Karyopherin β3: A new cellular target for the HPV-16 E5 oncoprotein

Krawczyk, Ewa; Hanover, John A.; Schlegel, Richard; Suprynowicz, Frank A.

doi:10.1016/j.bbrc.2008.04.122

Cited by 31 publications

(30 citation statements)

References 33 publications

(53 reference statements)

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“…Karyopherins are one group of carrier proteins involved in the selective nucleocytoplasmic transport. Accumulating evidences have identified the critical roles of karyopherins in malignant diseases and KPNA2 gains the most attention [21][22][23]. Previous report has measured the gene expression profiling of karyopherins in HCC and found overexpressed KPNA2 could promote the proliferation of HCC cells [7].…”

Section: Discussionmentioning

confidence: 99%

Pleomorphic adenoma gene 1 mediates the role of Karyopherin alpha 2 and has prognostic significance in hepatocellular carcinoma

Yuan

Yang

et al. 2014

J Exp Clin Cancer Res

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Background: Karyopherin alpha 2 (KPNA2) promotes tumor growth in hepatocellular carcinoma (HCC). We aimed to determine the content and clinical significance of mechanism underlying. Methods: The association of transcriptional factor pleomorphic adenoma gene 1 (PLAG1) with KPNA2 was explored by co-immunoprecipitation. In vitro gain-and loss-of-function models were established to explore the functional interaction. Clinical samples from 314 HCC patients were applied to explore the clinical significance. Results: We found that PLAG1 could associate with KPNA2 and be promoted into nucleus by KPNA2. The increment of proliferative and metastatic abilities by KPNA2 over-expression can be significantly retarded by PLAG1 inhibition. The co-enrichment of KPNA2 and PLAG1 in nucleus is observed in clinical samples and can distinguish patients with the worst prognosis. The positive PLAG1 expression is an independent risk factor of recurrence free survival (HR: 1.766, 1.315-2.371; P = 0.000) and overall survival (HR: 1.589, 1.138-2.220; P = 0.007). Especially for patients with positive KPNA2 staining (N = 152), the positive PLAG1 expression is the sole risk factor for both recurrence free survival (HR: 1.749, 1.146-2.670; P = 0.010) and overall survival (HR: 1.662, 1.007-2.744; P = 0.047).

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Section: Discussionmentioning

confidence: 99%

Pleomorphic adenoma gene 1 mediates the role of Karyopherin alpha 2 and has prognostic significance in hepatocellular carcinoma

Yuan

Yang

et al. 2014

J Exp Clin Cancer Res

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“…This process is thought to be mediated by the interaction of the HPV16 E5 protein with the 16-kDa pore-forming subunit of the vacuolar H ϩ -ATPase proton pump located in the ER (32,184). Recently, karyopherin beta 3 (KNb3) has also been identified as a cellular target for HPV16 E5 (108). Karyopherin is localized mainly in the cytoplasm near the nuclear envelope, and it has been suggested that a KNb3/ HPV16 E5 complex plays an important role in vesicle trafficking.…”

Section: Basic Biological Properties Of the Hpv16 E5 Proteinmentioning

confidence: 99%

The EVER Proteins as a Natural Barrier against Papillomaviruses: a New Insight into the Pathogenesis of Human Papillomavirus Infections

Łazarczyk

Cassonnet

Pons

et al. 2009

Microbiol Mol Biol Rev

133

128

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SUMMARY Infections by human papillomaviruses (HPVs) are the most frequently occurring sexually transmitted diseases. The crucial role of genital oncogenic HPV in cervical carcinoma development is now well established. In contrast, the role of cutaneous HPV in skin cancer development remains a matter of debate. Cutaneous beta-HPV strains show an amazing ubiquity. The fact that a few oncogenic genotypes cause cancers in patients suffering from epidermodysplasia verruciformis is in sharp contrast to the unapparent course of infection in the general population. Our recent investigations revealed that a natural barrier exists in humans, which protects them against infection with these papillomaviruses. A central role in the function of this HPV-specific barrier is played by a complex of the zinc-transporting proteins EVER1, EVER2, and ZnT-1, which maintain cellular zinc homeostasis. Apparently, the deregulation of the cellular zinc balance emerges as an important step in the life cycles not only of cutaneous but also of genital HPVs, although the latter viruses have developed a mechanism by which they can break the barrier and impose a zinc imbalance. Herein, we present a previously unpublished list of the cellular partners of EVER proteins, which points to future directions concerning investigations of the mechanisms of action of the EVER/ZnT-1 complex. We also present a general overview of the pathogenesis of HPV infections, taking into account the latest discoveries regarding the role of cellular zinc homeostasis in the HPV life cycle. We propose a potential model for the mechanism of function of the anti-HPV barrier.

