VRK2 Identifies Primary Astrocytomas With a Better Prognosis
VRK2 Identifies Primary Astrocytomas With a Better Prognosis
Malignant astrocytomas represent 70% of adult malignant primary brain tumors and are one of the most devastating cancers. Astrocytomas are classified in four grades on the basis of histological and clinical criteria established. Grade I astrocytomas occur more in children, are curable by surgery and might represent a separate disease from the astrocytomas of other grades, however, virtually all high-grade astrocytomas eventually progress and locally relapse regardless of improved diagnosis and multi-modality treatment. For most brain tumors the underlying cause is unknown, but most are the result of a multigenic process. Initiation and progression of astrocytomas are related to their genetic and chromosomal alterations. Malignant astrocytomas have well identified molecular characteristics and a basic pattern of common genetic alterations, which include PTEN, TP53, IDH1/2 and p16 mutations, and EGFR, CDK4 and MDM2 amplification.
The human vaccinia-related kinase (VRK) family of serine-threonine kinases is composed of three members, of which only two (VRK1 and VRK2) are catalytically active kinases. Recently, the VRK family has been implicated in different types of neurologic diseases. VRK1 has been associated with pontocerebellar hypoplasia with ataxias and muscular atrophy symptoms, and VRK2 has been linked to schizophrenia and epilepsy. But most of VRK proteins functional roles have been identified in the context of cancer biology. Nuclear VRK1 regulates cell cycle progression by controlling the exit from G0 phase, such as MYC and FOS, and phosphorylates several transcription factors such as p53 c-Jun, ATF2 and CREB, as well as histone H3 facilitating chromatin compaction. VRK1 also regulates cellular responses to radiation mediated by p53 or 53BP1. In addition, VRK1 and p53 form an autoregulatory loop where p53 downregulates VRK1 by the autophagic pathway. VRK1 is thus a new important regulator of cell proliferation, and high VRK1 protein levels have been associated with the proliferation phenotype in head and neck squamous cell carcinomas and lung cancer.
VRK2 has two isoforms, VRK2A and VRK2B. The full-length protein (known as VRK2A or VRK2) is located in the cytosol anchored to endoplasmic reticulum and mitochondrial membranes, while the shorter VRK2B is free and present in cytosol and nucleus. VRK2A effects are mediated mostly by its interactions with scaffold proteins that affect cellular signaling. The interaction of VRK2A with JIP1 is able to partially inhibit the stress response to hypoxia or to the interleukin1β. VRK2 also interacts with the KSR1 scaffold protein and downregulates the signal originated in the EGF/Ras/Raf/Mek/Erk pathway.
In this work we have tested the potential value of VRK1 and VRK2 protein levels as prognostic markers in low and high-grade astrocytomas, based on the observation that these proteins have an effect on proteins that are known to be affected in the pathogenesis of astrocytomas, such as p53, or EGFR signaling, as well as on other regulators of cell cycle progression.
Background
Malignant astrocytomas represent 70% of adult malignant primary brain tumors and are one of the most devastating cancers. Astrocytomas are classified in four grades on the basis of histological and clinical criteria established. Grade I astrocytomas occur more in children, are curable by surgery and might represent a separate disease from the astrocytomas of other grades, however, virtually all high-grade astrocytomas eventually progress and locally relapse regardless of improved diagnosis and multi-modality treatment. For most brain tumors the underlying cause is unknown, but most are the result of a multigenic process. Initiation and progression of astrocytomas are related to their genetic and chromosomal alterations. Malignant astrocytomas have well identified molecular characteristics and a basic pattern of common genetic alterations, which include PTEN, TP53, IDH1/2 and p16 mutations, and EGFR, CDK4 and MDM2 amplification.
The human vaccinia-related kinase (VRK) family of serine-threonine kinases is composed of three members, of which only two (VRK1 and VRK2) are catalytically active kinases. Recently, the VRK family has been implicated in different types of neurologic diseases. VRK1 has been associated with pontocerebellar hypoplasia with ataxias and muscular atrophy symptoms, and VRK2 has been linked to schizophrenia and epilepsy. But most of VRK proteins functional roles have been identified in the context of cancer biology. Nuclear VRK1 regulates cell cycle progression by controlling the exit from G0 phase, such as MYC and FOS, and phosphorylates several transcription factors such as p53 c-Jun, ATF2 and CREB, as well as histone H3 facilitating chromatin compaction. VRK1 also regulates cellular responses to radiation mediated by p53 or 53BP1. In addition, VRK1 and p53 form an autoregulatory loop where p53 downregulates VRK1 by the autophagic pathway. VRK1 is thus a new important regulator of cell proliferation, and high VRK1 protein levels have been associated with the proliferation phenotype in head and neck squamous cell carcinomas and lung cancer.
VRK2 has two isoforms, VRK2A and VRK2B. The full-length protein (known as VRK2A or VRK2) is located in the cytosol anchored to endoplasmic reticulum and mitochondrial membranes, while the shorter VRK2B is free and present in cytosol and nucleus. VRK2A effects are mediated mostly by its interactions with scaffold proteins that affect cellular signaling. The interaction of VRK2A with JIP1 is able to partially inhibit the stress response to hypoxia or to the interleukin1β. VRK2 also interacts with the KSR1 scaffold protein and downregulates the signal originated in the EGF/Ras/Raf/Mek/Erk pathway.
In this work we have tested the potential value of VRK1 and VRK2 protein levels as prognostic markers in low and high-grade astrocytomas, based on the observation that these proteins have an effect on proteins that are known to be affected in the pathogenesis of astrocytomas, such as p53, or EGFR signaling, as well as on other regulators of cell cycle progression.
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