scholarly journals Gamma Interferon and Cadmium Treatments Modulate Eukaryotic Initiation Factor 4E-Dependent mRNA Transport of Cyclin D1 in a PML-Dependent Manner

2002 ◽  
Vol 22 (17) ◽  
pp. 6183-6198 ◽  
Author(s):  
Ivan Topisirovic ◽  
Allan D. Capili ◽  
Katherine L. B. Borden
Keyword(s):  
Cyclin D1 ◽  
D1 Protein ◽  
Nuclear Bodies ◽  
Initiation Factor ◽  
Eukaryotic Initiation Factor ◽  
Mrna Transport ◽  
Protein Levels ◽  
Eukaryotic Initiation Factor 4E ◽  
Cadmium Treatment ◽  
Cyclin D1 Protein

ABSTRACT The eukaryotic initiation factor 4E (eIF4E), when dysregulated, transforms cells. A substantial fraction of eIF4E forms nuclear bodies that colocalize with those associated with the promyelocytic leukemia protein PML. Overexpression studies indicate that nuclear eIF4E promotes the transport of cyclin D1 mRNA from the nucleus to the cytoplasm and that PML is a key negative regulator of this function. Since previous studies used overexpression methods, the physiological relevance of eIF4E mRNA transport function or its interaction with PML remained unknown. Therefore, we monitored whether eIF4E-dependent transport could be modulated in response to environmental conditions. Here we report that cadmium treatment, which disperses PML nuclear bodies, leaves eIF4E bodies intact, leading to increased transport of cyclin D1 mRNA and increased cyclin D1 protein levels. Removal of cadmium allows PML to reassociate with eIF4E nuclear bodies, leading to decreased cyclin D1 transport and reduced cyclin D1 protein levels. In contrast, we show that treating cells with interferon increased the levels of PML protein at the PML-eIF4E nuclear body, leading to nuclear retention of cyclin D1 transcripts and reduced cyclin D1 protein levels. Neither interferon nor cadmium treatment altered cyclin D1 levels in PML−/− cells. Consistently, overexpression of a series of PML and eIF4E mutant proteins established that PML eIF4E interaction is required for the observed effects of cadmium and interferon treatment. The present study provides the first evidence that physiological factors modulate the mRNA transport functions of eIF4E and that this regulation is PML dependent.

Elevated levels of cyclin D1 protein in response to increased expression of eukaryotic initiation factor 4E

1993 ◽  
Vol 13 (12) ◽  
pp. 7358-7363
Author(s):  
I B Rosenwald ◽  
A Lazaris-Karatzas ◽  
N Sonenberg ◽  
E V Schmidt
Keyword(s):  
Cyclin D1 ◽  
D1 Protein ◽  
Initiation Factor ◽  
Eukaryotic Initiation Factor ◽  
3T3 Cells ◽  
Protein Levels ◽  
Eukaryotic Initiation Factor 4E ◽  
Cyclin D1 Protein ◽  
Nih 3T3 ◽  
Nih 3T3 Cells

Cyclin D1 is a G1-specific cyclin that has been linked to lymphoid, parathyroid, and breast tumors. Recent studies suggested that high protein levels of cyclin D1 are not always produced when cyclin D1 mRNA is overexpressed in transfected cells, suggesting that posttranscriptional events may be important in cyclin D1 regulation. The mRNA cap-binding protein (eukaryotic initiation factor 4E [eIF-4E]) is a potential regulatory of several posttranscriptional events, and it can itself induce neoplastic transformation. Consequently, we examined eIF-4E as a potential regulator of cyclin D1. Overexpression of cyclin D1 mRNA in NIH 3T3 cells did not increase cyclin D1 protein. In contrast, overexpression of eIF-4E markedly increased the amount of cyclin D1 protein in NIH 3T3 cells. This increase was specific to cyclin D1 in comparison with the retinoblastoma gene product, c-Myc, actin, and eukaryotic initiation factor 2 alpha. We also examined cyclin D1 protein in cells expressing an estrogen receptor-Myc fusion protein because we previously found that eIF-4E increases after induction of c-myc function. In these cells, increased levels of eIF-4E protein were closely followed by increases in levels of cyclin D1 protein, but the level of cyclin D1 mRNA was not increased. We conclude that increases in cyclin D1 levels may result from increased expression of eIF-4E, and this regulation may be one determinant of cyclin D1 levels in the cell.

scholarly journals Elevated levels of cyclin D1 protein in response to increased expression of eukaryotic initiation factor 4E.

