p53 inhibition by the LANA protein of KSHV protects against cell death

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV), or human herpesvirus 8, has been implicated in the development of Kaposi's sarcoma (KS) and several B-cell lymphoproliferative diseases. Most cells in lesions derived from these malignancies are latently infected, and different viral gene products have been identified in association with lytic or latent infection by KSHV. The latency-associated nuclear antigen (LANA), encoded by open reading frame 73 of the KSHV genome, is a highly immunogenic protein that is expressed predominantly during viral latency, in most KS spindle cells and in cell lines established from body-cavity-based lymphomas. Antibodies to LANA can be detected in a high percentage of HIV-infected individuals who subsequently develop KS, although its role in disease pathogenesis is not completely understood. p53 is a potent transcriptional regulator of cell growth whose induction leads either to cell-cycle arrest or apoptosis. Loss of p53 function correlates with cell transformation and oncogenesis, and several viral oncoproteins interact with p53 and modulate its biological activity. Here we show that LANA interacts with the tumour suppressor protein p53 and represses its transcriptional activity. This viral gene product further inhibits the ability of p53 to induce cell death. We propose that LANA contributes to viral persistence and oncogenesis in KS through its ability to promote cell survival by altering p53 function.

Latency-associated nuclear antigen expression and human herpesvirus-8 polymerase chain reaction in the evaluation of Kaposi sarcoma and other vascular tumors in HIV-positive patients

“…20 Additionally, LANA mimics the E6 and E7 viral oncoproteins of human papillomavirus in its ability to inhibit the function of p53. 21 LANA has an essential role in maintenance of the episomal DNA during latent infection and cell division, and also regulates gene expression in infected cells. 22 A relatively small number of studies have examined LANA expression by IHC.…”

AIDS-associated Kaposi's sarcoma: Is there still a role for interferon alfa?

“…The HHV-8 viral genome is noteworthy for the presence of a large number of human gene homologs that encode proteins involved in cell cycle regulation and signaling. These include genes expressed during viral latency (LANA-1, a viral cyclin homolog and vFLIP) that act variously to inhibit apoptosis and prevent cell-cycle arrest by pRB [27][28][29], and additional gene products transcribed during lytic replication corresponding to cellular proteins involved in cell cycle progression, apoptosis, proliferation and immune regulation. These include the K1 protein, a viral BCL-2 homolog, a viral GPCR, a viral homolog of IL-6, viral macrophage inflammatory proteins vMIPs, and several viral interferon regulatory factors [30][31][32][33][34].…”

Kaposi's sarcoma-associated herpesvirus-encoded LANA associates with glucocorticoid receptor and enhances its transcriptional activities

“…In addition, LANA interacts with a variety of cellular proteins in the host. LANA can directly bind to and inhibit tumor suppressor p53 [10]. Through direct binding to glycogen synthase kinase 3β and extracellular signal-regulated kinase (ERK), LANA enhances activation of ERK and c-myc.…”

“…Latency-associated nuclear antigen (LANA), a KSHV protein, is critical for the persistence of KSHV episomes, and functions in this capacity by tethering viral episomes to chromosomes during mitosis [7,8,9]. In addition, LANA interacts physically with various cellular proteins that regulate transcriptional activities, resulting in interfering with critical regulators of the cell cycle and enhancing anti-apoptotic effects [10,11,12,13].…”