It is well established that both p53 and MDM2 are short-lived proteins whose stabilities are tightly controlled through ubiquitination-mediated degradation. Although numerous studies indicate that the MDM2 E3 ligase a...It is well established that both p53 and MDM2 are short-lived proteins whose stabilities are tightly controlled through ubiquitination-mediated degradation. Although numerous studies indicate that the MDM2 E3 ligase activity, as well as the protein-protein interaction between p53 and MDM2, is the major focus for this regulation, emerging evidence suggests that the deu- biquitinase herpesvirus-associated ubiquitin-specific protease （HAUSP, also known as USP7） plays a critical role. Furthermore, HAUSP inhibition elevates p53 stability and might be beneficial for therapeutic purposes. In this review, we discuss the advances of this dynamic pathway and the contributions of positive and negative regulators affecting HAUSP activity. We also highlight the roles of HAUSP in cancer justifying the production of the first generation of HAUSP inhibitors.展开更多
Herpesvirus-associated ubiquitin-specific protease(HAUSP)is a USP family deubiquitinase.HAUSP is a protein of immense biological importance as it is involved in several cellular processes,including host-virus interact...Herpesvirus-associated ubiquitin-specific protease(HAUSP)is a USP family deubiquitinase.HAUSP is a protein of immense biological importance as it is involved in several cellular processes,including host-virus interactions,oncogenesis and tumor suppression,DNA damage and repair processes,DNA dynamics and epigenetic modulations,regulation of gene expression and protein function,spatio-temporal distribution,and immune functions.Since its discovery in the late 1990s as a protein interacting with a herpes virus regulatory protein,extensive studies have assessed its complex roles in p53-MDM2-related networks,identified numerous additional interacting partners,and elucidated the different roles of HAUSP in the context of cancer,development,and metabolic and neurological pathologies.Recent analyses have provided new insights into its biochemical and functional dynamics.In this review,we provide a comprehensive account of our current knowledge about emerging insights into HAUSP in physiology and diseases,which shed light on fundamental biological questions and promise to provide a potential target for therapeutic intervention.展开更多
The p53 pathway is a highly complex signaling network including several key regulators.HAUSP is a critical component of the p53 pathway acting as a deubiquitinase for both p53 and its key repressor Mdm2.Here,we identi...The p53 pathway is a highly complex signaling network including several key regulators.HAUSP is a critical component of the p53 pathway acting as a deubiquitinase for both p53 and its key repressor Mdm2.Here,we identified a novel HAUSP-interacting protein,HLA-B-associated transcript 3(Bat3)and found it to be capable of inducing p53 stabilization and activation via a HAUSP-dependent mechanism,resulting in cell growth inhibition.Surprisingly,the deubiquitylating enzymatic activity of HAUSP was not required for this phenomenon.Co-immunoprecipitation showed that p53 coexisted in a complex with Bat3 and HAUSP in vivo,and HAUSP may serve as a binding mediator to enhance the interaction between p53 and Bat3.Further studies revealed that formation of this three-protein complex interfered with the binding of p53 to its proteasome receptor S5a and promoted the accumulation of p53 in nucleus.Notably,Mdm2 protein abundance is also regulated by Bat3 in the presence of HAUSP.Overexpression of Bat3 and HAUSP increases Mdm2 protein levels without influencing the p53–Mdm2 interaction and Mdm2-mediated p53 ubiquitination,indicating that Bat3–HAUSP-mediated protein stabilization is not specific to p53 and different mechanisms may be involved in Bat3-mediated regulation of p53–Mdm2 pathway.Together,our study unravels a novel mechanism by which p53 is stabilized and activated by HAUSP-mediated interaction with Bat3 and implies that Bat3 might function as a tumor suppressor through the stabilization of p53.展开更多
Neuroblastoma (NBL) is one of the most common solid tumors and around 15% of cancer mortality in children. Amplification of the N-Myc proto-oncogene is strongly correlated with advanced disease and poor clinical outco...Neuroblastoma (NBL) is one of the most common solid tumors and around 15% of cancer mortality in children. Amplification of the N-Myc proto-oncogene is strongly correlated with advanced disease and poor clinical outcome in NBL. Recent studies described that ubiquitin-specific protease 7 (USP7;also known as HAUSP) interacts with N-Myc, induces deubiquitination and subsequent stabilization of N-Myc that in-turn potentiates N-Myc function, and treatment with the HAUSP inhibitor (P22077) blocked such effects.展开更多
文摘It is well established that both p53 and MDM2 are short-lived proteins whose stabilities are tightly controlled through ubiquitination-mediated degradation. Although numerous studies indicate that the MDM2 E3 ligase activity, as well as the protein-protein interaction between p53 and MDM2, is the major focus for this regulation, emerging evidence suggests that the deu- biquitinase herpesvirus-associated ubiquitin-specific protease （HAUSP, also known as USP7） plays a critical role. Furthermore, HAUSP inhibition elevates p53 stability and might be beneficial for therapeutic purposes. In this review, we discuss the advances of this dynamic pathway and the contributions of positive and negative regulators affecting HAUSP activity. We also highlight the roles of HAUSP in cancer justifying the production of the first generation of HAUSP inhibitors.