1993 ◽  
Vol 13 (12) ◽  
pp. 7358-7363 ◽  
Author(s):  
I B Rosenwald ◽  
A Lazaris-Karatzas ◽  
N Sonenberg ◽  
E V Schmidt
Keyword(s):  
Cyclin D1 ◽  
D1 Protein ◽  
Initiation Factor ◽  
Eukaryotic Initiation Factor ◽  
3T3 Cells ◽  
Protein Levels ◽  
Eukaryotic Initiation Factor 4E ◽  
Cyclin D1 Protein ◽  
Nih 3T3 ◽  
Nih 3T3 Cells

Cyclin D1 is a G1-specific cyclin that has been linked to lymphoid, parathyroid, and breast tumors. Recent studies suggested that high protein levels of cyclin D1 are not always produced when cyclin D1 mRNA is overexpressed in transfected cells, suggesting that posttranscriptional events may be important in cyclin D1 regulation. The mRNA cap-binding protein (eukaryotic initiation factor 4E [eIF-4E]) is a potential regulatory of several posttranscriptional events, and it can itself induce neoplastic transformation. Consequently, we examined eIF-4E as a potential regulator of cyclin D1. Overexpression of cyclin D1 mRNA in NIH 3T3 cells did not increase cyclin D1 protein. In contrast, overexpression of eIF-4E markedly increased the amount of cyclin D1 protein in NIH 3T3 cells. This increase was specific to cyclin D1 in comparison with the retinoblastoma gene product, c-Myc, actin, and eukaryotic initiation factor 2 alpha. We also examined cyclin D1 protein in cells expressing an estrogen receptor-Myc fusion protein because we previously found that eIF-4E increases after induction of c-myc function. In these cells, increased levels of eIF-4E protein were closely followed by increases in levels of cyclin D1 protein, but the level of cyclin D1 mRNA was not increased. We conclude that increases in cyclin D1 levels may result from increased expression of eIF-4E, and this regulation may be one determinant of cyclin D1 levels in the cell.

scholarly journals Requirement of Cyclin D1 in Mesangial Cell Mitogenesis

2000 ◽  
Vol 11 (8) ◽  
pp. 1398-1408
Author(s):  
STEFAN LANG ◽  
ANDREA HARTNER ◽  
R. BERND STERZEL ◽  
HARALD O. SCHÖCKLMANN
Keyword(s):  
Growth Factor ◽  
Protein Expression ◽  
Cyclin D1 ◽  
Transforming Growth Factor ◽  
D1 Protein ◽  
Transforming Growth Factor Β1 ◽  
Protein Levels ◽  
Cyclin D1 Protein

Abstract. Hyperplasia of mesangial cells (MC) is a frequent finding in glomerulonephritis. The control and function of cyclin D1, a regulator of cell cycle progression, in MC proliferation in vivo and in vitro were investigated. In a rat model of mesangioproliferative glomerulonephritis, increases in the number of cyclin D1-positive MC nuclei were prominent on day 5 of the disease, preceding the peak of MC hyperplasia. In growth-arrested rat MC in culture, mitogenic stimulation with serum or platelet-derived growth factor (PDGF) led to rapid increases in cyclin D1 protein expression. Transforming growth factor-β1 inhibited PDGF induction of cyclin D1 protein at 12 h. In an examination of the subcellular distribution of cyclin D1, it was observed that stimulation of MC with PDGF for 6 h caused translocation of cyclin D1 from the cytoplasm into the nucleus. Coincubation with PDGF and transforming growth factor-β1 completely inhibited this effect, without altering the cellular cyclin D1 protein abundance at that time point. To test whether reduction of cyclin D1 protein levels was sufficient to inhibit mitogenesis, MC were transfected with antisense oligonucleotides (ODN) complementary to rat cyclin D1 mRNA. Antisense ODN against cyclin D1 reduced the serum- or PDGF-induced protein expression of cyclin D1 to 27 or 10% of control levels, respectively. These inhibitory effects were correlated with diminished cyclin-dependent kinase 4 activity. Antisense ODN against cyclin D1 also decreased the PDGF-induced increase in p21Waf-1 protein levels. The MC proliferation caused by serum or PDGF was markedly inhibited by antisense ODN against cyclin D1, as measured by [3H]thymidine uptake and cell counts. It is concluded that increased cyclin D1 protein expression of MC is required for MC proliferation. Targeting cyclin D1 expression may represent an effective means to inhibit MC proliferation in vitro and in vivo.

scholarly journals Phosphorylation of eukaryotic initiation factor 4E is dispensable for skeletal muscle hypertrophy

2019 ◽  
Vol 317 (6) ◽  
pp. C1247-C1255 ◽  
Author(s):  
Vandre C. Figueiredo ◽  
Davis A. Englund ◽  
Ivan J. Vechetti ◽  
Alexander Alimov ◽  
Charlotte A. Peterson ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Cyclin D1 ◽  
Ribosome Biogenesis ◽  
Muscle Hypertrophy ◽  
Phosphorylation Site ◽  
Initiation Factor ◽  
Eukaryotic Initiation Factor ◽  
Eukaryotic Initiation Factor 4E ◽  
Skeletal Muscle Hypertrophy ◽  
Mechanical Overload

