The Nm23-H1–h-Prune complex in cellular physiology: a ‘tip of the iceberg’ protein network perspective

Galasso, Alessia; Zollo, Massimo

doi:10.1007/s11010-009-0115-4

Cited by 32 publications

(23 citation statements)

References 56 publications

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“…S9A). BCH inhibits RhoA, a small GTPase that regulates the cytoskeleton, cell adhesion, and migration (16), whereas DHHA2 interacts with Nm23-H1, a metastasis suppressor (17). We found that endogenous PRUNE2 coimmunoprecipitates with RhoA and Nm23-H1 (Fig.…”

Section: Pca3mentioning

confidence: 63%

“…S10 E-J). These results, along with the established functions of interacting proteins (16)(17)(18), suggest that PRUNE2 primarily decreases tumor growth by inhibiting cell proliferation but also affects adhesion, spreading, and migration. We subsequently extended these results to human tumor xenograft models; LNCaP prostate cancer cells stably expressing PRUNE2-shRNA, ectopic PCA3, PCA3-shRNA, or controls were s.c. administered into SCID mice.…”

Section: Pca3mentioning

confidence: 80%

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PRUNE2 is a human prostate cancer suppressor regulated by the intronic long noncoding RNA PCA3

Salameh

Lee

Cardó-Vila

et al. 2015

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

234

191

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Prostate cancer antigen 3 (PCA3) is the most specific prostate cancer biomarker but its function remains unknown. Here we identify PRUNE2, a target protein-coding gene variant, which harbors the PCA3 locus, thereby classifying PCA3 as an antisense intronic long noncoding (lnc)RNA. We show that PCA3 controls PRUNE2 levels via a unique regulatory mechanism involving formation of a PRUNE2/PCA3 double-stranded RNA that undergoes adenosine deaminase acting on RNA (ADAR)-dependent adenosine-to-inosine RNA editing. PRUNE2 expression or silencing in prostate cancer cells decreased and increased cell proliferation, respectively. Moreover, PRUNE2 and PCA3 elicited opposite effects on tumor growth in immunodeficient tumor-bearing mice. Coregulation and RNA editing of PRUNE2 and PCA3 were confirmed in human prostate cancer specimens, supporting the medical relevance of our findings. These results establish PCA3 as a dominant-negative oncogene and PRUNE2 as an unrecognized tumor suppressor gene in human prostate cancer, and their regulatory axis represents a unique molecular target for diagnostic and therapeutic intervention.S everal lines of evidence demonstrate that long noncoding RNAs (lncRNAs) are functional in carcinogenesis through regulatory mechanisms such as promoter looping, alternative splicing, antisense gene silencing, transcriptional regulation, and DNA repair, thus potentially serving as tumor markers. A few lncRNA species have emerged as potential prostate cancer biomarkers such as prostate cancer gene expression marker-1 (PCGEM1) and prostate cancer noncoding RNA1 (PRNCR1), which enhance androgen receptor (AR)-dependent gene activation, and prostate cancer-associated ncRNA transcript-1 (PCAT1), which silences BRCA2 via posttranscriptional homologous recombination (1). Notably, the most specific biomarker in human prostate cancer identified to date is an lncRNA, prostate cancer antigen 3 (PCA3, also known as PCA3 DD3 or DD3 PCA3 ), which is up-regulated in human prostate cancer (2). Since its discovery more than 15 y ago, PCA3 has been extensively investigated (3) and has been approved for clinical applications to aid the diagnosis of prostate cancer in both the European Union and the United States. Paradoxically-despite its striking clinical specificity-the inherent cellular role of the lncRNA PCA3 in human prostate cancer, if any, remains completely unknown (1). Here we report a unique biological function for PCA3. Within a single functional genetic unit, we show that PCA3 is an antisense intronic lncRNA that down-regulates an as yet unrecognized tumor suppressor gene, a human homolog of the Drosophila prune gene, PRUNE2, through a process that involves RNA editing mediated by a supramolecular complex containing adenosine deaminase acting on RNA (ADAR) family members. We propose a working model in which PCA3 acts as a dominant-negative oncogene in prostate cancer and show consistent results in therapeutic preclinical models and in patient-derived human samples. Therefore, the molecular interaction of PRUNE2...

