HTLV-I Tax activates the anaphase promoting complex

Summary

Principal Investigator: Chou Zen Giam
Affiliation: Uniformed Services University of the Health Sciences
Country: USA
Abstract: DESCRIPTION (provided by applicant): HTLV-I is the causative agent of adult T-cell leukemia/lymphoma (ATL). HTLV-1 oncoprotein Tax is known to induce DNA damage, micronuclei formation, multinucleation, and DNA aneupoidy. The genomic instability induced by Tax is thought to play an important role in ATLL development. We have shown that the Tax can activate the anaphase promoting complex/cyclosome (APC/C), an E3 ubiquitin ligase that controls metaphase to anaphase transition and mitotic exit. APC/C activation by Tax leads to premature poly- ubiquitination and degradation of cell cycle regulators including cyclin A, cyclin B, securin, and Skp2. Skp2 is the substrate-targeting subunit of another E3 ligase known as SCFSkp2, which mediates the destruction of cyclin E/A-CDK2 inhibitor (CKI), p27. The degradation of Skp2 by APC/C as induced by Tax leads to SCFSkp2 inactivation and p27 stabilization. The mRNA level of another CKI, p21, also increases sharply as a result of promoter activation by Tax and mRNA stabilization due to Tax-induced APC/C activation. The massive surge in p21 and p27 in turn induces rapid senescence (Tax-IRS). Importantly, HeLa and SupT1 T cells infected by HTLV-1 arrest in senescence as well. By contrast, cells deficient in p21 and p27, such as HOS, escaped Tax- IRS and continue to divide after HTLV-1 infection or Tax expression. They however developed dramatic multinucleation and double-stranded DNA breaks, most likely as a result of constitutive APC/C activation. As might be expected, p27 is down-regulated and p21, mis-localized, in HTLV-1-transformed T (HTxT) cells which express Tax abundantly. The p21 and p27 deficiencies apparently allow HTxT cells to overcome Tax-induced senescence. Consistent with the idea that precocious activation of APC/C is deleterious to the cell, we recently found that the prototypic HTxT cell line, MT4, in addition to p21 and p27 deficiencies, expressed a much lower level of Cdh1, the substrate-targeting subunit of APC/C. Recent data from multiple labs indicate that premature APC/C activation through the depletion of Emi1, the S/G2 inhibitor of APC/C, disrupts Cdt1-geminin imbalance and promotes re-replication of DNA. The aberrant DNA replication (re-/hyper-replication) in turn causes multinucleation, double-stranded DNA breaks and DNA damage checkpoint activation. Emi1 depletion also results in premature degradation of Skp2 by APC/C, p27 stabilization, and senescence. Remarkably, the cell cycle phenotypes of Emi1 knockdown resemble those of Tax. These new findings validate our observations and raise many more interesting questions that will be addressed in the following three specific aims: aim 1, to elucidate the mechanism by which Tax activates APC/C;aim 2, to investigate the biological consequences of Tax-mediated APC/C activation;and aim 3, to determine how transformed T cells adapt to Tax expression. PUBLIC HEALTH RELEVANCE: Human T-lymphotropic virus type I (HTLV-1) infects more than 20 million people world-wide. A significant percentage of infected individuals develop adult T-cell leukemia and a paralytic neurological disease known as HTLV-1-associated myelopathy/tropical spastic paraparesis. This project will elucidate the mechanism by which HTLV-1 oncoprotein Tax disrupts cellular control over DNA replication and induces senescence. The study will provide molecular insights that can lead to the development of treatment strategies for human cancer.
Funding Period: ----------------2005 - ---------------2015-
more information: NIH RePORT

Top Publications

  1. pmc Requirement of hCenexin for proper mitotic functions of polo-like kinase 1 at the centrosomes
    Nak Kyun Soung
    Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
    Mol Cell Biol 26:8316-35. 2006
  2. pmc NF-κB inhibition facilitates the establishment of cell lines that chronically produce human T-lymphotropic virus type 1 viral particles
    Muhammad Atif Zahoor
    Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA
    J Virol 88:3496-504. 2014
  3. pmc Induction of CC-chemokines with antiviral function in macrophages by the human T lymphotropic virus type 2 transactivating protein, Tax2
    Glorilee Balistrieri
    Infectious Diseases Division, Department of Medicine, Medical College of Wisconsin, 9200 W Wisconsin Avenue, Milwaukee, WI 53226, USA
    Viral Immunol 26:3-12. 2013
  4. pmc HTLV-1 tax-induced rapid senescence is driven by the transcriptional activity of NF-κB and depends on chronically activated IKKα and p65/RelA
    Yik Khuan Ho
    Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA
    J Virol 86:9474-83. 2012
  5. pmc Regulation of Human T-Lymphotropic Virus Type I Latency and Reactivation by HBZ and Rex
    Subha Philip
    Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America
    PLoS Pathog 10:e1004040. 2014
  6. pmc Human T-cell leukemia virus type 1 infection leads to arrest in the G1 phase of the cell cycle
    Meihong Liu
    Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA
    J Virol 82:8442-55. 2008
  7. ncbi HTLV-1 Tax and adult T-cell leukemia
    Chou Zen Giam
    Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd, Bethesda, MD 20814, USA
    Front Biosci 12:1496-507. 2007
  8. ncbi Self-regulated Plk1 recruitment to kinetochores by the Plk1-PBIP1 interaction is critical for proper chromosome segregation
    Young H Kang
    Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA
    Mol Cell 24:409-22. 2006
  9. pmc Polymyxin B, in combination with fluconazole, exerts a potent fungicidal effect
    Bing Zhai
    Department of Biology, Texas A and M University, College Station, TX, USA
    J Antimicrob Chemother 65:931-8. 2010
  10. pmc Induction of p21(CIP1/WAF1) expression by human T-lymphotropic virus type 1 Tax requires transcriptional activation and mRNA stabilization
    Ling Zhang
    Department of Microbiology and Immunology, Uniformed Services University, Bethesda, MD 20814, USA
    Retrovirology 6:35. 2009