The eukaryotic initiation factor 4E (eIF4E) is a major mRNA cap-binding protein that has a central role in translation initiation. Ser209 is the single phosphorylation site within eIF4E and modulates its activity in response to MAPK pathway activation. It has been reported that phosphorylation of eIF4E at Ser209 promotes translation of key mRNAs, such as cyclin D1, that regulate ribosome biogenesis. We hypothesized that phosphorylation at Ser209 is required for skeletal muscle growth in response to a hypertrophic stimulus by promoting ribosome biogenesis. To test this hypothesis, wild-type (WT) and eIF4E knocked-in (KI) mice were subjected to synergist ablation to induce muscle hypertrophy of the plantaris muscle as the result of mechanical overload; in the KI mouse, Ser209 of eIF4E was replaced with a nonphosphorylatable alanine. Contrary to our hypothesis, we observed no difference in the magnitude of hypertrophy between WT and KI groups in response to 14 days of mechanical overload induced by synergist ablation. Similarly, the increases in cyclin D1 protein levels, ribosome biogenesis, and translational capacity did not differ between WT and KI groups. Based on these findings, we conclude that phosphorylation of eIF4E at Ser209 is dispensable for skeletal muscle hypertrophy in response to mechanical overload.

scholarly journals Arrest of G1-S Progression by the p53-Inducible Gene PC3 Is Rb Dependent and Relies on the Inhibition of Cyclin D1 Transcription

2000 ◽  
Vol 20 (5) ◽  
pp. 1797-1815 ◽  
Author(s):  
Daniele Guardavaccaro ◽  
Giuseppina Corrente ◽  
Francesca Covone ◽  
Laura Micheli ◽  
Igea D'Agnano ◽  
...  
Keyword(s):  
Cyclin D1 ◽  
D1 Protein ◽  
Down Regulation ◽  
Inhibition Of Proliferation ◽  
Protein Levels ◽  
Growth Inhibitory ◽  
Cyclin D1 Protein ◽  
Cdk4 Activity ◽  
Inducible Gene

ABSTRACT The p53-inducible gene PC3 (TIS21, BTG2) is endowed with antiproliferative activity. Here we report that expression ofPC3 in cycling cells induced accumulation of hypophosphorylated, growth-inhibitory forms of pRb and led to G1 arrest. This latter was not observed in cells with genetic disruption of the Rb gene, indicating that thePC3-mediated G1 arrest was Rb dependent. Furthermore, (i) the arrest of G1-S transition exerted by PC3 was completely rescued by coexpression of cyclin D1 but not by that of cyclin A or E; (ii) expression of PC3 caused a significant down-regulation of cyclin D1 protein levels, also in Rb-defective cells, accompanied by inhibition of CDK4 activity in vivo; and (iii) the removal from the PC3 molecule of residues 50 to 68, a conserved domain of the PC3/BTG/Tob gene family, which we term GR, led to a loss of the inhibition of proliferation as well as of the down-regulation of cyclin D1 levels. These data point to cyclin D1 down-regulation as the main factor responsible for the growth inhibition by PC3. Such an effect was associated with a decrease of cyclin D1 transcript and of cyclin D1 promoter activity, whereas no effect of PC3 was observed on cyclin D1 protein stability. Taken together, these findings indicate that PC3 impairs G1-S transition by inhibiting pRb function in consequence of a reduction of cyclin D1 levels and that PC3 acts, either directly or indirectly, as a transcriptional regulator of cyclin D1.

Eukaryotic Initiation Factor-4E and Cyclin D1 Expression Associated with Patient Survival in Lung Cancer

2009 ◽  
Vol 10 (1) ◽  
pp. 58-66 ◽  
Author(s):  
Thaer Khoury ◽  
Sadir Alrawi ◽  
Nithva Ramnath ◽  
Qiang Li ◽  
Melissa Grimm ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cyclin D1 ◽  
Patient Survival ◽  
Initiation Factor ◽  
Eukaryotic Initiation Factor ◽  
Eukaryotic Initiation Factor 4E

scholarly journals Active Src Elevates the Expression of β-Catenin by Enhancement of Cap-Dependent Translation

2005 ◽  
Vol 25 (12) ◽  
pp. 5031-5039 ◽  
Author(s):  
Rotem Karni ◽  
Yael Gus ◽  
Yuval Dor ◽  
Oded Meyuhas ◽  
Alexander Levitzki
Keyword(s):  
Cyclin D1 ◽  
Cancer Cells ◽  
Transcriptional Activity ◽  
Wnt Pathway ◽  
Target Genes ◽  
Mtor Pathway ◽  
Initiation Factor ◽  
Erk Pathway ◽  
Eukaryotic Initiation Factor ◽  
Eukaryotic Initiation Factor 4E

ABSTRACT The proto-oncogene pp60c-Src (c-Src) is activated in many types of cancer and contributes to the transformed phenotype of the tumor, although its role is not yet fully understood. Here we report that active Src elevates the levels of β-catenin by enhancing cap-dependent translation. Src induces phosphorylation of the eukaryotic initiation factor 4E via the Ras/Raf/ERK pathway and the phosphorylation of its inhibitor 4E-BP1 via the PI3K/mTOR pathway. Activated Src enhances the accumulation of nuclear β-catenin and enhances its transcriptional activity, elevating target genes such as cyclin D1. This novel activation of the Wnt pathway by Src most probably contributes to the oncogenic phenotype of cancer cells.

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