The over-expression of Pim-2 promote the tumorigenesis of prostatic carcinoma through phosphorylating eIF4B

Kawaguchi, Ren; Gou, Xin; Xiao, Mingzhao; Wang, Ming; Liu, Chaodong; Tang, Zhaobing; He, Weiyang

doi:10.1002/pros.22693

Cited by 24 publications

(19 citation statements)

References 20 publications

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“…Overexpression of Pim1 contributes to tumorigenosis (33), and the levels of Pim proteins are associated with their actual activities. Indeed, elevated levels of Pim kinases have been associated with solid tumors and hematological malignancies (14,16). Although Pim1 but not Pim2 or Pim3 was initially identified as an NS5A interactor in our protein array assay, we also demonstrated that both Pim2 and Pim3 interacted with NS5A by coimmunoprecipitation assay.…”

Section: Discussionmentioning

confidence: 55%

Pim Kinase Interacts with Nonstructural 5A Protein and Regulates Hepatitis C Virus Entry

Park

Min

Park

et al. 2015

J Virol

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The life cycle of hepatitis C virus (HCV) is highly dependent on host cellular proteins for virus propagation. In order to identify the cellular factors involved in HCV propagation, we performed protein microarray assay using the HCV nonstructural 5A (NS5A) protein as a probe. Of ϳ9,000 human cellular proteins immobilized in a microarray, approximately 90 cellular proteins were identified as NS5A interactors. Of these candidates, Pim1, a member of serine/threonine kinase family composed of three different isoforms (Pim1, Pim2, and Pim3), was selected for further study. Pim kinases share a consensus sequence which overlaps with kinase activity. Pim kinase activity has been implicated in tumorigenesis. In the present study, we verified the physical interaction between NS5A and Pim1 by both in vitro pulldown and coimmunoprecipitation assays. Pim1 interacted with NS5A through amino acid residues 141 to 180 of Pim1. We demonstrated that protein stability of Pim1 was increased by NS5A protein and this increase was mediated by protein interplay. Small interfering RNA (siRNA)-mediated knockdown or pharmacological inhibition of Pim kinase abrogated HCV propagation. By employing HCV pseudoparticle entry and single-cycle HCV infection assays, we further demonstrated that Pim kinase was involved in HCV entry at a postbinding step. These data suggest that Pim kinase may represent a new host factor for HCV entry. IMPORTANCEPim1 is an oncogenic serine/threonine kinase. HCV NS5A protein physically interacts with Pim1 and contributes to Pim1 protein stability. Since Pim1 protein expression level is upregulated in many cancers, NS5A-mediated protein stability may be associated with HCV pathogenesis. Either gene silencing or chemical inhibition of Pim kinase abrogated HCV propagation in HCVinfected cells. We further showed that Pim kinase was specifically required at an early entry step of the HCV life cycle. Thus, we have identified Pim kinase not only as an HCV cell entry factor but also as a new anti-HCV therapeutic target.

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Section: Discussionmentioning

confidence: 55%

Pim Kinase Interacts with Nonstructural 5A Protein and Regulates Hepatitis C Virus Entry

Park

Min

Park

et al. 2015

J Virol

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“…PIM-2 kinase is expressed in hematopoietic cells and functions by phosphorylating various target substrates and thus subsequently affects cell survival, cell proliferation, transcriptional activation, and protein translation. Major studies in cancer cell signaling demonstrated that PIM-2 kinase is intimately involved in the survival and proliferation of different cancer cell types, such as B cell lymphoma (5), multiple myeloma (6), and prostate cancer (7,8), suggesting that it could be a potential therapeutic target for cancer therapy. Despite a growing interest in targeting PIM-2 kinase, there is not yet a specific PIM-2 inhibitor in the clinic, possibly owing to specificity issues relating to the similar structure of PIM isoforms (9).…”

Section: Introductionmentioning

confidence: 99%

PIM-2 protein kinase negatively regulates T cell responses in transplantation and tumor immunity

Daenthanasanmak¹,

Wu²,

Iamsawat³

et al. 2018

Journal of Clinical Investigation

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“…Among the candidates that reproducibly yielded androgen-independent tumors were mutated KRAS; RAF1, a known prostate cancer oncogene (16) that was recently described to confer metastatic potential in an in vivo model (10); ERBB2, AKT1, and constitutively active MEK1, which have been implicated in androgen independence (3); and PIM1 and PIM2, which have previously been demonstrated to be important oncogenes in prostate cancer (17, 18). In addition, we found that a wild-type form (NP_055212.2) of the Never In Mitosis A (NIMA) related kinase 6 (NEK6) scored strongly in this assay.…”

Section: Resultsmentioning

confidence: 99%

Castration Resistance in Prostate Cancer Is Mediated by the Kinase NEK6

et al. 2017

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In prostate cancer, the development of castration resistance is pivotal in progression to aggressive disease. However, understanding of the pathways involved remains incomplete. In this study, we performed a high-throughput genetic screen to identify kinases that enable tumor formation by androgen-dependent prostate epithelial (LHSR-AR) cells under androgen-deprived conditions. In addition to the identification of known mediators of castration resistance, which served to validate the screen, we identified a mitotic-related serine/threonine kinase, NEK6, as a mediator of androgen-independent tumor growth. NEK6 was overexpressed in a subset of human prostate cancers. Silencing NEK6 in castration-resistant cancer cells was sufficient to restore sensitivity to castration in a mouse xenograft model system. Tumors in which castration resistance was conferred by NEK6 were predominantly squamous in histology with no evidence of AR signaling. Gene expression profiling suggested that NEK6 overexpression stimulated cytoskeletal, differentiation and immune signaling pathways and maintained gene expression patterns normal decreased by castration. Phosphoproteome profiling revealed the transcription factor FOXJ2 as a novel NEK6 substrate, with FOXJ2 phosphorylation associated with increased expression of newly identified NEK6 transcriptional targets. Overall, our studies establish NEK6 signaling as a central mechanism mediating castration-resistant prostate cancer.

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The over-expression of Pim-2 promote the tumorigenesis of prostatic carcinoma through phosphorylating eIF4B

Abstract: Pim-2 was over-expressed in PCA cell lines and tissues. It may inhibit the apoptosis of PCA cells through phosphorylating eIF4B, thus promote the tumorigenesis of PCA.

Cited by 24 publications

References 20 publications

Pim Kinase Interacts with Nonstructural 5A Protein and Regulates Hepatitis C Virus Entry

Pim Kinase Interacts with Nonstructural 5A Protein and Regulates Hepatitis C Virus Entry

PIM-2 protein kinase negatively regulates T cell responses in transplantation and tumor immunity

Castration Resistance in Prostate Cancer Is Mediated by the Kinase NEK6

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