| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Molecular Biology and Genetics |
Centre de Biologie du Développement, CNRS-UMR5547, Université Paul Sabatier, Bâtiment 4R3, 31062 Toulouse, Cedex 4 [A. G., D. M.]; Institut Claudius Régaud, INSERM E9910, 20 rue du Pont Saint Pierre, 31052 Toulouse [S. G.]; UPR CNRS 2163 and Service d’Anatomie et de Cytologie Pathologiques, Hôpital Purpan, 31059 Toulouse, Cedex [F. M., G. D.]; Institut de Pharmacologie et de Biologie Structurale, UMR 5089, 31062 Toulouse, Cedex [P. M.], France
 |
ABSTRACT |
|---|
 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
. The Tg line with the highest amount of Tg p37AUF1 protein developed sarcomas. The tumors strongly expressed AUF1 Tg protein and Cyclin D1. Taken together, our data show that: (a) AUF1 is a key regulatory factor of gene expression in vivo; and (b) the deregulation of this heterogeneous nuclear ribonucleoprotein leads to tumorigenesis. |
INTRODUCTION |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
), and cell cycle regulatory genes (cyclin A, B1, and D1, p21), is mainly controlled by modulation of their mRNA stability (1, 2, 3, 4, 5, 6, 7)
. This regulation is largely exerted through the interaction of RNA-binding proteins with the ARE contained in their 3' UTR. The list of mRNAs containing the ARE has considerably increased with genome sequencing programs, as attested by the recent construction of an ARE-containing mRNA database (8)
. AUF1/hnRNPD was the first purified protein shown to mediate ARE-directed mRNA degradation in vitro (9, 10, 11)
. Subsequently, other AUBPs were characterized, such as HuR, an ubiquitously expressed member of the ELAV family of ribonucleoproteins (12
, 13) , which enhances the stability of ARE-containing mRNA (5
, 6 , 14, 15, 16)
, and tristetraprolin, a member of a class of Cys-Cys-Cys-His zinc finger proteins, which promotes deadenylation and degradation of TNF and GM-CSF mRNAs (17
, 18)
. The mechanism(s) underlying AUBPs activities is the subject of intensive study. On the one hand, they rely on the nature of the ARE with which they interact. Indeed, AREs of different mRNAs vary in several aspects, such as their length, the proportion of uridylate residues, the number, and the distance between the AUUUA pentameric repeats. These characteristics, as well as the mechanisms through which they confer mRNA instability, have been the basis of their classification into three categories (2) . Thus, overlapping AUUUA repeats are found in the class II AREs, included in the 3' UTR of mRNAs encoding cytokines/lymphokines or inflammatory mediators, whereas these repeats are dispersed in class I AREs and absent in class III AREs (2) . On the other hand, the assembly of a protein complex on a given ARE is controlled not only by the relative abundance and affinity of the different AUBPs toward the ARE but also by their ability to elicit interactions with auxiliary proteins and form various complexes that might play different roles in mRNA fate, including localization, (de)stabilization, or translation. These characteristics vary depending on the type and functional state of the cell under analysis. This might be explained, at least in part, by the contribution of different signaling pathways, which have been shown to play an important role in stabilization of certain ARE-containing mRNAs (19, 20, 21, 22, 23, 24) or in the control of mRNA translation (25) .
Despite important information yielded by in vitro or ex vivo studies, these systems are limited in predicting AUBP biological functions. To reach this goal, we constructed Tg mice overexpressing AUF1. We chose the p37AUF1 isoform, one of the four AUF1 isoforms resulting from alternative pre-mRNA splicing (26 , 27) , because it has the strongest affinity for AREs in vitro (27) and the highest destabilizing effect on c-fos mRNA in K562 cells (10) . We also noticed previously that p37AUF1 is less abundant than the three other isoforms in different tissues throughout development (28 , 29) . Widespread Tg expression was ensured by the ubiquitously expressed ß-actin regulatory sequences. We show that in the three different Tg lines analyzed, p37AUF1 overexpression correlates with decreased or increased abundance of several ARE-containing mRNAs, depending on the class of ARE they contain. Concomitantly, an important lethality was observed in two of the three Tg lines, one of which developed sarcomas.
|
MATERIALS AND METHODS |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Proteins Extracts and Quantitative Western Blot Analysis.
