Cancer Cell Biology Training Program

Our lab investigates the mechanisms by which the DNA tumor virus Kaposi’s Sarcoma-associated Herpesvirus (KSHV) causes cellular transformation. KSHV is a gammaherpesvirus that establishes a persistent infection in the human host and is the etiological agent of several malignancies including Kaposi’s sarcoma, primary effusion lymphoma, and multicentric Castleman’s disease.  Kaposi’s sarcoma is the most common AIDS-associated malignancy worldwide, and all KSHV-associated malignancies have poor prognosis and few efficacious treatment options [1].

KSHV expresses a number of viral signaling proteins that are thought to contribute to host cell transformation [2]. The KSHV K15 protein has previously been shown to activate the MAPK and NF-κB pathways [3].  Activation of the NF-kB pathway typically has pleiotropic effects on cells, but can cause inflammation, cell survival, and cell growth and proliferation. My project is focused on determining the mechanism by which K15 activates this important signaling pathway by investigating whether it signals primarily through the canonical or noncanonical NF-kB pathway. I will also determine if K15 has any cellular binding partners that modulate its ability to activate NFkB signaling. KSHV K15 has also been implicated in the regulation of two cellular microRNAs (miRNA), which are small non-coding RNAs that regulate protein expression by the targeted degradation of mRNA transcripts [4]. K15 is capable of inducing host cell migration and invasion by upregulation of the host miRNAs miR21 and 31 through an SH2 motif in its C-terminal tail [5]. I am also investigating whether K15 may utilize miRNAs to modulate cellular processes that lead to oncogenic transformation and cell survival.

It is important to understand the mechanisms by which individual viral proteins modulate cell signaling pathways in order to develop targeted therapeutics for the diseases associated with KSHV.  The focus of my project is to determine how the KSHV K15 protein contributes to host cell transformation by manipulating host cell signaling pathways. This research may help to uncover novel viral or cellular druggable targets for the treatment of KSHV-associated malignancies in the future.

• Sunil M, Reid E, Lechowicz MJ. (2010). Update on HHV-8-Associated Malignancies. Current Infectious Disease Report. 12: 147-157.
  
  
• Wen KW, Damania B. (2010). Kaposi sarcoma-associated herpesvirus (KSHV): Molecular biology and oncogenesis. Cancer Letters. 289: 140-150.
  
  
• Brinkmann MM, Glenn M, Rainbow L, Kieser A, Henke-Gendo C, Schulz TF. (2003). Activation of mitogen-activated protein kinase and NF-kappaB pathways by a Kaposi's sarcoma-associated herpesvirus K15 membrane protein. Journal of Virology. 77: 9346-48.
  
  
• Bartel DP. (2004). MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 116: 281-97.
  
  
• Tsai YH, Wu MF, Wu YH, Chang SJ, Lin SF, Sharp TV, Wang HW. (2009). The M type K15 protein of Kaposi's sarcoma-associated herpesvirus regulates microRNA expression via its SH2-binding motif to induce cell migration and invasion. Journal of Virology. 83: 622-32.

Figure 1: Modulation of host signaling pathways by K15