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Section: Pca3mentioning

confidence: 63%

Section: Pca3mentioning

confidence: 80%

PRUNE2 is a human prostate cancer suppressor regulated by the intronic long noncoding RNA PCA3

Salameh

Lee

Cardó-Vila

et al. 2015

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

234

191

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“…13 Other functions identified for polyP in mammalian cells include cell proliferation, 14 angiogenesis, 15 apoptosis, 16 osteoblast function, 17 bone mineralization, 18,19 energy metabolism, 20 and tumor metastasis. 21,22 In this review, we explore the recently reported roles of polyP in blood clotting and inflammation. Studies from our laboratory and others have shown that polyP acts at the beginning, middle, and end of the blood clotting cascade (Figure 2), with prohemostatic, prothrombotic, and proinflammatory effects.…”

Section: Introductionmentioning

confidence: 99%

Polyphosphate: an ancient molecule that links platelets, coagulation, and inflammation

Morrissey

Choi

Smith

2012

Blood

331

295

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AbstractInorganic polyphosphate is widespread in biology and exhibits striking prohemostatic, prothrombotic, and proinflammatory effects in vivo. Long-chain polyphosphate (of the size present in infectious microorganisms) is a potent, natural pathophysiologic activator of the contact pathway of blood clotting. Medium-chain polyphosphate (of the size secreted from activated human platelets) accelerates factor V activation, completely abrogates the anticoagulant function of tissue factor pathway inhibitor, enhances fibrin clot structure, and greatly accelerates factor XI activation by thrombin. Polyphosphate may have utility as a hemostatic agent, whereas antagonists of polyphosphate may function as novel antithrombotic/anti-inflammatory agents. The detailed molecular mechanisms by which polyphosphate modulates blood clotting reactions remain to be elucidated.

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“…25,26 H-prune contains two DHH domains at its N-terminus, followed by a third C-terminal domain, which was previously shown to be responsible for the interaction with different partners such as GSK-3beta and with Nm23-H1. 27,28 The conformational analysis of the C-terminal domain of h-prune performed by nuclear magnetic resonance showed that it assumes a random coil conformation with the exception of some protein regions with helical structural propensity and a disulfide bridge as unique rigid linkage. 20 In particular, the recombinant C-terminal domain of h-prune (residues 354-453, c-prune) was sufficient to bind the characterized interacting Nm23-H1 endogenous protein as verified by Western blotting analysis and nuclear magnetic resonance spectroscopy.…”

Section: Introductionmentioning

confidence: 99%

gH625 is a viral derived peptide for effective delivery of intrinsically disordered proteins

Smaldone¹,

Falanga²,

Capasso³

et al. 2013

IJN

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A genetically modified recombinant gH625-c-prune was prepared through conjugation of c-prune with gH625, a peptide encompassing 625-644 residues of the glycoprotein H of herpes simplex virus 1, which has been proved to possess the ability to carry cargo molecules across cell membranes. C-prune is the C-terminal domain of h-prune, overexpressed in breast, colorectal, and gastric cancers, interacting with multiple partners, and representing an ideal target for inhibition of cancer development. Its C-terminal domain results in an intrinsically disordered domain (IDD), and the peculiar properties of gH625 render it an optimal candidate to act as a carrier for this net negatively charged molecule by comparison with the positively charged TAT. A characterization of the recombinant gH625-c-prune fusion protein was conducted by biochemical, cellular biology and confocal microscopy means in comparison with TAT-c-prune. The results showed that the gH625-c-prune exhibited the ability to cross biomembranes, opening a new scenario on the use of gH625 as a novel multifunctional carrier.

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The Nm23-H1–h-Prune complex in cellular physiology: a ‘tip of the iceberg’ protein network perspective

Cited by 32 publications

References 56 publications

PRUNE2 is a human prostate cancer suppressor regulated by the intronic long noncoding RNA PCA3

PRUNE2 is a human prostate cancer suppressor regulated by the intronic long noncoding RNA PCA3

Polyphosphate: an ancient molecule that links platelets, coagulation, and inflammation

gH625 is a viral derived peptide for effective delivery of intrinsically disordered proteins

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