Jun activation domain-binding protein 1 negatively regulate p27kip1 in non-Hodgkin’s lymphomas

Abstract

Objective: Recent evidences suggest that Jun activation domain-binding protein 1(Jab1) specifically interacts with the Cdk inhibitor p27kip1 and induces nuclear export and subsequent degradation of p27kip1. The purpose of this study is to investigate whether Jab1 expression is correlated with p27kip1 level in Non-Hodgkin's Lymphomas(NHLs) and how it influenced the stability of p27kip1, as well as whether Jab1 expression is associated with clinicopathologic variables and prognosis of NHLs.Methods: Immunohistochemical and/or Western blot analysis was done in 116 cases of NHLs and Jurkat cells.Results: Immunohistochemical analysis showed that Jab1 expression was negatively associated with p27kip1 level and significantly associated with unfavorable clinicopathologic variables. Overexpression Jab1 in lymphoma cell lines Jurkat resulted in decreased p27kip1 level and advanced progression from G1 to S phase of the cell cycle. Subcellular fractionation confirmed Jab1 could lead to nuclear export of p27kip1. Phosphorylation of p27kip1 at Ser10 and Thr157 was significantly increased after Jab1 transient transfected, while Thr187 phosphorylation was decreased. Immunoprecipitation demonstrated that Jab1 overexpression facilitated p27kip1 to dissociate from Cdk2 and associated with Cdk4. Finally, Survival analysis revealed that Jab1 overexpression is significantly associated with overall survival (P=0.000). When Jab1 and p27kip1 are combined, patients with Jab1(+)/p27kip1(-) revealed poorer overall survival (P=0.001). Multivariate analysis revealed that Jab1 protein is an independent prognostic indicator for overall survival.Conclusions: These findings suggest that Jab1 protein may contribute to the tumor progression through Jab1-mediated p27kip1 degradation and that control of Jab1 expression is a novel therapeutic target in patients with NHLs.