基金This work was supported by grants received from Council of Scientific and Industrial Research(CSIR),DST(DST-Nanomission-SR/NM/NS-1058/2015)DBT(Bio-cluster,Kolkata),Govt.of India.
文摘Herpesvirus-associated ubiquitin-specific protease(HAUSP)is a USP family deubiquitinase.HAUSP is a protein of immense biological importance as it is involved in several cellular processes,including host-virus interactions,oncogenesis and tumor suppression,DNA damage and repair processes,DNA dynamics and epigenetic modulations,regulation of gene expression and protein function,spatio-temporal distribution,and immune functions.Since its discovery in the late 1990s as a protein interacting with a herpes virus regulatory protein,extensive studies have assessed its complex roles in p53-MDM2-related networks,identified numerous additional interacting partners,and elucidated the different roles of HAUSP in the context of cancer,development,and metabolic and neurological pathologies.Recent analyses have provided new insights into its biochemical and functional dynamics.In this review,we provide a comprehensive account of our current knowledge about emerging insights into HAUSP in physiology and diseases,which shed light on fundamental biological questions and promise to provide a potential target for therapeutic intervention.
基金This work was supported by the National Natural Science Foundation of China(31500703,31371351,and 31671488)the Program for New Century Excellent Talents in University of China(NCET-09-0737).
文摘The p53 pathway is a highly complex signaling network including several key regulators.HAUSP is a critical component of the p53 pathway acting as a deubiquitinase for both p53 and its key repressor Mdm2.Here,we identified a novel HAUSP-interacting protein,HLA-B-associated transcript 3(Bat3)and found it to be capable of inducing p53 stabilization and activation via a HAUSP-dependent mechanism,resulting in cell growth inhibition.Surprisingly,the deubiquitylating enzymatic activity of HAUSP was not required for this phenomenon.Co-immunoprecipitation showed that p53 coexisted in a complex with Bat3 and HAUSP in vivo,and HAUSP may serve as a binding mediator to enhance the interaction between p53 and Bat3.Further studies revealed that formation of this three-protein complex interfered with the binding of p53 to its proteasome receptor S5a and promoted the accumulation of p53 in nucleus.Notably,Mdm2 protein abundance is also regulated by Bat3 in the presence of HAUSP.Overexpression of Bat3 and HAUSP increases Mdm2 protein levels without influencing the p53–Mdm2 interaction and Mdm2-mediated p53 ubiquitination,indicating that Bat3–HAUSP-mediated protein stabilization is not specific to p53 and different mechanisms may be involved in Bat3-mediated regulation of p53–Mdm2 pathway.Together,our study unravels a novel mechanism by which p53 is stabilized and activated by HAUSP-mediated interaction with Bat3 and implies that Bat3 might function as a tumor suppressor through the stabilization of p53.
文摘Neuroblastoma (NBL) is one of the most common solid tumors and around 15% of cancer mortality in children. Amplification of the N-Myc proto-oncogene is strongly correlated with advanced disease and poor clinical outcome in NBL. Recent studies described that ubiquitin-specific protease 7 (USP7;also known as HAUSP) interacts with N-Myc, induces deubiquitination and subsequent stabilization of N-Myc that in-turn potentiates N-Myc function, and treatment with the HAUSP inhibitor (P22077) blocked such effects.
