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 1 型 (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) 的病原体，ATL 是一种对大多数抗癌方法具有抗药性的侵袭性血液恶性肿瘤。重要的是，导致致癌细胞转化和 T 细胞白血病发生的分子事件仍有待完全确定。 HTLV-1 基因组中由保守的 3' 核苷酸序列（称为 pX）编码的几种非结构和调节蛋白（Tax、Rex、p30II、p13II、p12I、p8I、Hbz）可解除细胞信号传导通路的调节并促进肿瘤性 T 细胞转化。虽然逆转录病毒反式激活因子 Tax 被认为是 HTLV-1 的主要癌蛋白，但其他 pX 因子在肿瘤发生和恶性疾病进展中的作用尚未得到广泛研究。我们在这一领域取得了重大进展，并提供了第一个证据，证明 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，这取决于 TIP60 乙酰转移酶向 p30II/c-MYC 转录复合物的募集。显性失活 TIP60Q377E/G380E 突变体抑制 p30II 和 c-MYC 之间的合作，并消除体外致癌灶的形成。 p30II 的 TIP60 相互作用结构域已在生化蛋白质相互作用研究中定位到氨基酸残基 99-154，该残基位于 p30II 蛋白质的暴露表面上。 TIP60 乙酰转移酶是 c-MYC 和 p53 肿瘤抑制因子的转录辅助因子。我们的初步数据进一步证明 p30II 诱导 p53 并与之相互作用，并反式激活 G2/M 抗凋亡基因 14-3-3s。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 p30II/c-MYC 致癌活性。 TIP60 乙酰化 p53 的赖氨酸残基 K120，并差异调节细胞生长停滞/存活和促凋亡信号的表达。由于 c-myc 癌基因激活诱导 p53 依赖性细胞凋亡，我们假设 p30II 协调调节 p53 存活基因（例如 14-3-3s、p21Waf1/Cip1、p53R2、gadd45、tigar）和 c-MYC，以防止 c-MYC 诱导的细胞死亡并促进异常淋巴增殖。 HTLV-1感染的细胞。拟议的研究将以我们的初步研究为基础，解决以下具体目标：(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。我们的研究结果暗示了一种通过与常见转录辅因子 TIP60 相互作用来转化病毒来放松 c-MYC 和 p53 调节的新范例。拟议的研究将增进我们对癌蛋白和肿瘤抑制因子在病毒癌变中的作用的基本理解。 公共健康相关性：许多致癌病毒通过与癌蛋白和肿瘤抑制因子的相互作用促进异常细胞生长和增殖。我们已经证明，HTLV-1 p30II 蛋白与 c-MYC 和 p53 的共同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。拟议的研究将增进我们对逆转录病毒致癌过程中涉及的分子事件的理解，并可能阐明抗癌治疗的新靶点。这个R15 AREA项目将为本科生和研究生提供极好的癌症研究培训机会，让他们更好地为基础或临床肿瘤科学的未来职业做好准备。