Regulation of nucleolin expression by miR-194, miR-206, and HuR.

Nucleolin is a proliferation-associated protein that is overexpressed in multiple types of cancer. The mechanisms leading to overexpression of nucleolin in specific cancers are not fully understood. This study found that nucleolin is notably elevated in breast cancer cell lines MCF-7 and MDA-231 compared to nonmalignant breast epithelial MCF-10A cells.

Regulatory mechanism of G protein-coupled receptor trafficking to the plasma membrane: a role for mRNA localization.

Trafficking and localization of G protein-coupled receptors (GPCRs) to the plasma membrane and its retention in the agonist-naive state are critically important for signaling by these receptors. Agonist-induced desensitization of activated GPCRs and their removal from the cell surface have been studied and reviewed extensively. However, less attention has been given to the regulatory mechanisms and different steps that control the trafficking of newly synthesized receptors to the plasma membrane.

The 3'-untranslated region length and AU-rich RNA location modulate RNA-protein interaction and translational control of β2-adrenergic receptor mRNA.

Posttranscriptional controls play a major role in β(2)-adrenergic receptor (β(2)-AR) expression. We recently reported that β(2)-AR mRNA translation is suppressed by elements in its 3'-untranslated region (UTR). We also identified T-cell-restricted intracellular antigen-related protein (TIAR) and HuR as prominent AU-rich (ARE) RNA-binding proteins that associate with β(2)-AR mRNA 3'-UTR.

Mechanism of regulation of bcl-2 mRNA by nucleolin and A+U-rich element-binding factor 1 (AUF1).

The antiapoptotic Bcl-2 protein is overexpressed in a variety of cancers, particularly leukemias. In some cell types this is the result of enhanced stability of bcl-2 mRNA, which is controlled by elements in its 3'-untranslated region. Nucleolin is one of the proteins that binds to bcl-2 mRNA, thereby increasing its half-life.

Direct binding of glyceraldehyde 3-phosphate dehydrogenase to telomeric DNA protects telomeres against chemotherapy-induced rapid degradation.

Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is a glycolytic enzyme that displays several non-glycolytic activities, including the maintenance and/or protection of telomeres. In this study, we determined the molecular mechanism and biological role of the interaction between GAPDH and human telomeric DNA. Using gel-shift assays, we show that recombinant GAPDH binds directly with high affinity (K(d)=45 nM) to a single-stranded oligonucleotide comprising three telomeric DNA repeats, and that nucleotides T1, G5, and G6 of the TTAGGG repeat are essential for binding.

Regulation of Bcl-2 expression by HuR in HL60 leukemia cells and A431 carcinoma cells.

Overexpression of the proto-oncogene bcl-2 promotes abnormal cell survival by inhibiting apoptosis. Expression of bcl-2 is determined, in part, by regulatory mechanisms that control the stability of bcl-2 mRNA. Elements in the 3'-untranslated region of bcl-2 mRNA have been shown to play a role in regulating the stability of the message.

Plasma membrane nucleolin is a receptor for the anticancer aptamer AS1411 in MV4-11 leukemia cells.

AS1411 is a DNA aptamer that is in phase II clinical trials for relapsed or refractory acute myeloid leukemia and for renal cell carcinoma. AS1411 binds to nucleolin, a protein that is overexpressed in the cytoplasm and on the plasma membrane of some tumor cells compared with normal cells. Studies were performed to determine whether cell surface nucleolin is a receptor for AS1411 in the acute myeloid leukemia cell line MV4-11.

The nucleolin targeting aptamer AS1411 destabilizes Bcl-2 messenger RNA in human breast cancer cells.

We sought to determine whether nucleolin, a bcl-2 mRNA-binding protein, has a role in the regulation of bcl-2 mRNA stability in MCF-7 and MDA-MB-231 breast cancer cells. Furthermore, we examined the efficacy of the aptamer AS1411 in targeting nucleolin and inducing bcl-2 mRNA instability and cytotoxicity in these cells. AS1411 at 5 micromol/L inhibited the growth of MCF-7 and MDA-MB-231 cells, whereas 20 micromol/L AS1411 had no effect on the growth rate or viability of normal MCF-10A mammary epithelial cells.

PMA induces stabilization of oncostatin M mRNA in human lymphoma U937 cells.

OSM (oncostatin M) is a pleiotropic cytokine belonging to the IL (interleukin) 6 family that modulates the growth of some cancer cell lines. We have found that PMA treatment of human U937 lymphoma cells increased the steady-state levels of OSM mRNA. Furthermore, the half-life of OSM mRNA was increased from 2.

