Ingrid K Ruf
Assistant Professor, Molecular Biology and Biochemistry
School of Biological Sciences
School of Biological Sciences
B.S., The Ohio State University, Molecular Genetics
Ph.D., Emory University, Genetic and Molecular Biology
Ph.D., Emory University, Genetic and Molecular Biology
University of California, Irvine
3236 McGaugh Hall
Mail Code: 3900
Irvine, CA 92697
3236 McGaugh Hall
Mail Code: 3900
Irvine, CA 92697
Research Interests
viral oncogenesis, viral latency, signal transduction, cancer
Appointments
Department of Virology, St. Jude Children's Research Hospital
Department of Biochemistry, St. Jude Children's Research Hospital
Department of Biochemistry, St. Jude Children's Research Hospital
Research Abstract
Epstein-Barr Virus (EBV) is a ubiquitous human herpesvirus that establishes a life-long latent infection within B-lymphocyte. While the vast majority of EBV-infected individuals carry the virus without ever developing an EBV-associated malignancy, EBV does have appreciable oncogenic potential when maintained as a latent infection. EBV is associated with a number of lymphomas, including Burkitt lymphoma (BL) and Hodgkin’s lymphoma, as well as several non-lymphoid tumors. Despite the fact that EBV was originally isolated from BL cells over 40 years ago, the contribution of EBV to EBV-dependent tumorigenicity remains essentially undefined.
Endemic BL is a B-cell tumor characterized by deregulated expression of the c-MYC proto-oncogene (a result of a chromosomal translocation), and almost invariably carries EBV as a latent infection. In EBV-infected BL tumors and cell lines, EBV adopts a restricted pattern of viral gene expression in which only a limited set of gene products are expressed. Interestingly, the viral genes expressed in this so-called restricted latency program do not include those known to overtly influence cell growth potential or those known to be required for B-cell growth transformation (immortalization) by the virus. Thus, the dominant factor believed to be responsible for the development and maintenance of tumorigenicity in BL is constitutive expression of c-MYC. Consequently, the question of what (if anything) the virus contributes to tumorigenicity has remained a controversy in the EBV field. However, a recent observation that the spontaneous loss of the EBV genome from a highly tumorigenic BL cell line was associated with a concomitant loss of tumorigenic potential provided the first evidence that EBV may in fact directly contribute to tumorigenicity in BL, despite the lack of expression of a known viral “transforming” protein.
Following this discovery, I began to investigate the molecular mechanisms through which latent EBV infection contributes directly to BL. I have demonstrated that EBV-dependent tumorigenic potential is likely due in part to enhanced cell survival (decreased apoptosis) promoted by both an increase in the expression of the anti-apoptotic Bcl-2 protein and an EBV-induced post-transcriptional down-regulation of c-MYC protein that occurs under environmental conditions that favor c-MYC-induced apoptosis. However, to date the EBV genes responsible for this phenotype has not been defined. Subsequent studies aimed at defining the molecular contribution of individual EBV latent gene products to tumorigenic potential, revealed that a significant contribution is provided by two small but highly expressed non-coding RNAs, EBER-1 and EBER-2. Despite the fact that the EBER RNAs are the most abundant EBV transcript in latently infected cells and were discovered two decades ago, their functions and contribution to EBV biology remain essentially unknown. Thus, while we have established that the EBERs clearly enhance tumorigenic potential, their mechanism(s) of action as well as the cellular genes targeted by the EBERs have not been defined.
The overall goal of my current and future research program is to answer several long-standing questions within the EBV field with respect to the contribution of EBV to BL, and to oncogenesis in general. My work to date indicates that EBV can contribute to BL through at least two avenues: an RNA (EBER)-dependent mechanism that enhances tumorigenic potential independent of a substantial effect on apoptosis, and an additional mechanism mediated by an as-yet-unidentified EBV gene(s) that counters the pro-apoptotic consequences of deregulated c-MYC in BL. Current work in focused on defining the mechanisms by which the EBERs modulate cellular gene expression (both at the level of RNA and protein), identification of EBER-regulated proteins, and the assessment of the potential role of EBERs in inhibition of cellular anti-viral response pathways. In addition to providing insights into the role of EBV in BL, this work will be relevant to our understanding of maintenance of latency in the healthy EBV-immune host, where the pattern of latent viral gene expression is very similar to that in BL and contributes to viral pathogenic potential by promoting long-term survival of latently infected B cells.