Scientific Experts

  • Ling Zhang
  • Chou Zen Giam
  • Huijun Zhi
  • Subha Philip
  • Yik Khuan Ho
  • Liangpeng Yang
  • Muhammad Atif Zahoor
  • Nak Kyun Soung
  • Glorilee Balistrieri
  • Bing Zhai
  • Meihong Liu
  • Kyung S Lee
  • Young H Kang
  • Yeon Sun Seong
  • Laura Castillo
  • Mark A Beilke
  • Christy Barrios
  • Tochi C Umunakwe
  • Hsiu Ming Shih
  • Dominic Debiaso
  • Naoe Kotomura
  • Michael J Schell
  • Sandra Bixler
  • Jun Zhang
  • Kathy Jung
  • Xin Xiang
  • Xiaorong Lin
  • Henry Zhou
  • Zheng Xia
  • Baoying Liu
  • Randall Merling
  • Kuan Teh Jeang
  • Heejeong Yoon
  • Susan Garfield
  • Keiju Kamijo
  • Toru Miki
  • Chang H Ahn
  • Timothy D Veenstra
  • Yu Liang Kuo
  • Sang Moon Yun
  • Ryoko Kuriyama
  • Hongtao Yu
  • Jung Eun Park
  • Keetae Kim
  • Seung R Kim
  • Jeong K Bang
  • Young Hwi Kang
  • Li Rong Yu

Detail Information

Publications12

  1. pmc Requirement of hCenexin for proper mitotic functions of polo-like kinase 1 at the centrosomes
    Nak Kyun Soung
    Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
    Mol Cell Biol 26:8316-35. 2006
    ..Our results further suggest that the anti-Odf2 immunoreactive centrosomal antigen previously detected in non-germ line cells is likely hCenexin1...
  2. pmc NF-κB inhibition facilitates the establishment of cell lines that chronically produce human T-lymphotropic virus type 1 viral particles
    Muhammad Atif Zahoor
    Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA
    J Virol 88:3496-504. 2014
    ....
  3. pmc Induction of CC-chemokines with antiviral function in macrophages by the human T lymphotropic virus type 2 transactivating protein, Tax2
    Glorilee Balistrieri
    Infectious Diseases Division, Department of Medicine, Medical College of Wisconsin, 9200 W Wisconsin Avenue, Milwaukee, WI 53226, USA
    Viral Immunol 26:3-12. 2013
    ..This suggests that HTLV-2 could alter innate immune responses in macrophagic reservoirs of HIV-1 in HIV-1/HTLV-2 co-infected individuals, and could guide the development of HIV-1 treatments...
  4. pmc HTLV-1 tax-induced rapid senescence is driven by the transcriptional activity of NF-κB and depends on chronically activated IKKα and p65/RelA
    Yik Khuan Ho
    Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA
    J Virol 86:9474-83. 2012
    ..The senescence checkpoint triggered by Tax is driven by the transcriptional activity of NF-κB, which depends on activated IKKα and p65/RelA...
  5. pmc Regulation of Human T-Lymphotropic Virus Type I Latency and Reactivation by HBZ and Rex
    Subha Philip
    Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America
    PLoS Pathog 10:e1004040. 2014
    ..HBZ maintains viral latency by down-regulating Tax-induced NF-κB activation and senescence, and by inhibiting Rex-mediated expression of viral structural proteins. ..
  6. pmc Human T-cell leukemia virus type 1 infection leads to arrest in the G1 phase of the cell cycle
    Meihong Liu
    Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA
    J Virol 82:8442-55. 2008
    ..These infected cells can expand clonally, accumulate additional chromosomal abnormalities, and progress to cancer...
  7. ncbi HTLV-1 Tax and adult T-cell leukemia
    Chou Zen Giam
    Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd, Bethesda, MD 20814, USA
    Front Biosci 12:1496-507. 2007
    ....
  8. ncbi Self-regulated Plk1 recruitment to kinetochores by the Plk1-PBIP1 interaction is critical for proper chromosome segregation
    Young H Kang
    Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA
    Mol Cell 24:409-22. 2006
    ..Thus, Plk1 self-regulates the Plk1-PBIP1 interaction to timely localize to the kinetochores and promote proper chromosome segregation...
  9. pmc Polymyxin B, in combination with fluconazole, exerts a potent fungicidal effect
    Bing Zhai
    Department of Biology, Texas A and M University, College Station, TX, USA
    J Antimicrob Chemother 65:931-8. 2010
    ..The objective of this study was to identify existing clinical compounds that either possess a fungicidal activity alone or can act synergistically with fungistatic antifungals...
  10. pmc Induction of p21(CIP1/WAF1) expression by human T-lymphotropic virus type 1 Tax requires transcriptional activation and mRNA stabilization
    Ling Zhang
    Department of Microbiology and Immunology, Uniformed Services University, Bethesda, MD 20814, USA
    Retrovirology 6:35. 2009
    ..The possible involvement of Tax-mediated APC/C activation in p21(CIP1/WAF1) mRNA stabilization is discussed...
  11. pmc Complex cell cycle abnormalities caused by human T-lymphotropic virus type 1 Tax
    Liangpeng Yang
    Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd, Bethesda, MD 20814, USA
    J Virol 85:3001-9. 2011
    ....