ene to encode AC480 EGFR inhibitor a transcription factor. Previous studies from our group and others suggest that MIZ 1 positively regulates expression of other favorable neuroblastoma genes and genes encoding CDK inhibitors . We thus investigated if MIZ 1 protein expression AC480 EGFR inhibitor was also upregulated in the 17 DMAG treated cell lines. As shown in Fig. 8, MIZ 1 protein was detected in the four cell lines treated with 17 DMAG. However, it was noted that treatment of these cells with 17 DMAG induced a smaller molecular weight MIZ 1 protein as compared to that of MIZ 1 detected in MIZ 1 transfected cells. In addition, results shown in Fig. 8 were reproducible when different anti MIZ 1 antibodies were used.
It should be noted that based on the deduced amino acid sequence of MIZ 1, its expected molecular weight is 88 kDa.
CAL-101 CAL-101 To further confirm data shown in Fig. 8, we performed EBVis a human herpesvirus that causes infectiousmononucleosis and persists in the host for life, but is normally well controlled by the immune system. Nevertheless, EBV is also associated with human malignancies of both epithelial and B cell origin, including lymphoproliferative disease, Burkitt lymphoma, nasopharyngeal carcinoma, and gastric cancer. In addition, increasing evidence suggests that EBV infection may contribute to certain autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, and lupus.
Like all herpesviruses, EBV can infect cells in either latent or lytic forms. EBNA1 is the one viral protein expressed in all three forms of latent viral infection, and is the only viral protein absolutely required for persistence of EBV infection in host cells.
EBNA1 mediates replication of the viral episome during latent infection by recruiting host replication initiation factors to the initiation site in the latent origin of replication, oriP. EBNA1 also plays essential roles in partitioning of viral episomes during cell division, and activates transcription of other essential viral transforming proteins in cells with type III latency. In addition, increasing evidence suggests that EBNA1 may directly contribute to tumorigenesis by inhibiting apoptosis.
Collectively, the fundamental roles of EBNA1 in maintenance of the viral episome, as well as its possible direct contributions to tumorigenesis, make it a particularly desirable target for therapeutic strategies.
However, drugs that inhibit expression of EBNA1 or its functions are not currently available. Here we demonstrate that Hsp90 inhibitors can be used to inhibit expression of EBNA1 in cells with various types of latent EBV infection, and thatHsp90 inhibitors preventEBVtransformation of primary B cells and are highly toxic to EBV immortalized lymphoblastoid cell lines. Heat shock proteins are a class of molecular chaperones that facilitate proper protein folding and stability. Unlike other Hsps, only a small subset of cellular proteins are thought to be clients ofHsp90. Hsp90 inhibitors such as geldanamycin and its analogues bind to the ATP binding motif of Hsp90 and inhibit its protein chaperoning activity, consequently resulting in misfolding of cellular client proteins. Hsp90 inhibitors are often more toxic to tumor cells than to normal cells, not only because a number of Hsp90 client proteins contribute to tumor cell growth,