Survivin is a master regulator of cell proliferation and cell viability and is highly expressed in most human
tumors. The molecular network linked to
survivin expression in
tumors has not been completely elucidated. In this study, we show that
latency-associated nuclear antigen (LANA), a multifunctional
protein of Kaposi's sarcoma-associated herpesvirus (KSHV) that is found in
Kaposi's sarcoma tumors, upregulates
survivin expression and increases the proliferation of KSHV-infected B cells. Analysis of pathway-specific gene arrays showed that
survivin expression was highly upregulated in BJAB cells expressing LANA. The
mRNA levels of
survivin were also upregulated in HEK 293 and BJAB cells expressing LANA. Similarly,
protein levels of
survivin were significantly higher in LANA-expressing, as well as KSHV-infected, cells.
Survivin promoter activity assays identified GC/Sp1 and p53 cis-acting elements within the core promoter region as being important for LANA activity. Gel mobility shift assays revealed that LANA forms a complex with Sp1 or Sp1-like
proteins bound to the GC/Sp1 box of the
survivin promoter. In addition, a LANA/p53 complex bound to the p53 cis-acting
element within the
survivin promoter, indicating that upregulation of
survivin expression can also occur through suppression of p53 function. Furthermore, immunohistochemistry analyses revealed that
survivin expression was upregulated in KSHV-associated
Kaposi's sarcoma tissue, suggesting that LANA plays an important role in the upregulation of
survivin expression in KSHV-infected endothelial cells. Knockdown of
survivin expression by lentivirus-delivered
small hairpin RNA resulted in loss of cell proliferation in KSHV-infected cells. Therefore, upregulation of
survivin expression in KSHV-associated human cells contributes to their proliferation.