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. Persistent infection with oncogenic or high-risk HPVs in other tissues also leads to the development of cancers. Two viral oncoproteins, E6 and E7, of oncogenic HPVs are involved in cervical carcinogenesis and are known to destabilize cellular tumor suppressor proteins and to induce aberrant expression of a subset of oncogenic and tumor-suppressive miRNAs and lncRNAs. In HPV16 and HPV18, E6 and E7 are transcribed as a single bicistronic E6E7 RNA bearing 3 exons and 2 introns, with the intron 1 in the E6 coding region. Splicing of the intron 1 in E6E7 pre-mRNA disrupts the E6 ORF, but is required to reinitiate translation of the E7 ORF downstream. Thus, RNA splicing regulates the production of viral E6 and E7. We found that cellular RNA splicing factors, including SRSF3 (SRp20), control virus early-to-late switch through binding to viral RNA cis-elements. We demonstrated that SRp20 is a proto-oncogene essential for cell proliferation. When overexpressed, it induces tumor formation. Together, the HPV infection-induced degradation of host tumor suppressive proteins, aberrant expression of oncogenic and tumor-suppressive miRNAs and lncRNAs, and enhancement of SRp20 expression could be three distinguishable mechanisms leading to the development of cervical cancer. 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 (MCD). Among those malignancies, KS occurs frequently in the patients infected with HIV. PEL and MCD feature the increased levels of cytokines (IL6 and IL10). Latent KSHV infection in KS lesions and PEL-derived B cells can be reactivated as lytic KSHV infection by various stress conditions or inflammation. In KSHV lytic infection, a viral lytic gene ORF57 encodes a multifunctional, caspase-7 sensitive protein to regulate the expression of a subset of viral lytic genes at the posttranscriptional level. We demonstrated that ORF57 carries out this function by binding to RNA and interacting with cellular RNA-binding proteins. ORF57 functions as a viral splicing factor and promotes RNA splicing by interacting with the spliceosomal machinery and by attenuation of SRSF3 activities. ORF57 binds to and stabilizes viral RNAs by interaction with host RNA capping, export, and polyadenylation factors. ORF57 promotes IL6 expression by interrupting miRNA-mediated RNA instability and translational repression.

National Institute of Health (NIH)
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Massimelli, Maria J; Majerciak, Vladimir; Kruhlak, Michael et al. (2013) Interplay between polyadenylate-binding protein 1 and Kaposi's sarcoma-associated herpesvirus ORF57 in accumulation of polyadenylated nuclear RNA, a viral long noncoding RNA. J Virol 87:243-56
Bodaghi, Sohrab; Jia, Rong; Zheng, Zhi-Ming (2009) Human papillomavirus type 16 E2 and E6 are RNA-binding proteins and inhibit in vitro splicing of pre-mRNAs with suboptimal splice sites. Virology 386:32-43
Wang, Xiaohong; Wang, Hsu-Kun; McCoy, J Philip et al. (2009) Oncogenic HPV infection interrupts the expression of tumor-suppressive miR-34a through viral oncoprotein E6. RNA 15:637-47
Jia, Rong; Liu, Xuefeng; Tao, Mingfang et al. (2009) Control of the papillomavirus early-to-late switch by differentially expressed SRp20. J Virol 83:167-80
Majerciak, Vladimir; Zheng, Zhi-Ming (2009) Kaposi's sarcoma-associated herpesvirus ORF57 in viral RNA processing. Front Biosci 14:1516-28
Jia, Rong; Zheng, Zhi-Ming (2009) Regulation of bovine papillomavirus type 1 gene expression by RNA processing. Front Biosci 14:1270-82
Wang, Xiaohong; Tang, Shuang; Le, Shu-Yun et al. (2008) Aberrant expression of oncogenic and tumor-suppressive microRNAs in cervical cancer is required for cancer cell growth. PLoS One 3:e2557
Majerciak, Vladimir; Yamanegi, Koji; Allemand, Eric et al. (2008) Kaposi's sarcoma-associated herpesvirus ORF57 functions as a viral splicing factor and promotes expression of intron-containing viral lytic genes in spliceosome-mediated RNA splicing. J Virol 82:2792-801