Our Science – Zheng Website

Zhi-Ming Zheng, M.D., Ph.D.

HIV and AIDS Malignancy Branch Investigator Building 10, Room 6N106 NCI-Bethesda Bethesda, MD 20892-1868 Phone:   301-594-1382 or 1383 Fax:   301-480-8250 E-Mail:   zhengt@exchange.nih.gov

Biography

Dr. Zhi-Ming Zheng received his medical and virological training in China and was a Yale-China exchange scholar at Yale University. Dr. Zheng served as an associate professor, chief of the Clinical Virology Laboratory, and deputy as well as acting director of the Virus Research Institute at Hubei Medical University (now Wuhan University School of Medicine), China. He received his Ph.D. from the University of South Florida School of Medicine. He was an IRTA fellow and later a senior staff in the Laboratory of Tumor Virus Biology before he heads his section in the HIV and AIDS Malignancy Branch of NCI. His research interests center on the RNA processing and tumorigenesis of tumor viruses including papillomaviruses and Kaposi's sarcoma-associated herpesvirus.

Research

Viral RNA Splicing and Oncogenesis

The Zheng laboratory studies protein-RNA interactions and their subsequent consequences in oncogenic DNA tumor virus infection. More specifically, the laboratory focuses on how protein-RNA interactions regulate gene expression of high-risk human papillomaviruses and Kaposi sarcoma-associated herpesvirus. In particular, this study aims to understand how RNA splicing and small regulatory RNAs regulates viral and cellular gene expression during oncogenic virus infection. Our long-term goal is to develope a series of RNA-based therapeutic approaches to control viral or cellular gene expression and to identify some biomarkers for clinical diagnosis and prognosis.

1. Papillomavirus infection and viral gene expression.
Human papillomavirus type 16 (HPV16) or 18 (HPV18) infection, acquired primarily via sexual transmission, is widely recognized as a leading cause of cervical and anal cancer. Infection with oncogenic HPV in other tissues could also lead to development of cancer. For example, we recently demonstrated that colorectal oncogenic HPV infection is common in patients (51%) with colorectal cancer. High prevalence and incidence of cervical HPV infection have been observed among HIV-positive and immunodeficient women. Cervical cancer has been the most common malignancy among women with AIDS in both Europe and the United States. Two viral oncoproteins, E6 and E7, of HPV16 and HPV18 are involved in cervical carcinogenesis and are known to destabilize cellular tumor suppressor proteins p53 and pRb, respectively. Recently, we showed that high-risk HPV infection also deregulates the expression of tumor-suppressive miR-34a and p18Ink4c through viral oncoprotein E6. In HPV16 and HPV18, E6 and E7 are transcribed as a single bicistronic RNA bearing 3 exons and 2 introns, with the intron 1 in the E6 coding region. Splicing of the intron 1 in the E6E7 bicistronic pre-mRNAs is highly efficient and the majority of the spliced transcripts in cancer tissues and cervical cancer cell lines are E6*I, a spliced product without intron 1. We have hypothesized that the E6 is expressed from a small portion of the bicistronic RNAs with retention of the intron 1. This hypothesis raises several important questions: 1. Why is an efficient splicing of the intron 1 in the E6E7 pre-mRNAs needed since the splicing disrupts E6 expression? 2. What proportion of the E6E7 pre-mRNAs escape the splicing of intron 1 and what regulates this escaping? 3. How could an RNA molecule containing an intron be exported to the cytoplasm to translate E6 protein? To address these questions will lead us to understand the mechanisms that are involved in RNA splicing regulation. In the past few years, we demonstrated that the intron 1 splicing subjects to exon definition (size) by a cap structure on the RNA 5' end. Although the E6E7 mRNAs with the intron 1 retention encode viral oncoprotein E6, the spliced E6*I mRNAs is mainly resposible for the expression of E7 oncoprotein. Based on these observations, we have developed several E6 and E7-specific siRNAs to selectively silence the expression of each viral oncogene. We further demonstrated that aberrant expression of oncogenic and tumor-suppressive microRNAs in cervical cancer is required for cancer cell growth and viral oncoproteins are partially responsible for this deregulation.

2. KSHV Gene expression and post-transcriptional regulation.
KSHV is a lymphotropic DNA tumor virus that induces Kaposi sarcoma (KS), primary effusion lymphoma (PEL) or body cavity-based B-cell lymphoma, and multicentric Castleman disease. Among those malignancies, KS occurs frequently in patients infected with HIV. Latent KSHV infection in KS lesions and PEL-derived B cells features the highly restricted expression of only five viral genes. The lytic KSHV infection can be induced by chemicals or hypoxia in PEL-derived B cells with latent KSHV infection. In this lytic switch, a KSHV transactivator, ORF50, is absolutely required. ORF50 is an immediate-early gene transcribed as a polycistronic RNA with 5 exons and 4 introns. ORF50 is positioned in the virus genome with both K8 (an early gene encoding a K-bZIP protein) and K8.1 (a late gene encoding a viral envelope glycoprotein) and shares a single polyadenylation site downstream of K8.1 coding region. Accordingly, the transcripts of the three genes overlap each other and undergo extensive RNA splicing. Our initial study was to investigate how this complicated gene expression is regulated. We found there are two major isoforms of spliced RNA products, α (exclusion of K8 intron 2 or ORF50 intron 3) and β (inclusion of K8 intron 2 or ORF50 intron 3) in KSHV lytic infection. By profiling the transcription and splicing products of ORF50, K8 and K8.1, we demonstrated that KSHV K8β is derived from a splicing intermediate and antagonizes K8α-mediated induction of p21 and p53 and blocks K8α-CDK2 interaction. We further showed that KSHV ORF57 promotes RNA splicing of K8β to produce K8α. KSHV ORF57 is an ICP27 homolog of herpes simplex viruses and is essential for KSHV replication and virus production. Demonstration of that ORF57, a mRNA transcript accumulator (MTA), is a viral splicing factor was a surprise since its homologs in other herpesviruses are all splicing suppressive in reported studies. ORF57 is a phosphorylated nuclear protein bearing three nuclear localization signals in its N-terminus and its activities mostly take place in the nucleus of an infected cell. In the analysis of the gene structure and expression of KSHV ORF56 (viral primase), ORF57, ORF58 (EB virus BMRF2 homology) and ORF59 (viral DNA polymerase processing factor), we demonstrated that both ORF56 and ORF59 are expressed as bicistronic RNAs that subject to ORF57 up-regulation. Works are in progress to understand the mechanisms on how KSHV ORF57 regulates the expression of viral and cellular genes post-transcriptionally.

We have collaborated with Elliot Androphy, University of Massachusetts; Joel Palefsky; University of California San Francisco; Shou-Jiang Gao, University of Texas; Craig Meyers, Pennsylvania State University; Janet Rader, Washington University in St. Louis; Tom Broker and Louise Chow, University of Alabama at Birmingham, Robert Yarchoan, Michael Kruhlak, J. Philip McCoy, Jr., Curtis Harris, Kenneth Kraemer, Carl Baker; Lauren Wood, and Harvey Alter, NIH.

This page was last updated on 9/12/2008.