HTLV-I Tax induces DNA breaks and inhibits HR repair through activation of NF-kB

HTLV-I Tax 通过激活 NF-kB 诱导 DNA 断裂并抑制 HR 修复

• 批准号: 8847287
• 负责人: CHRISTOPHE P NICOT
• 金额: $ 22.4万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8847287
• 关键词: Acute; Acute Adult T-Cell Leukemia/Lymphoma; Adult T-Cell Leukemia/Lymphoma; Affect; Aneuploidy; Cell Line; Cell Proliferation; Cells; Chromosomal Instability; Chromosomal translocation; Chromosome Segregation; Complement; DNA; DNA Damage; DNA Double Strand Break; DNA Repair; DNA biosynthesis; DNA replication fork; DNA-Directed DNA Polymerase; DNA-dependent protein kinase; Data; Defect; Development; Disease; Double Strand Break Repair; Epigenetic Process; Genes; Genetic; Genetic Transcription; Genome; Genomic Instability; Human; Human T-Cell Leukemia Viruses; Human T-lymphotropic virus 1; Individual; Lead; Life Expectancy; Lymphoma; Malignant Neoplasms; Mediating; Molecular; Molecular Cloning; Mutation; NF-kappa B; Nonhomologous DNA End Joining; Normal Cell; Nucleotide Excision Repair; Oncogene Proteins; Oncogenic; Pathogenesis; Pathway interactions; Physiological; Play; Polymerase; Published Comment; Publishing; Retroviridae; Role; S Phase; Spinal Cord Diseases; Study Section; Survival Rate; T-Lymphocyte; Taxes; Therapeutic; Transformed Cell Line; Type I DNA Topoisomerases; XRCC5 gene; anaphase-promoting complex; base; homologous recombination; insertion/deletion mutation; insight; micronucleus; mutant; overexpression; p53-binding protein 1; prevent; recombinational repair; repaired; research study; transforming virus; treatment strategy

DESCRIPTION (provided by applicant): Human T-cell leukemia virus type I (HTLV-I) infects more than 25 million people world-wide. A significant percentage of infected individuals develop adult T-cell leukemia/lymphoma (ATLL) or HTLV-I-associated myelopathy (HAM/TSP). HTLV-I-associated diseases are invariably fatal with limited therapeutic options and a life expectancy of 4-6 months for acute ATL and 10 months for the lymphoma type. Projected 4-year survival rates for acute- and lymphoma-type ATL stand at 5 and 5.7%, respectively. HTLV-I is the only known transforming human retrovirus; yet the mechanisms by which the virus transforms human T-cells are still poorly understood. The genomic instability caused by the oncoprotein Tax is thought to play an important role in ATL development. Tax has been shown to constitutively activate NF-kB and stimulate cell proliferation. In addition, Tax prematurely activates the anaphase promoting complex, inhibits nucleotide excision repair and represses topoisomerase I and beta-polymerase. This project will elucidate the mechanisms employed by Tax to increase genetic instability in pre-tumoral cells and the cellular genes involved in the adaptation/tolerance of DNA damage and transformation.

描述（由申请人提供）：人类T细胞白血病病毒I型（HTLV-I）感染全球超过2500万人。感染者中有很大比例发展为成人T细胞白血病/淋巴瘤（ATLL）或HTLV-I相关性脊髓病（HAM/TSP）。HTLV-I相关疾病总是致命的，治疗选择有限，急性ATL的预期寿命为4-6个月，淋巴瘤类型为10个月。急性和淋巴瘤型ATL的预计4年生存率分别为5%和5.7%。HTLV-I是唯一已知的转化人类逆转录病毒;然而，该病毒转化人类T细胞的机制仍然知之甚少。由癌蛋白Tax引起的基因组不稳定性被认为在ATL发展中起重要作用。Tax已显示组成性激活NF-kB并刺激细胞增殖。此外，Tax过早激活后期促进复合物，抑制核苷酸切除修复并抑制拓扑异构酶I和β-聚合酶。该项目将阐明Tax增加肿瘤前细胞遗传不稳定性的机制，以及参与DNA损伤和转化适应/耐受的细胞基因。

项目成果

Current views on the role of Notch signaling and the pathogenesis of human leukemia.

当前关于Notch信号传导作用和人白血病发病机理的看法。

• DOI: 10.1186/1471-2407-11-502
• 发表时间: 2011-11-30
• 期刊: BMC cancer
• 影响因子: 3.8
• 作者: Pancewicz J;Nicot C
• 通讯作者: Nicot C

Tumor Suppressor Inactivation in the Pathogenesis of Adult T-Cell Leukemia.

• DOI: 10.1155/2015/183590
• 发表时间: 2015
• 期刊: Journal of oncology
• 作者: Nicot C

Therapy-induced selective loss of leukemia-initiating activity in murine adult T cell leukemia.

治疗引起的鼠类成人T细胞白血病中白血病发射活性的选择性丧失。

• DOI: 10.1084/jem.20101095
• 发表时间: 2010-12-20
• 期刊: The Journal of experimental medicine
• 作者: El Hajj H;El-Sabban M;Hasegawa H;Zaatari G;Ablain J;Saab ST;Janin A;Mahfouz R;Nasr R;Kfoury Y;Nicot C;Hermine O;Hall W;de Thé H;Bazarbachi A
• 通讯作者: Bazarbachi A

Celecoxib disrupts the canonical apoptotic network in HTLV-I cells through activation of Bax and inhibition of PKB/Akt.

Celecoxib 通过激活 Bax 和抑制 PKB/Akt 来破坏 HTLV-I 细胞中的典型凋亡网络。

• DOI: 10.1007/s10495-007-0148-7
• 发表时间: 2008
• 期刊: Apoptosis : an international journal on programmed cell death
• 作者: Sinha-Datta,Uma;Taylor,JohnM;Brown,Megan;Nicot,Christophe
• 通讯作者: Nicot,Christophe

WRN-targeted therapy using inhibitors NSC 19630 and NSC 617145 induce apoptosis in HTLV-1-transformed adult T-cell leukemia cells.

• DOI: 10.1186/s13045-016-0352-4
• 发表时间: 2016-11-09
• 期刊: Journal of hematology & oncology
• 影响因子: 28.5
• 作者: Moles R;Bai XT;Chaib-Mezrag H;Nicot C
• 通讯作者: Nicot C