Microbiology & Immunology | Faculty | Cross-Appointed | Shou-Jiang (SJ) Gao, Ph.D.
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Microbiology & Immunology Cross-Appointed Faculty

  Research | More on Shou-Jiang Gao | Publications | Lab Members


Shou-Jiang (SJ) Gao, Ph.D.
Professor

University of Texas Health Science Center at San Antonio
Greehey Children's Cancer Research Institute
(210) 562-9030
Fax: (210) 562-9014
Email: gaos@uthscsa.edu
 

Research

 

The primary interest of our research is to understand the pathogenic mechanisms of tumor viruses with the goal to identify targets for effective therapeutic and preventive applications. We currently use Kaposi’s sarcoma-associated herpesvirus (KSHV) and its associated cancer, Kaposi’s sarcoma (KS), as a model system to study how an oncogenic virus modulates cellular pathways and host environments to facilitate its infection and replication, and causes cancer.

 

KS is an inflammatory vascular spindle cell cancer of proliferative endothelial cells commonly found in AIDS patients. In some African regions, KS has become the dominant cancer in both adult and pediatric patients with or without HIV infection. In addition to its importance as an emerging pathogen of major human diseases, KSHV is an excellent model for studying inflammation and angiogenesis, and interactions of virus-host and virus-virus.

 

KSHV is a gammaherpesvirus encoding close to 100 genes and 12 microRNAs. We have developed an efficient bacteria-mammalian shuttle system for the genetic manipulation of KSHV by cloning the 170 kb KSHV genome as a bacteria artificial chromosome, and a highly efficient infection system of primary human umbilical vein endothelial cells, in which KSHV transforms the infected cells into angiogenic proliferative spindle phenotypes closely resembling KS tumor cells. We employ comprehensive genetic, genomic, molecular, cellular, and biochemical approaches to define the molecular basis of the sophisticated interplays of virus-cell interactions. To this end, we have examined the viral transcriptional and replication programs, and the altered cellular pathways following KSHV infection. KSHV infection modulates multiple cellular pathways such as mitogen-activated protein kinase (MAPK) pathways to facilitate its infection and replication. KSHV activation of MAPK pathways leads to malignant cellular proliferation by accelerating cell cycle progression, cell invasion by inducing matrix metalloproteinases, and neoangiogenesis by inducing inflammatory and angiogenic cytokines. KSHV infection also induces chromosome instability, which predisposes the infected cells to cellular transformation. These works have identified MAPK pathways and other angiogenic pathways as potential therapeutic and preventive targets. Ongoing experiments are testing inhibitors of these pathways in animal models with the hope that some of them can be taken into clinical trials in the near future. In the same time, we are also conducting translational clinical projects to validate these laboratory findings with the emphasis on the KSHV-host and KSHV-HIV interactions.

 

To identify KSHV genes that are essential for malignant cellular transformation, we have generated mutagenesis library that contains mutants of all known KSHV genes and microRNAs. We currently focus on KSHV latent genes, microRNAs, genes that induce angiogenesis, and genes that regulate KSHV latency and reactivation.

 

We initially identified and characterized the KSHV immunodominant major latent protein, LNA (LANA). LNA has since been shown to be a multi-functional viral protein that maintains the stability of viral episomes and targets multiple cellular pathways. We demonstrated that LNA is essential for KSHV episome persistence and represses viral lytic transcriptional program in the context viral infection. In addition, we have identified a novel nuclear protein KLIP1 that interacts with LNA, and shown that KLIP1 is a cell cycle-dependent potent transcriptional repressor manipulated by LNA in KSHV latent infection. Recent studies have shown that KLIP1 interacts with myeloid leukemia factor 1 (MLF1), and possibly has a role in the genesis of erythroleukemias. KLIP1 is also a component of centromere, and regulates cytokinesis

 

We were the first to identify and characterize the first KSHV oncogene viral interferon regulatory factor (vIRF). vIRF is the first viral protein identified to have sequence homology to cellular IRFs, a family of transcriptional factors that are involved in a variety of functions including but not limiting to oncogenesis, cell proliferation, differentiation, apoptosis, and host defense. We have defined the transcriptional mechanism controlling vIRF expression and identified a novel transcriptional silencer, which could have implication for the transcriptional repression of other KSHV lytic genes in KSHV latency.

