title: Tripeptidyl Peptidase II Is Required for c-MYC-Induced Centriole Overduplication and a Novel Therapeutic Target in c-MYC-Associated Neoplasms.
abstract: Centrosome aberrations are frequently detected in c-MYC-associated human malignancies. Here, we show that c-MYC-induced centrosome and centriole overduplication critically depend on the protease tripeptidyl peptidase II (TPPII). We found that TPPII localizes to centrosomes and that overexpression of TPPII, similar to c-MYC, can disrupt centriole duplication control and cause centriole multiplication, a process during which maternal centrioles nucleate the formation of more than a single daughter centriole. We report that inactivation of TPPII using chemical inhibitors or siRNA-mediated protein knockdown effectively reduced c-MYC-induced centriole overduplication. Remarkably, the potent and selective TPPII inhibitor butabindide not only potently suppressed centriole aberrations but also caused significant cell death and growth suppression in aggressive human Burkitt lymphoma cells with c-MYC overexpression. Taken together, these results highlight the role of TPPII in c-MYC-induced centriole overduplication and encourage further studies to explore TPPII as a novel antineoplastic drug target.
authors.affiliation: Cancer Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Duensing
authors.forename: Sebastian
authors.initials: S
authors.lastname: Darr
authors.forename: Rolando
authors.initials: R
authors.lastname: Cuevas
authors.forename: Nadja
authors.initials: N
authors.lastname: Melquiot
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Brickner
authors.forename: Anette
authors.initials: A
authors.lastname: Duensing
authors.forename: Karl
authors.initials: K
authors.lastname: Münger