Protein extracts and quantitative Western blot analysis were performed as described previously (29)
. The following antibodies were used: polyclonal rabbit anti-AUF1 antibody (1871; gift of G. Brewer) diluted 1/6000, monoclonal anti-AUF1 antibody (5B9; gift of G. Dreyfuss, Philadelphia, PA) diluted 1/1000, and monoclonal antihuman c-Myc antibody (9E10) diluted 1/600. The uniformity of loading was checked with the gelcode blue reagent (Pierce) and by performing parallel immunoblots using anti- actin antibodies (MAB1501; Chemicon).
Immunohistochemical Analysis.
Deparaffined sections (5 µm) of normal and pathological mouse tissue samples fixed in formol were stained with H&E or subjected to immunostaining. Tg expression in adult tissues and tumors was analyzed using the 9E10 antibody which reacts with myc tagged AUF1 protein. All tumors were also analyzed with a number of other antibodies, specific to or cross-reacting with mouse antigens, to determine the nature of undifferentiated tumors occurring in these animals. The panel for immunostaining included antibodies against high molecular weight cytokeratins (KL1; Immunotech, Marseille; dilution 1/50), muscle actin HHF35 (DAKO A/S; dilution 1/100), smooth muscle actin 1A5 (Immunotech; dilution 1/2), desmine (DAKO A/S; dilution 1/50), S100 protein (DAKO A/S; dilution 1/800), Neuron-Specific Enolase (DAKO A/S; dilution 1/150), lymphocyte-associated antigens, such as B (CD79a; DAKO A/S; dilution 1/10) and T (CD3; DAKO A/S; dilution 1/2), and mouse leukocyte common antigens (CD45R/B220; PharMingen; undiluted). Cyclin D1 was detected using DCS-6 (dilution 1/25) antibody from Novocastra. Immunostaining was revealed by the streptavidin-biotin-peroxidase complex method using DAKO StrepABComplex/HRP Duet (Mouse/Rabbit) Kit (code no. K0492; DAKO A/S), without prior trypsinization, as described elsewhere (32
, 33)
. When necessary, immunostaining on paraffin sections was performed using the method described by Shi et al. (34)
, with some modifications (32)
.
DNA Analysis.
The hypothesis that the tumors could have a T or B lymphoid origin was tested by a Southern blot analysis performed on DNA extracted from different tumors and tail of the same animal. The DNAs were EcoRI or PvuII restricted and probed with a DJ4 or TCR probe, respectively, which allows one to observe immunoglobulin heavy chain or TCR locus (35)
.
RNA Extraction and S1 Mapping Assay.
Total RNAs were extracted from different tissues of WT and Tg mice with the Trizol procedure following manufacturer’s instructions (Life Technologies, Inc.). S1 mapping analysis was performed as described previously (35)
. The AUF1 probe used to quantify Tg mRNAs corresponds to a 427-nt-long BamHI/BglII fragment, including the Myc tag and the first 183 nt of p37 AUF1 sequence. It hybridizes simultaneously to Tg 427-nt long and Endo 183-nt long p37 and p42 mRNAs. The two bands observed for Tg mRNAs (Fig. 3)
correspond to two alternative 3' splice sites, one located at the junction between ßactin intron 1 and exon 2 and the other one in the Myc Tag sequence. Because of the presence of a translation initiation site in each one of the five Myc epitopes, the myc-tagged AUF1 proteins synthesized from both mature mRNA species will differ only in the number of myc epitopes in their NH2-terminal part.
|
Ct values: 2-[(Ct sample gene X - Ct sample P0) - (Ct calibrator gene X - Ct calibrator P0)]
where Ct indicates the number of cycles when DNA amplification is 3-fold the baseline (in linear amplification phase), calibrator corresponds to one of the WT tissue sample.
