title: Recruitment of the tumour suppressor protein p73 by Kaposi's Sarcoma Herpesvirus latent nuclear antigen contributes to the survival of primary effusion lymphoma cells.
abstract: Kaposi's Sarcoma Herpesvirus (KSHV) is the causative agent of Kaposi's Sarcoma (KS) and two rare lymphoproliferative disorders, primary effusion lymphoma (PEL) and the plasmablastic variant of multicentric Castleman's disease (MCD). The KSHV latency-associated nuclear antigen-1 (LANA), required for the replication and maintenance of latent viral episomal DNA, is involved in the transcriptional regulation of viral and cellular genes and interacts with different cellular proteins, including the tumour suppressor p53. Here, we report that LANA also recruits the p53-related nuclear transcription factor p73, which influences cellular processes like DNA damage response, cell cycle progression and apoptosis. Both the full-length isoform TAp73α, as well as its dominant negative regulator ΔNp73α, interact with LANA. LANA affects TAp73α stability and sub-nuclear localisation, as well as TAp73α-mediated transcriptional activation of target genes. We observed that the small-molecule inhibitor Nutlin-3, which disrupts the interaction of p53 and p73 with MDM2, induces apoptotic cell death in p53 wild-type, as well as p53-mutant PEL cell lines, suggesting a possible involvement of p73. The small-molecule RETRA, which activates p73 in the context of mutant p53, leads to the induction of apoptosis in p53-mutant PEL cell lines. RNAi-mediated knockdown of p73 confirmed that these effects depend on the presence of the p73 protein. Furthermore, both Nutlin-3 and RETRA disrupt the LANA-p73 interaction in different PEL cell lines. These results suggest that LANA modulates p73 function and that the LANA-p73 interaction may represent a therapeutic target to interfere with the survival of latently KSHV-infected cells.
authors.affiliation: Institute of Virology, Hannover Medical School, Hannover, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Santag
authors.forename: W
authors.initials: W
authors.lastname: Jäger
authors.forename: C B
authors.initials: CB
authors.lastname: Karsten
authors.forename: S
authors.initials: S
authors.lastname: Kati
authors.forename: M
authors.initials: M
authors.lastname: Pietrek
authors.forename: D
authors.initials: D
authors.lastname: Steinemann
authors.forename: G
authors.initials: G
authors.lastname: Sarek
authors.forename: P M
authors.initials: PM
authors.lastname: Ojala
authors.forename: T F
authors.initials: TF
authors.lastname: Schulz
mesh_terms: D000956:Antigens, Viral / Q000737:chemistry / Q000502:physiology*; D017209:Apoptosis; D001665:Binding Sites; D002396:Catechols / Q000494:pharmacology; D002470:Cell Survival; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000502:physiology*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D054685:Lymphoma, Primary Effusion / Q000188:drug therapy / Q000473:pathology*; D009687:Nuclear Proteins / Q000737:chemistry / Q000502:physiology*; D010879:Piperazines / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000502:physiology*
chemical_list: C529061:2-(4,5-dihydro-1,3-thiazol-2-ylthio)-1-(3,4-dihydroxyphenyl)ethanone; D000956:Antigens, Viral; D002396:Catechols; D004268:DNA-Binding Proteins; D007093:Imidazoles; D009687:Nuclear Proteins; D010879:Piperazines; C000606460:TP73 protein, human; D013844:Thiazoles; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C109540:latency-associated nuclear antigen; C482205:nutlin 3