In addition, authors of these two studies detected only the effects of inhibition of PI3K or AKT on the reactivation of KSHV in PEL cell lines, but the upstream and downstream effectors were not shown. MAPK cascades are key signaling pathways involved in the regulation of cell proliferation, survival and differentiation. It is not surprising that

many viruses including KSHV target MAPK pathways as a means to manipulate cellular function and to control viral infection and replication. Studies from Gao’s group demonstrated that ERK, c-Jun N-terminal kinase (JNK) and p38 selleck chemical multiple MAPK pathways had general roles in regulating the life cycle of KSHV by mediating both viral infection and switch from viral latency to lytic replication [39, 40]. Among three major MAPK pathways, ERK MAPK pathway has particularly been the subject of intense research in cancer treatment [41]. Because of the fact that KSHV can cause malignancies, KSHV researchers pay more attention to ERK MAPK pathway. There were some reports which focused on activation of ERK MAPK and KSHV replication. For instance, Ford et al. demonstrated that inhibiting B-Raf/MEK/ERK signaling by using MEK-specific inhibitors or siRNA construct targeting B-Raf restrained 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced KSHV lytic replication [42]. Cohen et al. Luminespib in vivo also showed an essential role of ERK signaling in TPA-induced reactivation of KSHV by using MEK-specific inhibitors

[43]. Yu et al. revealed that Raf/MEK/ERK pathway mediated Ras-induced KSHV reactivation and the same pathway also mediated TPA-induced KSHV reactivation and spontaneous reactivation in PEL cells, by screening expression of a mammalian cDNA library

[44]. A more recent study also showed that alloferon inhibited lytic reactivation of KSHV through down-regulation of ERK [45]. Here, we demonstrated a consistent result that activation of ERK signaling partially contributed to HSV-1-induced KSHV replication. 5. Conclusions In summary, we have showed that not JAK1/STAT3 or JAK1/STAT6 but PTEN/PI3K/AKT/GSK-3β and ERK MAPK signal pathways partially contributed to HSV-1-induced KSHV replication. These findings provided further insights into the molecular mechanism controlling KSHV lytic replication and shed light on the pathogenesis of KSHV-induced malignancies. Acknowledgements Meloxicam and Funding We thank Drs D. Link, K. Zhang, B-H Jiang, and G. Chen for plasmids STAT3-DN, STAT6-DN, PI3K-DN, AKT-DN, and MEK-DN. This work was supported by grants from the National Basic Research Selleck Fosbretabulin Program of China (973 Program) (2011CB504803), National Natural Science Foundation of China (grants 30972619 and 81171552 to C.L., 30900064 to D.Q., and 81071345 to Y.Z.), Natural Science Foundation of Ministry of Education of Jiangsu Province (great project 10KJA310032 to C.L. and grant 09KJB310007 to D.Q.), and Research Fund for the Doctoral Program of Higher Education of China (New Teacher Fund, grant 20093234120004 to D.Q.). References 1.