Endemic BL is a B-cell tumor characterized by deregulated expression of the c-MYC proto-oncogene (a result of a chromosomal translocation), and almost invariably carries EBV as a latent infection. In EBV-infected BL tumors and cell lines, EBV adopts a restricted pattern of viral gene expression in which only a limited set of gene products are expressed. Interestingly, the viral genes expressed in this so-called restricted latency program do not include those known to overtly influence cell growth potential or those known to be required for B-cell growth transformation (immortalization) by the virus. Thus, the dominant factor believed to be responsible for the development and maintenance of tumorigenicity in BL is constitutive expression of c-MYC. Consequently, the question of what (if anything) the virus contributes to tumorigenicity has remained a controversy in the EBV field. However, a recent observation that the spontaneous loss of the EBV genome from a highly tumorigenic BL cell line was associated with a concomitant loss of tumorigenic potential provided the first evidence that EBV may in fact directly contribute to tumorigenicity in BL, despite the lack of expression of a known viral “transforming” protein.
Following this discovery, I began to investigate the molecular mechanisms through which latent EBV infection contributes directly to BL. I have demonstrated that EBV-dependent tumorigenic potential is likely due in part to enhanced cell survival (decreased apoptosis) promoted by both an increase in the expression of the anti-apoptotic Bcl-2 protein and an EBV-induced post-transcriptional down-regulation of c-MYC protein that occurs under environmental conditions that favor c-MYC-induced apoptosis. However, to date the EBV genes responsible for this phenotype has not been defined. Subsequent studies aimed at defining the molecular contribution of individual EBV latent gene products to tumorigenic potential, revealed that a significant contribution is provided by two small but highly expressed non-coding RNAs, EBER-1 and EBER-2. Despite the fact that the EBER RNAs are the most abundant EBV transcript in latently infected cells and were discovered two decades ago, their functions and contribution to EBV biology remain essentially unknown. Thus, while we have established that the EBERs clearly enhance tumorigenic potential, their mechanism(s) of action as well as the cellular genes targeted by the EBERs have not been defined.
The overall goal of my current and future research program is to answer several long-standing questions within the EBV field with respect to the contribution of EBV to BL, and to oncogenesis in general. My work to date indicates that EBV can contribute to BL through at least two avenues: an RNA (EBER)-dependent mechanism that enhances tumorigenic potential independent of a substantial effect on apoptosis, and an additional mechanism mediated by an as-yet-unidentified EBV gene(s) that counters the pro-apoptotic consequences of deregulated c-MYC in BL. Current work in focused on defining the mechanisms by which the EBERs modulate cellular gene expression (both at the level of RNA and protein), identification of EBER-regulated proteins, and the assessment of the potential role of EBERs in inhibition of cellular anti-viral response pathways. In addition to providing insights into the role of EBV in BL, this work will be relevant to our understanding of maintenance of latency in the healthy EBV-immune host, where the pattern of latent viral gene expression is very similar to that in BL and contributes to viral pathogenic potential by promoting long-term survival of latently infected B cells.
Publications
Houmani JL and Ruf IK. Growth-promoting properties of Epstein-Barr virus EBER-1 RNA correlate with ribosomal protein L22 binding. J. Virol. 83: 9844-9853, 2009.
Ruf IK, Houmani JL, and Sample JT. Dysregulation of UBP43 expression alters interferon-stimulated gene expression in Burkitt lymphoma cells. PLoS One 4(6): e6023, 2009
Houmani JL and Ruf IK. Clusters of basic amino acids contribute to RNA binding and nucleolar localization of ribosomal protein L22. PLoS One 4(4): e5306, 2009.
