/Cip1, p53R2, gadd45, tigar) and c-MYC to prevent c-MYC-induced cell-death and promote aberrant lymphoproliferation in HTLV-1感染的细胞。拟议的研究将通过解决以下特定目的来建立我们的初步研究：（1）确定HTLV-1 P30II-TIP60和P30II-P53生化相互作用如何调节C-MYC和p53功能。 （2）确定p53如何增强P30II和C-MYC之间的合作以促进致癌转化。我们的发现暗示了通过与常见的转录辅助因子TIP60相互作用来转化病毒，从而暗示了对C-Myc和p53进行放松管制的新范式。拟议的研究将提高我们对癌蛋白和抑制肿瘤在病毒癌变中的作用的基本理解。 公共卫生相关性：许多诱导癌症的病毒通过与癌蛋白和肿瘤抑制剂的相互作用来促进异常的细胞生长和增殖。我们已经证明，HTLV-1 P30II蛋白与C-MYC和p53的常见转录辅助因子相互作用，并协调调节C-Myc致癌活性和p53抗凋亡功能。拟议的研究将促进我们对逆转录病毒致癌物涉及的分子事件的理解，并可能阐明用于抗癌治疗的新靶标。这个R15地区项目将为本科生和研究生提供出色的癌症研究培训机会，以更好地为基础或临床肿瘤科学的未来职业做好准备。