 

KSHV encodes a replication and transcription activator, RTA (ORF50). The expression of RAT is sufficient and necessary for activating for KSHV lytic replication. RTA targets both viral and cellular genes to achieve its functions. We are currently mapping the viral and cellular targets and promoter binding sites of RTA in the whole-genome scale. These works should provide insights into the mechanisms of KSHV replication.

 

Key Words
KSHV/HHV8, Kaposi's sarcoma, AIDS-related malignancies, Angiogenesis, Inflammation, microRNA, Herpesvirus, Latency and Reactivation


 

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Publications

  • Muñoz-Fontela C, Villar LM, Hernandez F, Gallego P, Rodriguez E, Arroyo J, Gao S-J, Avila J, Rivas M. Induction of paclitaxel resistance by the KSHV latent protein LANA2. Journal of Virology, in press.
  • Xie JP, Ajibade AO, Ye FC, Kuhne K and Gao S-J. MEK/ERK, JNK and p38 multiple mitogen-activated protein kinase pathways are essential for the reactivation of Kaposi’s sarcoma-associated herpesvirus from latency. Virology, 2007 Oct 25; [Epub ahead of print].
  • Cloutier N, Eyll OV, Lefort S, Janelle M-E, Gao S-J, Flamand L. Development of a mouse model for the identification of HHV-8 genes contributing to tumorigenesis. Archives of Virology. 2007 Oct 18; [Epub ahead of print].
  • Nun T, Kroll DJ, Oberlies NH, Soejarto DD, Case R, Piskaut P, Matainaho T, Hilscher C, Wang L, Dittmer DP, Gao S-J and Damania B. Development of a fluorescence-based assay to screen antiviral drugs against Kaposi’s sarcoma-associated herpesvirus. Molecular Cancer Therapeutics, 2007, 6, 2360-2370.
  • Qian LW, Xie JP, Ye FC and Gao S-J. Kaposi’s sarcoma-associated herpesvirus infection promotes invasion of primary human umbilical vein endothelial cells by inducing matrix metalloproteinases. Journal of Virology, 2007, 81, 7001-7010.
  • Greene W, Kuhne K, Ye FC, Chen JG, Zhou FC, Lei XF, and Gao S-J. Molecular biology of KSHV in relation to AIDS-associated oncogenesis. In: AIDS-Associated Viral Oncogenesis. 2007, pp: 69-127. Craig Meyers (Ed.). Springer Science+Business Media.
  • Mutlu AD, Cavallin LE, Vincent L, Chiozzini C, Eroles P, Asgari Z, Hooper AT, La Perle KMD, Hilsher C, Gao S-J, Dittmer D, Rafii S and Mesri EA. In vivo-restricted and reversible malignancy induced by human herpesvirus-8 KSHV: a cell and animal model of virally induced Kaposi's sarcoma. Cancer Cell, 2007, 11, 245-258.
  • Ye FC, Blackbourn DJ, Mengel M, Xie JP, Qian LW, Greene W, Yeh I-T, Graham D, and Gao S-J. Kaposi’s sarcoma-associated herpesvirus promotes angiogenesis by inducing angiopoietin-2 expression via AP-1 and Ets1. Journal of Virology, 2007, 81, 3980-3991.
  • Majerciak M, Pripuzova N, McCoy JP, Gao S-J and Zheng Z-M. Targeted disruption of KSHV ORF57 in the viral genome is detrimental for the expression of ORF59, K8, and K8.1 and the production of infectious virus. Journal of Virology, 2007, 81, 1062-1071.
  • Zhu FX, Li XJ, Zhou FC, Gao S-J and Yan Yuan. Functional characterization of Kaposi's sarcoma-associated herpesvirus ORF45 by BAC-based mutagenesis. Journal of Virology, 2006, 80, 12187-12196.
  • Nair P, Pan HY, Stallings RL and Gao S-J. Recurrent genomic imbalances in primary effusion lymphomas. Cancer Genetics and Cytogenetics. 2006, 171, 119-121.
