Robert Harrod

Research Interests

Molecular Mechanisms of Viral Carcinogenesis: HTLVs and High-Risk Subtype HPVs

My laboratory is studying how certain transforming viruses cause cancers in humans. It is estimated approximately 15-20% of human cancers are caused by oncogenic viruses, 然而，感染因子解除对宿主细胞生长/增殖途径的调控从而促进肿瘤疾病的建立和进展的分子病因学尚不完全清楚. 我们的研究主要集中在推进我们对人类t细胞白血病病毒1型(HTLV-1)和高危亚型人乳头瘤病毒(hpv)致癌的分子生物学和生化事件的理解。.

HTLV-1是一种复杂的逆转录病毒，可感染并转化CD4+ t淋巴细胞，导致成人t细胞白血病/淋巴瘤(ATLL)，这是一种侵袭性的、通常致命的血液恶性肿瘤，对大多数抗癌治疗具有高度耐药性. At present, there are 10-20 million HTLV-1-infected individuals worldwide, with most clustered in the tropical endemic regions of Southeast Asia (i.e., Japan, Taiwan, Malaysia, and the Philippines), the Middle East, Northern and Central Africa, Central and South America, Australo-Melanesia, and certain islands of the Caribbean. In the United States, Florida and Hawaii have the highest incidences of HTLV-1-related diseases. Recent evidence also suggests HTLV-1 may be a re-emerging health threat in some global regions, such as Australia. 高危亚型人乳头状瘤病毒与宫颈癌和头颈癌有因果关系，这些癌症的临床结果往往很差，死亡率很高. 我们的研究表明HTLV-1和高危亚型hpv编码与细胞癌基因合作的蛋白质, including c-Myc, 通过与转录共激活因子的分子相互作用和p53调控的促生存信号的差异调节，促进htlv -1诱导的t细胞淋巴瘤和hpv诱导的癌的体外细胞永生化/转化和体内异种移植模型的肿瘤发生. Importantly, 这些研究揭示了病毒感染肿瘤细胞存活所必需的几个关键因素, as determined through siRNA-knockdown experiments, and may be candidates for the translational design of targeted therapeutics.

我的实验室的研究得到了国家癌症研究所/国家卫生研究院的资助.

Selected Publications

Bowley T, Malu A, Adams NM, Savage J, Saberi M, VanderHagen M, Alame R, Keating M, Yates C, and R Harrod (2024). HTLV-1潜伏期维持因子p30II诱导TIGAR磷酸化和缺氧不依赖的线粒体靶向，类似于酪氨酸激酶受体信号传导，抑制癌基因诱导的氧化毒性. Journal of Antivirals & Antiretrovirals, 16(2): 100000313 [1-16; open access].

Yapindi L, Bowley T, Kurtaneck N, Bergeson RL, James K, Wilbourne J, Harrod CK, Hernandez BY, Emerling BM, Yates C, and R Harrod (2023). 人乳头瘤病毒E6癌蛋白激活p53调控的促生存信号和缺氧无关的线粒体靶向TIGAR. Virology 585:1-20.

Yapindi L, Hernandez BY, sirna -抑制TIGAR超敏化人乳头瘤病毒转化细胞对化疗药物引起氧化应激诱导的凋亡的影响. Journal of Antivirals & Antiretrovirals 13(4): 223 [open access].

Newman RA, Sastry KJ, Arav-Boger R, Matos R, and R Harrod (2020) Antiviral effects of oleandrin. Journal of Experimental Pharmacology 12: 503-515.

Harrod R (2019) Silencers of HTLV-1 and HTLV-2: the pX-encoded latency-maintenance factors. Retrovirology, in press [invited review].

Malu A, Hutchison T, Yapindi L, Smith K, Nelson K, Bergeson R, Pope J, Romeo M, Harrod C, Ratner L, Van Lint C, 人类t细胞白血病病毒1型癌蛋白分离NF-kappa-B p65^RelA-Stathmin complexes and causes catastrophic mitotic spindle damage and genomic instability. Virology 535: 83-101.

Hutchison T, Yapindi L, Malu A, Newman RA, Sastry KJ, 植物苷夹竹桃苷抑制HTLV-1的感染性和环境依赖性病毒学突触的形成. Journal of Antivirals & Antiretrovirals, in press.

Hutchison T, Malu A, Yapindi L, Bergeson R, Peck K, Romeo M, Harrod C, Pope J, Smitherman L, Gwinn W, Ratner L, Yates C, and R Harrod (2018) The Tp53-Induced Glycolysis and Apoptosis Regulator 介导HTLV-1 p30II与逆转录病毒癌蛋白Tax和HBZ之间的合作，并在HTLV-1诱导的淋巴瘤的体内异种移植模型中高表达. Virology 520: 39-58.

