Poly(C)-binding proteins as transcriptional regulators of gene expression

Department of Pharmacology, University of Minnesota Medical School, 6-120 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455, USA.
Biochemical and Biophysical Research Communications (Impact Factor: 2.3). 04/2009; 380(3):431-6. DOI: 10.1016/j.bbrc.2009.01.136
Source: PubMed


Poly(C)-binding proteins (PCBPs) are generally known as RNA-binding proteins that interact in a sequence-specific fashion with single-stranded poly(C). They can be divided into two groups: hnRNP K and PCBP1-4. These proteins are involved mainly in various posttranscriptional regulations (e.g., mRNA stabilization or translational activation/silencing). In this review, we summarize and discuss how PCBPs act as transcriptional regulators by binding to specific elements in gene promoters that interact with the RNA polymerase II transcription machinery. Transcriptional regulation of PCBPs might itself be regulated by their localization within the cell. For example, activation by p21-activated kinase 1 induces increased nuclear retention of PCBP1, as well as increased promoter activity. PCBPs can function as a signal-dependent and coordinated regulator of transcription in eukaryotic cells. We address the molecular mechanisms by which PCBPs binding to single- and double-stranded DNA mediates gene expression.

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Available from: Hack sun Choi, Jun 23, 2014
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    • "HnRNP K is involved in transcriptional processes, where it has multiple effects, acting as both an activator and a repressor (see review by Choi et al. [37]). In vivo, it interacts directly with the RNA polymerase machinery through its association with TATAbox binding protein (TBP), a subunit of the eukaryotic transcription factor TFIID. "
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    ABSTRACT: The heterogeneous nuclear ribonucleoprotein K (hnRNP K) is a nucleic acid-binding protein that serves as a docking platform integrating transduction pathways to nucleic acid-directed processes. Recently, this protein has emerged as an important player in carcinogenesis process. HnRNP K is overexpressed in several human cancers and its aberrant cytoplasmic localization has been associated with a worse prognosis for patients, suggesting that it has a role in cancer progression. Herein, we provide a brief overview of the multifunctional roles of hnRNP K and discuss clinical studies that have demonstrated its involvement in cancer development and progression.
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    • "Although hnRNP K can regulate gene expression by binding to DNA and RNA [6,57], we found that it induces MMP12 mRNA expression by activating the MMP12 promoter rather than stabilizing the MMP12 mRNA (Additional file 4: Figure S1). Similar to the transcriptional induction of MMP12 by AP-1 [29,30], NFκB [29], β-catenin [58,59], YB-1 [60] and PPARα agonist [61], we herein show that hnRNP K can induce MMP12 expression through its association with the sequence −42 to −33 bp upstream of the MMP12 transcription start site. "
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    ABSTRACT: Background Overexpression of heterogeneous nuclear ribonucleoprotein K (hnRNP K), a DNA/RNA binding protein, is associated with metastasis in nasopharyngeal carcinoma (NPC). However, the mechanisms underlying hnRNP K-mediated metastasis is unclear. The aim of the present study was to determine the role of matrix metalloproteinase (MMP) in hnRNP K-mediated metastasis in NPC. Methods We studied hnRNP K-regulated MMPs by analyzing the expression profiles of MMP family genes in NPC tissues and hnRNP K-knockdown NPC cells using Affymetrix microarray analysis and quantitative RT-PCR. The association of hnRNP K and MMP12 expression in 82 clinically proven NPC cases was determined by immunohistochemical analysis. The hnRNP K-mediated MMP12 regulation was determined by zymography and Western blot, as well as by promoter, DNA pull-down and chromatin immunoprecipitation (ChIP) assays. The functional role of MMP12 in cell migration and invasion was demonstrated by MMP12-knockdown and the treatment of MMP12-specific inhibitor, PF-356231. Results MMP12 was overexpressed in NPC tissues, and this high level of expression was significantly correlated with high-level expression of hnRNP K (P = 0.026). The levels of mRNA, protein and enzyme activity of MMP12 were reduced in hnRNP K-knockdown NPC cells. HnRNP K interacting with the region spanning −42 to −33 bp of the transcription start site triggered transcriptional activation of the MMP12 promoter. Furthermore, inhibiting MMP12 by MMP12 knockdown and MMP12-specific inhibitor, PF-356231, significantly reduced the migration and invasion of NPC cells. Conclusions Overexpression of MMP12 was significantly correlated with hnRNP K in NPC tissues. HnRNP K can induce MMP12 expression and enzyme activity through activating MMP12 promoter, which promotes cell migration and invasion in NPC cells. In vitro experiments suggest that NPC metastasis with high MMP12 expression may be treated with PF-356231. HnRNP K and MMP12 may be potential therapeutic markers for NPC, but additional validation studies are warranted.
    Full-text · Article · May 2014 · BMC Cancer
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    • "In general, functions of the hnRNPs in various cellular biological processes are based on their nucleic acid binding properties recognizing a wide range of RNA and ssDNA sequences, along with following formation of nucleotide-protein complexes that mediate ssDNA or RNA processing. The hnRNPs assembling on DNA participate in DNA repair, chromatin remodelling, telomere maintenance, and gene transcription [40–45]. Meanwhile, the hnRNPs interacting with RNA take part in every step of RNA metabolism including mRNA splicing, capping and polyadenylation, trafficking, translation, and turnover [15, 46–48]. "
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    ABSTRACT: Stem cells possess huge importance in developmental biology, disease modelling, cell replacement therapy, and tissue engineering in regenerative medicine because they have the remarkable potential for self-renewal and to differentiate into almost all the cell types in the human body. Elucidation of molecular mechanisms regulating stem cell potency and differentiation is essential and critical for extensive application. Heterogeneous nuclear ribonucleoproteins (hnRNPs) are modular proteins consisting of RNA-binding motifs and auxiliary domains characterized by extensive and divergent functions in nucleic acid metabolism. Multiple roles of hnRNPs in transcriptional and posttranscriptional regulation enable them to be effective gene expression regulators. More recent findings show that hnRNP proteins are crucial factors implicated in maintenance of stem cell self-renewal and pluripotency and cell differentiation. The hnRNPs interact with certain sequences in target gene promoter regions to initiate transcription. In addition, they recognize 3'UTR or 5'UTR of specific gene mRNA forming mRNP complex to regulate mRNA stability and translation. Both of these regulatory pathways lead to modulation of gene expression that is associated with stem cell proliferation, cell cycle control, pluripotency, and committed differentiation.
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