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“…In addition, RanBP5 has been shown to interact with proteins from a range of viruses (Arnold et al, 2006;Chung et al, 2000;Darshan et al, 2004;Deng et al, 2006;Klucevsek et al, 2006;Krawczyk et al, 2008;Nelson et al, 2003). In influenza A virus, RanBP5 could be displaced from PB1 or the PB1 : PA dimer by the addition of non-hydrolysable RanGTP in vitro, and depletion of RanBP5 reduced the nuclear accumulation of PB1 and of PB1 : PA.…”

Section: Introductionmentioning

confidence: 99%

Characterization of the interaction between the influenza A virus polymerase subunit PB1 and the host nuclear import factor Ran-binding protein 5

Hutchinson

Orr

Liu

et al. 2011

Journal of General Virology

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The influenza A virus RNA polymerase is a heterotrimer that transcribes and replicates the viral genome in the cell nucleus. Newly synthesized RNA polymerase subunits must therefore be imported into the nucleus during an infection. While various models have been proposed for this process, the consensus is that the polymerase basic protein PB1 and polymerase acidic protein PA subunits form a dimer in the cytoplasm and are transported into the nucleus by the betaimportin Ran-binding protein 5 (RanBP5), with the PB2 subunit imported separately to complete the trimeric complex. In this study, we characterized the interaction of PB1 with RanBP5 further and assessed its importance for viral growth. In particular, we found that the N-terminal region of PB1 mediates its binding to RanBP5 and that basic residues in a nuclear localization signal are required for RanBP5 binding. Mutating these basic residues to alanines does not prevent PB1 forming a dimer with PA, but does reduce RanBP5 binding. RanBP5-binding mutations reduce, though do not entirely prevent, the nuclear accumulation of PB1. Furthermore, mutations affecting RanBP5 binding are incompatible with or severely attenuate viral growth, providing further support for a key role for RanBP5 in the influenza A virus life cycle. INTRODUCTIONInfluenza A virus is the prototypic orthomyxovirus and a serious pathogen of humans and animals. The viral genome consists of eight segments of negative-sense, ssRNA, which are encapsidated as viral ribonucleoprotein complexes (vRNPs) by multiple copies of nucleoprotein (NP) and the trimeric RNA-dependent RNA polymerase (RdRP; consisting of the polymerase basic proteins PB1 and PB2, and the polymerase acidic protein PA) (Palese & Shaw, 2007). Unusually among RNA viruses, orthomyxoviruses replicate their genomes in the nucleus. Consequently, newly synthesized viral proteins must be imported into the nucleus to allow the assembly and export of new vRNPs, as well as to regulate host processes in the infected cell. Of the proteins expressed by influenza A virus, nuclear import is observed for the three polymerase proteins and NP, as well as matrix (M1) protein, non-structural (NS1) protein, nuclear export protein (NEP) and PB1-F2 (Chen et al., 2001;Smith et al., 1987). Nuclear import of structures larger than 20-30 kDa is selective and energy dependent, requiring binding of nuclear import factors (NIFs) through nuclear localization signals (NLSs) on import substrates (Görlich & Kutay, 1999). A number of influenza A virus proteins have been shown to contain NLSs and to bind NIFs Naito et al., 2007; Resa-Infante et al., 2008;Tarendeau et al., 2007). PB1 and PA, despite both having signals that can promote nuclear import when individually expressed (Akkina et al., 1987;Nath & Nayak, 1990;Nieto et al., 1994), do not accumulate efficiently in the nucleus unless expressed together, a requirement that appears to be particularly marked for PB1 (Fodor & Smith, 2004;Huet et al., 2010;Nieto et al., 1992). Although all possible pairwise interact...

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Karyopherin β3: A new cellular target for the HPV-16 E5 oncoprotein

Cited by 31 publications

References 33 publications

Pleomorphic adenoma gene 1 mediates the role of Karyopherin alpha 2 and has prognostic significance in hepatocellular carcinoma

Pleomorphic adenoma gene 1 mediates the role of Karyopherin alpha 2 and has prognostic significance in hepatocellular carcinoma

The EVER Proteins as a Natural Barrier against Papillomaviruses: a New Insight into the Pathogenesis of Human Papillomavirus Infections

Characterization of the interaction between the influenza A virus polymerase subunit PB1 and the host nuclear import factor Ran-binding protein 5

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