Overexpression of nucleolin in chronic lymphocytic leukemia cells induces stabilization of bcl2 mRNA.

B-cell chronic lymphocytic leukemia (CLL) is characterized by the accumulation of clonal B cells that are resistant to apoptosis as a result of bcl2 oncogene overexpression. Studies were done to determine the mechanism for the up-regulation of bcl-2 protein observed in CD19+ CLL cells compared with CD19+ B cells from healthy volunteers. The 11-fold higher level of bcl-2 protein in CLL cells was positively correlated with a 26-fold elevation in the cytosolic level of nucleolin, a bcl2 mRNA-stabilizing protein.

Identification of Ebp1 as a component of cytoplasmic bcl-2 mRNP (messenger ribonucleoprotein particle) complexes.

The 3'-UTR (untranslated region) of bcl-2 mRNA contains an ARE (AU-rich element) that potentially regulates the stability of bcl-2 mRNA in a cell specific fashion. Previous studies have demonstrated that multiple proteins interact with bcl-2 mRNA in HL-60 (human leukaemia-60) cells, potentially contributing to the overexpression of Bcl-2 protein. Treatment of HL-60 cells with taxol or okadaic acid has been shown to induce destabilization of bcl-2 mRNA, which was associated with decreased binding of trans-acting factors to bcl-2 mRNA.

Complex haplotype structure of the human GNAS gene identifies a recombination hotspot centred on a single nucleotide polymorphism widely used in association studies.

The alpha subunit of the heterotrimeric G protein Gs (Gsalpha) is involved in numerous physiological processes and is a primary determinant of cellular responses to extracellular signals. Genetic variations in the Gsalpha gene may play an important role in complex diseases and drug responses. To characterize the genetic diversity in this locus, we resequenced exons and flanking introns of the gene in 44 genomic samples and analysed the haplotype structure of the gene in an additional 50 African-Americans and 50 Caucasians.

Retinoid-induced apoptosis in HL-60 cells is associated with nucleolin down-regulation and destabilization of Bcl-2 mRNA.

All-trans retinoic acid (ATRA) induces differentiation of promyelocytic leukemia cells, but the mechanisms by which cellular differentiation leads to apoptosis are not well understood. Studies were done to address the question whether ATRA-induced apoptosis is a consequence of destabilization of bcl-2 mRNA and decreased cellular levels of the anti-apoptotic protein, bcl-2. ATRA induced differentiation of HL-60 cells along the granulocytic pathway within 48 h.

Drug-induced destabilization of bcl-2 mRNA: a new approach for inducing apoptosis in tumor cells.

Recent evidence suggests that the 3' untranslated region (3' UTR) of some mRNAs is a molecular hotspot for pathology. The 3' UTR of bcl-2 mRNA contains several AU-rich elements (AREs) that promote mRNA destabilization. Recent studies have demonstrated that the protein, nucleolin, binds to an ARE in bcl-2 mRNA, thereby protecting this mRNA from nuclease degradation.

Identification of nucleolin as an AU-rich element binding protein involved in bcl-2 mRNA stabilization.

bcl-2 mRNA contains an AU-rich element (ARE) that functions in regulating bcl-2 stability. Our earlier studies indicated that taxol- or okadaic acid-induced bcl-2 mRNA destabilization in HL-60 cells is associated with decreased binding of trans-acting factors to the ARE. To identify factors that play a role in the regulation of bcl-2 mRNA stability, bcl-2 ARE-binding proteins were purified from HL-60 cells.

Taxol- and okadaic acid-induced destabilization of bcl-2 mRNA is associated with decreased binding of proteins to a bcl-2 instability element.

The observation that overexpression of the anti-apoptotic protein Bcl-2 is associated with both cancer development and anti-cancer drug resistance suggests that factors which regulate bcl-2 expression may be important therapeutic targets. We report here that taxol or okadaic acid (OA) treatment of HL-60 cells reduced bcl-2 mRNA steady state levels to 50% of control cell levels in 20-24hr of treatment. The 3'-untranslated region of bcl-2 mRNA contains four potential A+U-rich elements (AREs), which are associated with mRNA destabilization.

Potential importance of glomerular citrate synthase activity in remnant nephropathy.

Background: Aldosterone fosters progressive renal injury, but the mechanism is unknown. Both Wistar-Furth rats, which are resistant to aldosterone actions, and adrenalectomized Sprague-Dawley rats, which lack aldosterone, are characterized by resistance to remnant nephropathy and by reduced whole kidney citrate synthase activity. Increase in citrate synthase activity is a well-characterized, specific renal response to aldosterone.