Sample JT, Ruf IK. Burkitt lymphoma. In: Tselis A, Jenson HB, eds. Epstein-Barr Virus: Diagnosis, Therapy and Management. Marcel Dekker, Inc. March 2006.
Ruf IK, Lackey K, Warudkar S, and Sample JT. Protection from interferon–induced apoptosis by Epstein-Barr virus small RNAs is not mediated by inhibition of PKR. J. Virol 79:14562-14569,2005.
Ruf IK, Rhyne PW, Yang H, Borza CM, Hutt-Fletcher LM, Cleveland JL, and Sample JT. Epstein-Barr virus regulates c-MYC, apoptosis, and tumorigenicity in Burkitt lymphoma. In: Takada K. ed. Epstein-Barr virus and human cancer. Heidelberg: Springer-Verlag, Current Topics in Microbiology and Immunology,258:153-160, 2001.
Zhao B, Dalbies-Tran R, Juang H, Ruf I, Sample JT, Wang F, and Sample CE. Transcriptional regulatory properties of Epstein-Barr virus nuclear antigen 3C are conserved in simian lymphocryptoviruses. J Virol 77:5639-5648, 2003.
Swart R, Ruf IK, Sample JT, and Longnecker R. Latent membrane protein 2A-mediated effects on the phosphatidylinositol 3-kinase/Akt pathway. J. Virol 74:10838-10845, 2000.
Ruf IK, Rhyne PW, Yang C, Cleveland JL, and Sample JT. Epstein-Barr virus small RNAs potentiate tumorigenicity of Burkitt lymphoma cells independently of an effect on apoptosis. J. Virol 74:10223-10228, 2000.
Ruf IK, Sample J. Repression of Epstein-Barr virus EBNA-1 gene transcription by pRb during restricted latency. J. Virol. 73:7943-7951, 1999.
Ruf IK, Moghaddam A, Wang F, Sample J. Mechanisms that regulate Epstein-Barr virus EBNA-1 gene transcription during restricted latency are conserved among Lymphocryptoviruses of old world primates. J. Virol. 73:1980-1989, 1999.
Ruf IK, Rhyne PW, Yang H, Borza C, Hutt-Fletcher LM, Cleveland JL, and Sample JT. Epstein-Barr virus regulates c-MYC, apoptosis and tumorigenicity in Burkitt lymphoma. Mol.Cell.Biol. 19:1651-1660, 1999.
Nonkwelo C, Ruf IK, Sample J. Interferon-independent and -induced regulation of Epstein-Barr Virus EBNA-1 gene transcription in Burkitt lymphoma. J. Virol. 71:6887-6897, 1997.
Nonkwelo C, Ruf IK, Sample J. The Epstein-Barr Virus EBNA-1 promoter Qp requires an initiator-like element. J. Virol. 71:354-361, 1997.
Ruf IK, Rawlins DR. Identification and characterization of ZIIBC, a complex formed by the ZII site of the Epstein-Barr virus BZLF1 promoter. J. Virol. 69:7648-7657, 1995.
Ling PD, Hsieh JJ-D, Ruf IK, Rawlins DR, Hayward SD. EBNA-2 upregulation of EBV latency promoters and the cellular CD23 promoter utilize a common targeting intermediate, CBF1.J.Virol. 68:5375-5383, 1994.
Professional Societies
International Association for Research on Epstein-Barr Virus and Associated Diseases
American Society for Microbiology
American Association for the Advancement of Science (AAAS)
American Society for Virology
Graduate Programs
Cellular and Molecular Biosciences
Research Centers
Center for Virus Research
Cancer Research Institute
Link to this profile
https://faculty.uci.edu/profile/?facultyId=4945
https://faculty.uci.edu/profile/?facultyId=4945
Last updated
12/03/2009
12/03/2009