Nuclear shift of hnRNP K protein in neoplasms and other states of enhanced cell proliferation

Ostrowski, Jerzy; Bomsztyk, Karol

doi:10.1038/sj.bjc.6601250

Cited by 65 publications

(62 citation statements)

References 46 publications

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“…42 A physical interaction of b-catenin/TCF-4 complex with several hnRNPs, involved in the regulation of pre-mRNA splicing, has been described 43 and some types of alternative splicing are considered to promote prostate cancer progression. 44,45 As hnRNP K is involved in the regulation of transcription and translation of specific mRNAs depending on its phosphorylation status, 10,46 we propose a model where AKT directly controls hnRNP K and b-catenin phosphorylation and their transcriptional activities leading to NED (Fig. 6).…”

Section: Discussionmentioning

confidence: 99%

“…7 The importance of immuno-histological detection of NED in prostatic adenocarcinoma with respect to disease at presentation and Gleason grade is gaining acceptance, and a correlation of immunohistochemically detected markers of neuroendocrine differentiation with clinical predictors of disease progression in prostate cancer has been reported. 8 Using proteomic analysis of the nuclear matrix, we previously reported that hnRNP K, a member of the hnRNP family with pleiotropic functions, [9][10][11][12] was overexpressed in PC specimens with involvement of seminal vesicles and that its expression level was closely correlated with Gleason score and poor prognosis. 13 It has been recently demonstrated that hnRNP K regulates the expression of AR by a posttranscriptional mechanism 14 and that NE cells in malignant prostatic tissues show no androgen receptors.…”

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confidence: 99%

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Regulation of neuroendocrine differentiation by AKT/hnRNPK/AR/β‐catenin signaling in prostate cancer cells

Ciarlo

Benelli

Barbieri

et al. 2011

Intl Journal of Cancer

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Current diagnostic tools cannot predict clinical failure and androgen-independent disease progression for patients with prostate cancer (PC). The survival signaling pathways of prostate cells play a central role in the progression of tumors to a neuroendocrine (NE) phenotype. NE cells demonstrate attributes that suggest that they are an integral part of the signaling cascade leading to castration-resistant PC. In this study, making use of in vitro neuroendocrine differentiation (NED) of human LNCaP and mouse TRAMP-C2 cells after androgen withdrawal, and of the transgenic adenocarcinoma of mouse prostate (TRAMP) model, we characterized a sequence of molecular events leading to NED and identified a number of markers that could be detectable by routine analyses not only in castration resistant PC but also in hormone naïve PC at the time of initial diagnosis. We found that NED associates with AKT activation that in turn regulates heterogeneous nuclear ribonucleoprotein K (hnRNP K), androgen receptor (AR) and b-catenin levels. Addition of molecules targeting membrane-bound receptors and protein kinases blocks NE differentiation in LNCaP and TRAMP-C2 cells. The extent of AKT phosphorylation and hnRNP K, AR and b-catenin levels may have a potential value as prognostic indicators discriminating between androgen-responsive and unresponsive cells and could be used as molecular targets to monitor the anti-tumor action of new therapeutic protocols based on antireceptor agents and/or neuroendocrine hormone antagonists.PC is one of the most common malignancies among males in the western world and a major health problem in many industrialized countries. PC develops and progresses under the influence of androgenic steroids. This influence is consistent with the use of androgen depletion therapies to treat patients with advanced disease.1 However, most patients finally relapse with hormone-refractory prostate cancer and available treatment options are only palliative. Therefore, an understanding of what drives progression to androgen independence is critical. The prostate is known to be dependent not only on androgens but also on growth factors and neuropeptides secreted by NE cells that maintain normal prostate function and play a role in the development of pathological conditions.2 Adult prostate gland possesses basal (proliferating) cells, secretory (luminal) cells and the less abundant (<0.1%) NE cells. Approximately 10% of prostatic carcinoma reveals extensive and multifocal NE features and the presence of NE markers is usually associated with poor prognosis. 3,4 Interestingly, along with the androgen-independent status, an increase in the number of NE cells has been reported in some studies and long-term androgen ablation therapy tends to select prostate tumor populations that are enriched in NE cells.5 These cells lack nuclear androgen receptor 6 ; thus they represent an androgen-insensitive cell phenotype in the prostate and it has been hypothesized that NE cells can lead to the development and growth of androgen-refract...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Regulation of neuroendocrine differentiation by AKT/hnRNPK/AR/β‐catenin signaling in prostate cancer cells

Ciarlo

Benelli

Barbieri

et al. 2011

Intl Journal of Cancer

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“…These findings are consistent with the results of the RNA EMSAs and, taken together with the mRNA half-life measurements, strongly indicate that hnRNP E1, as part of a 3=-UTR RNP complex, plays an important function in the active stabilization of eNOS mRNA. hnRNP E proteins are known to shuttle between the nucleus and cytoplasm, with functional consequences for the translational efficiencies of their target mRNAs (e.g., ␣2-globin mRNA) (51)(52)(53)(54). Indeed, chromatin immunoprecipitations (ChIPs) against hnRNP E1 revealed specific E1 enrichment at eNOS P2/P3/P4 elements compared to the amount at the eNOS promoter (data not shown).…”

Section: Fig 3 Enos-stabilizing Rnp Complexes Contain Hnrnp E1 (A) Imentioning

confidence: 99%

Active Stabilization of Human Endothelial Nitric Oxide Synthase mRNA by hnRNP E1 Protects against Antisense RNA and MicroRNAs