  • Pan HY, Xie JP, Ye FC, and Gao S-J. Modulation of KSHV infection and replication by MEK/ERK, JNK and p38 multiple mitogen-activated protein kinase pathways during primary infection. Journal of Virology, 2006, 80, 5371-5382.
  • Lu F, Day L, Gao S-J, and Lieberman PM. Acetylation of the latency-associated nuclear antigen regulates repression of Kaposi’s sarcoma-associated herpesvirus lytic transcription. Journal of Virology, 2006, 80, 5273-5282.
  • Fang Q, Liu J, Bai ZQ, Kang T, He ZH, Hu ZH, Gao SJ. KSHV seroprevalence in the general population of Hubei in China. Virologica Sinica, 2006, 21, 97-101.
  • Xie JP, Pan HY, Yoo SM and Gao S-J. Induction of AP-1 and interleukin 6 during KSHV primary infection mediated by multiple MAPK pathways. Journal of Virology, 2005, 79, 15027-15037.
  • Yoo SM, Zhou FC, Ye FC, Pan HY and Gao S-J. Early and sustained expression of latent and host modulating genes in coordinated transcriptional program of KSHV productive primary infection of human primary endothelial cells. Virology, 2005, 343, 47-64.
  • Krishnan HH, Sharma-Wali N, Zeng L, Gao S-J and Chandran B. Envelope glycoprotein B of Kaposi’s sarcoma-associated herpesvirus (KSHV) is essential for egress from infected cells. Journal of Virology, 2005, 79, 10952-10967.
  • Si MW, Jagirdar J, Zhang YJ, Gao S-J, and Yeh TI. Detection of KSHV in transbronchial biopsies in patients with Kaposi's sarcoma. Applied Immunohistochemistry and Molecular Morphology, 2005, 13, 61-65.
  • Deng JH, Zhang YJ, Wang XP and Gao S-J. Lytic replication-defective Kaposi's sarcoma-associated herpesvirus (KSHV): potential role in infection and malignant transformation. Journal of Virology, 2004, 78, 11108-11120.
  • Pan H-Y, Zhou FC, Gao S-J. KSHV infection induces abnormal centrosome duplication and chromosome instability. Cancer Research, 2004, 64, 4064-4068.
  • Ye FC, Zhou FC, Yoo SM, Xie JP and Gao S-J. Disruption of Kaposi's sarcoma-associated herpesvirus latent nuclear antigen leads to abortive episome persistence. Journal of Virology, 2004, 78, 11121-11129.
  • Luna RE, Zhou FC, Baghian A, Chouljenko V, Forghani V, Gao S-J, Kousoulas KG. Kaposi’s sarcoma-associated herpesvirus glycoprotein K8.1 is dispensable for viral entry and may facilitate virion egress. Journal of Virology, 2004, 78, 6389-6398.
  • Baillargeon J, Pollock BH, Leach CT, and Gao S-J. The association of neoplasms and HIV infection in the correctional setting. International Journal of STD and AIDS, 2004, 15, 348-51.

 

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Lab Members

  Location: Greehey Children's Cancer Research Institute

  • Zhiqiang Bai, M.S., Research Scholar
  • Jacky Chen, Ph.D., Assistant Professor, Research
  • Yvette Flahive, B.S., Lab Manager
  • Whitney Greene, Ph.D., Postdoctoral Fellow
  • Moraima Guadalupe, Ph.D., Postdoctoral Fellow
  • Tao Kang, B.S., Research Scholar
  • Xiufend Lei, Ph.D., Instructor
  • Li-Wu Qian, M.D., Ph.D., Postdoctoral Fellow
  • Azeneth Sexauer, Ph.D., Postdoctoral Fellow
  • Jianping Xie, M.D., Postdoctoral Fellow
  • Fengchun Ye, Ph.D., Assistant Professor, Research
  • Fuchun Zhou, Ph.D., Assistant Professor, Research


    • Graduate Students in Dr. Gao's Lab:
    Tyfffany Jones

    The following students are from the M&I Track:
    Kurt Kuhn
    Qiuhu Li


     

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