Romeo M, Hutchison T, Malu A, White A, Kim J, Gardner R, Smith K, Nelson K, Bergeson R, McKee R, Harrod C, Ratner L, Lüscher B, Martinez E, 人t细胞白血病病毒1型p30II蛋白在病毒癌变过程中激活p53，诱导TIGAR，抑制癌基因诱导的氧化应激. Virology 518: 103-115.

Romeo MM, Ko B, Kim J, Brady R, Heatley HC, He J, Harrod CK, Barnett B, Ratner L, Lairmore MD, Martinez E, Lüscher B, Robson CN, Henriksson M, and R Harrod (2015). c-MYC癌蛋白的乙酰化是与HTLV-1 p30II辅助蛋白合作以及p30II/c-MYC诱导致癌细胞转化所必需的. Virology 476: 271-288.

R Harrod (2011) Inhibiting HDACs in a preclinical model of HTLV-1-induced Adult T-cell Lymphoma. Leukemia Res. 35: 1436-1437.

Sharma A, Awasthi S, Harrod CK, Matlock EF, Khan S, Xu L, Chan S, Yang H, Thammavaram CK, Rasor RA, Burns DK, Skiest DJ, Van Lint C, Girard AM, McGee M, Monnat RJ Jr, Werner综合征解旋酶是HIV-1长末端重复转录激活和逆转录病毒复制的辅助因子. J. Biol. Chem. 282: 12048-12057.

Nguyen TL-N, de Walque S, Veithen E, Deckoninck A, Martinelli V, de Launoit Y, Burny A, Harrod R, 和C Van Lint(2007)牛白血病病毒启动子通过环AMP反应元件调节因子tau亚型的转录调控. J. Biol. Chem. 282: 20854-20867.

Awasthi S, Sharma A, Wong K, Zhang J, Matlock EF, Rogers L, Motloch P, Takemoto S, Taguchi H, Cole MD, Lüscher B, Dittrich O, Tagami H, Nakatani Y, McGee M, Girard AM, Gaughan L, Robson CN, Monnat RJ Jr, Myc转化潜能的HTLV-1增强子稳定Myc- tip60转录相互作用. Mol. Cell. Biol. 25: 6178-6198.

Nicot C, Harrod R, Ciminale V, and G Franchini(2005)人类t细胞白血病/淋巴瘤病毒1型非结构基因及其功能. Oncogene 24: 6026-6034.

Wong K, Sharma A, Awasthi S, Matlock EF, Rogers L, Van Lint C, Skiest DJ, Burns DK, 和R Harrod (2005) HIV-1与p300和PCAF转录共激活因子的相互作用通过CREB抑制组蛋白乙酰化和神经营养因子信号传导. J. Biol. Chem. 280: 9390-9399.

Wong K, Zhang J, Awasthi S, Sharma A, Rogers L, Matlock EF, Van Lint C, Karpova T, McNally J, 和R Harrod(2004)神经生长因子受体信号诱导p300/ creb结合蛋白相关因子和hGCN5乙酰转移酶的组蛋白乙酰转移酶结构域依赖性核易位. J. Biol. Chem. 279: 55667-55674.

*Harrod R, Nacsa J, Van Lint C, Hansen J, Karpova T, McNally J, and G Franchini(2003)人类免疫缺陷病毒1型Tat/共激活物乙酰转移酶相互作用抑制p53k320乙酰化和肿瘤抑制因子应答转录. J. Biol. Chem. 278: 12310-12318 (*corresponding author).

Johnson JM, Harrod R, and G Franchini (2001) Molecular biology and pathogenesis of the HTLV-I. Int. J. Exp. Path. 82: 135-147.

Nicot C, 和R Harrod(2000)不同的p300反应机制通过HTLV-1 Tax促进caspase依赖性细胞凋亡. Mol. Cell. Biol. 20: 8580-8589.

Kuo YL, Tang Y, Harrod R, Cai P, 和CZ Giam (2000) HTLV 1型Tax的激酶诱导结构域样区域对NF-kappaB激活很重要. AIDS Research and Human Retroviruses 16: 1607-1612.

Harrod R, Kuo YL, Tang Y, Yao Y, Vassilev A, Nakatani Y, 和CZ Giam (2000) p300和P/CAF与HTLV-1 Tax在一个多hat /激活剂-增强剂复合体中相互作用. J. Biol. Chem. 275: 11852-11857.

Harrod R, Tang Y, Nicot C, Lu HS, Vassilev A, Nakatani Y, HTLV-1 Tax中暴露的kid -样结构域负责共激活子CBP/p300的招募. Mol. Cell. Biol. 18: 5052-5061.

Tang Y, Tie F, Boros I, Harrod R, Glover M, CREB基本结构域DNA结合表面对面的延伸α -螺旋和特定氨基酸残基对HTLV-1 Tax结合很重要. J. Biol. Chem. 273: 27339-27346.