Robb

Tai

et al. 2013

Molecular and Cellular Biology

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Human endothelial nitric oxide synthase (eNOS) mRNA is highly stable in endothelial cells (ECs). Posttranscriptional regulation of eNOS mRNA stability is an important component of eNOS regulation, especially under hypoxic conditions. Here, we show that the human eNOS 3= untranslated region (3= UTR) contains multiple, evolutionarily conserved pyrimidine (C and CU)-rich sequence elements that are both necessary and sufficient for mRNA stabilization. Importantly, RNA immunoprecipitations and RNA electrophoretic mobility shift assays (EMSAs) revealed the formation of heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1)-containing RNP complexes at these 3=-UTR elements. Knockdown of hnRNP E1 decreased eNOS mRNA half-life, mRNA levels, and protein expression. Significantly, these stabilizing RNP complexes protect eNOS mRNA from the inhibitory effects of its antisense transcript sONE and 3=-UTR-targeting small interfering RNAs (siRNAs), as well as microRNAs, specifically, hsa-miR-765, which targets eNOS mRNA stability determinants. Hypoxia disrupts hnRNP E1/eNOS 3=-UTR interactions via increased Akt-mediated serine phosphorylation (including serine 43) and increased nuclear localization of hnRNP E1. These mechanisms account, at least in part, for the decrease in eNOS mRNA stability under hypoxic conditions. Thus, the stabilization of human eNOS mRNA by hnRNP E1-containing RNP complexes serves as a key protective mechanism against the posttranscriptional inhibitory effects of antisense RNA and microRNAs under basal conditions but is disrupted under hypoxic conditions.

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“…Heterogeneous nuclear ribonucleoproteins (hnRNPs) are predominantly nuclear RNA-binding proteins that have been implicated in diverse molecular and cellular functions, including chromatin remodeling, transcription, splicing and translation (14,(25)(26)(27)(28). It acts as a docking platform to integrate signaling cascades by facilitating cross-talk between kinases and factors that mediate nucleic acid-directed processes (29).…”

Section: Identification Of Target Protein For Intracellular Antibody-mentioning

confidence: 99%

Loss-of-function screening by randomized intracellular antibodies: Identification of hnRNP-K as a potential target for metastasis

Inoue

Sawata

Taira

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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We have developed a loss-of-function screening system on the basis of intracellular expression of single domain antibodies. We demonstrate its use in identification of potential targets of metastasis of human cancerous cells. Randomized intracellular antibodies were expressed in highly metastatic cells, and a derivative pool of cells with loss of migration phenotype in chemotaxis assay was isolated. Isolation of antibodies from cells with loss of migration phenotype and identification of their target proteins revealed the involvement of the heterogeneous nuclear ribonucleoprotein K (hnRNP-K), a multifunctional signaling protein, in metastasis. Furthermore, we found that the cytoplasmic accumulation of hnRNP-K is crucial for its role in metastasis. The results demonstrate (i) the advantages of our functional interference screening over the gene-knockouts and genesilencing, (ii) hnRNP-K as a potential target of metastasis, and (iii) a potential anti-metastasis peptide validated in in vitro cell migration assays.heterogeneous nuclear ribonucleoprotein K ͉ randomized antibodies ͉ functional screening ͉ cytoplasmic accumulation ͉ antimetastasis M etastasis is a complex phenomenon that involves an array of genetic changes and coordination of many positive and negative factors leading to motile cells that can penetrate into and travel through the bloodstream forming secondary tumors elsewhere in the body. Despite the advances in cancer therapies and the understanding that metastasis is a selective, nonrandom and inefficient process, it significantly contributes to morbidity and mortality of cancer patients and is a major challenge yet to be met in cancer therapeutics (1-4). Increased cell motility is one of the early and essential phenotype of metastatic cancers. Although it has been demonstrated to involve concerted reorganization of the actin cytoskeleton that regulates cell shape, and motility through spatiotemporal activation of Rho-family GTPases (5-9), the molecular mechanisms and its upstream regulators, the potential targets of metastasis, have not been sufficiently defined (10). Amongst a large variety of approaches that can be adopted to identify ''metastasis genes,'' we chose to employ a functional interference of proteins by expression of intracellular antibodies, also called as ''specific functional ablators'' and ''functional therapeutical molecules'' (11-13). We anticipated that the functional interference may serve as a milder and finer approach to reveal biological complexities and pathways that cannot be resolved by gene-knockouts and genesilencing strategies that challenge structural integrity of cells.We constructed a randomized intracellular antibody library (iAb-lib) on the basis of the single heavy-chain small antigenbinding fragments (VHH) of camel antibody. By employing iAb-lib against cell migration of highly malignant human fibrosarcoma, we obtained a derivative cell population in which cell migration was compromised. Cloning and characterization of antibodies from the derivative nonmigrating...

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Nuclear shift of hnRNP K protein in neoplasms and other states of enhanced cell proliferation

Cited by 65 publications

References 46 publications

Regulation of neuroendocrine differentiation by AKT/hnRNPK/AR/β‐catenin signaling in prostate cancer cells

Regulation of neuroendocrine differentiation by AKT/hnRNPK/AR/β‐catenin signaling in prostate cancer cells

Active Stabilization of Human Endothelial Nitric Oxide Synthase mRNA by hnRNP E1 Protects against Antisense RNA and MicroRNAs

Loss-of-function screening by randomized intracellular antibodies: Identification of hnRNP-K as a potential target for metastasis

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