Pim kinases in hematological malignancies: where are we now and where are we going?

Mondello, Patrizia; Cuzzocrea, Salvatore; Mian, Michael

doi:10.1186/s13045-014-0095-z

Cited by 83 publications

(81 citation statements)

References 117 publications

(134 reference statements)

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“…It was reported previously that HCV transiently activates the PI3K-AKT pathway during virus entry (36). Growing evidence suggests that Pim kinases cross talk with PI3K-AKT kinases to produce synergetic effects on cell proliferation and survival signaling pathways (37)(38)(39). Therefore, we are tempted to speculate that Pim kinase might regulate HCV entry by promoting CD81 and claudin-1 receptor complex formation via PI3K-AKT signaling pathway.…”

Section: Discussionmentioning

confidence: 92%

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: 92%

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 kinases (proviral integration site for Moloney murine leukemia virus), which are proto-oncogenes, induce phosphorylation of critical downstream effectors of ABL (Abelson), JAK2 (janus kinase 2), and Flt-3 (FMS related tyrosine kinase) genes, and promote growth and survival through cell cycle regulation along with inhibition of apoptosis of malignant cells [198]. Overexpression of PIM kinases PIM1 and PIM2 has been reported in MCL [199–200].…”

Section: Novel Drugs For MCL Based On Signaling Pathwaysmentioning

confidence: 99%

Mantle cell lymphoma in the era of precision medicine-diagnosis, biomarkers and therapeutic agents

et al. 2016

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Despite advances in the development of clinical agents for treating Mantle Cell Lymphoma (MCL), treatment of MCL remains a challenge due to complexity and frequent relapse associated with MCL. The incorporation of conventional and novel diagnostic approaches such as genomic sequencing have helped improve understanding of the pathogenesis of MCL, and have led to development of specific agents targeting signaling pathways that have recently been shown to be involved in MCL. In this review, we first provide a general overview of MCL and then discuss about the role of biomarkers in the pathogenesis, diagnosis, prognosis, and treatment for MCL. We attempt to discuss major biomarkers for MCL and highlight published and ongoing clinical trials in an effort to evaluate the dominant signaling pathways as drugable targets for treating MCL so as to determine the potential combination of drugs for both untreated and relapse/refractory cases. Our analysis indicates that incorporation of biomarkers is crucial for patient stratification and improve diagnosis and predictability of disease outcome thus help us in designing future precision therapies. The evidence indicates that a combination of conventional chemotherapeutic agents and novel drugs designed to target specific dysregulated signaling pathways can provide the effective therapeutic options for both untreated and relapse/refractory MCL.

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“…The provirus integration sites for Moloney murine leukemia virus (PIM) kinases are a highly conserved family of serine/threonine kinases (1,2). The PIM kinase family is composed of 3 different isoforms, PIM-1, PIM-2, and PIM-3, which share high homology at the amino acid sequences (3) and have functional redundancy (4).…”

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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Pim kinases in hematological malignancies: where are we now and where are we going?

Cited by 83 publications

References 117 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

Mantle cell lymphoma in the era of precision medicine-diagnosis, biomarkers and therapeutic agents

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

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