Kaposi's sarcoma-associated herpesvirus (KSHV) is etiologically associated with 
the angioproliferative Kaposi's sarcoma (KS). KSHV infection and the expression 
of latency-associated nuclear antigen (LANA-1) upregulates the angiogenic 
multifunctional 123-amino-acid, 14-kDa protein angiogenin (ANG), which is 
detected in KS lesions and in KSHV-associated primary effusion lymphoma (PEL) 
cells. ANG knockdown or the inhibition of ANG's nuclear translocation resulted 
in decreased LANA-1 gene expression and reduced KSHV-infected endothelial and 
PEL cell survival (Sadagopan et al., J. Virol. 83:3342-3364, 2009). Further 
studies here demonstrate that LANA-1 and ANG colocalize and coimmunoprecipitate 
in de novo infected endothelial cells and in latently infected PEL (BCBL-1 and 
BC-3) cells. LANA-1 and ANG interaction occurred in the absence of the KSHV 
genome and other viral proteins. In gel filtration chromatography analyses of 
BC-3 cell lysates, ANG coeluted with LANA-1, p53, and Mdm2 in 
high-molecular-weight fractions, and LANA-1, p53, and Mdm2 also 
coimmunoprecipitated with ANG. LANA-1, ANG, and p53 colocalized in KSHV-infected 
cells, and colocalization between ANG and p53 was also observed in 
LANA-1-negative cells. The deletion constructs of ANG suggested that the 
C-terminal region of amino acids 104 to 123 is involved in LANA-1 and p53 
interactions. Silencing ANG or inhibiting its nuclear translocation resulted in 
decreased nuclear LANA-1 and ANG levels, decreased interactions between 
ANG-LANA-1, ANG-p53, and LANA-1-p53, the induction of p53, p21, and Bax 
proteins, the increased cytoplasmic localization of p53, the downregulation of 
Bcl-2, the increased cleavage of caspase-3, and the apoptosis of cells. No such 
effects were observed in KSHV-negative BJAB cells. The phosphorylation of p53 at 
serine 15, which is essential for p53 stabilization and for p53's apoptotic and 
cell cycle regulation functions, was increased in BCBL-1 cells transduced with 
short hairpin RNA targeting ANG. Together, these studies suggest that the 
antiapoptosis observed in KSHV-infected cells and the suppression of p53 
functions are mediated in part by ANG, and KSHV has probably evolved to utilize 
angiogenin's multiple functions for the maintenance of its latency and cell 
survival. Thus, targeting ANG to induce the apoptosis of cells latently infected 
with KSHV is an attractive therapeutic strategy against KSHV infection and 
associated malignancies.