Primers were chosen with the assistance of Primer Express (PE Applied Biosystems); their sequences are available on request.
cDNA synthesis: reverse transcription of total RNA was performed using Superscript II RNase H- reverse transcriptase (Life Technologies, Inc.) and random hexamer (250 ng of random hexamer were used for 2 µg of total RNA).
PCR amplification: PCR reactions were performed using a PE 5700 apparatus (PE Applied Biosystems) and the Syber Green master mix 2X (PE Applied Biosystems) with 300 nM each primer in 25 µl of final reaction volume. Each appropriate diluted reverse transcript sample (5 µl) was used per reaction. The thermal cycling conditions included an initial denaturation step (95°C for 10 min) and 40 cycles (95°C for 15 s; 60°C for 1 min). Experiments were performed in duplicates.
|
RESULTS |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
was based on three main considerations: (a) the p37 AUF1 cDNA was placed under the control of human ß-actin regulatory sequences (including the promoter, the first noncoding exon and the first intron) to drive Tg expression in a wide variety of tissues, as shown for other reporters (36
, 37)
; (b) a tag corresponding to five successive human c-Myc epitopes was fused in frame to the NH2 terminus of the p37AUF1 protein to discriminate between Tg and endogenous AUF1 expression and to follow the Tg cellular localization; and (c) the p37AUF1 cDNA was linked to the late SV40 3' UTR, including a polyadenylation site to avoid any possible post-transcriptional control of Tg expression via AUF1 3' UTR (38)
. Three different Tg lines, AUF1-1, -2, and -3, were derived (see "Materials and Methods"), which carried between 5 and 10 copies of the Tg in their genome, as revealed by Southern blot analysis (data not shown).
|
and data not shown). These results were supported by immunohistochemical analysis (data not shown).
|
None of the available AUF1 antibodies recognized the myc-tagged AUF1 protein in Western blot analysis, a situation sometimes encountered with myc-tagged proteins [see e.g., ß-Catenin (39)
and myc-tagged AUF14
]; thus, we estimated the level of Tg overexpression using an S1 nuclease protection assay with a probe hybridizing with both the Tg and the endogenous AUF1 mRNAs (see Fig. 3A
and "Materials and Methods"). Depending on the tissue and line considered, the level of accumulation of Tg mRNA was 2–20 times that of the sum of the endogenous p37 and p42 mRNAs, as illustrated for muscle cells in Fig. 3B
. This experiment also verified that Tg expression did not alter endogenous AUF1 expression (Fig. 3B
and 4A
). This result was confirmed by Western blot analysis showing that the quantity of the different p37, p40, p42, and p45 endogenous isoforms and their relative abundance was identical between Tg and WT protein extracts from various tissues (data not shown).
|
for class II; and c-jun for class III. These experiments were performed by RTQ RT-PCR using RNAs from WT and Tg tissues expressing high (brain, testis, or spleen) or low (muscle and liver) levels of endogenous AUF1 proteins (29)
. Except for a 2.8-fold increase in c-fos expression in the brain of AUF1–1 mice, we did not observe modification in the expression of the various representative ARE-mRNAs in tissues with high-endogenous AUF1 protein expression, in any AUF1 strain (data not shown). By contrast, in tissues with low levels of endogenous AUF1 protein and strong ß-actin promoter activity, such as the skeletal muscle, we observed, in all three Tg lines, a reproducible 2.5–7-fold increase of c-myc, c-fos, and c-jun mRNA (Fig. 5
, A and B), except c-fos in line AUF1–2. These values are certainly underestimated because their measure was realized from crude tissue extracts in which not 100% of the cells expressed the Tg, as mentioned above. By contrast, no significant modification of class II ARE-containing mRNAs was found (data not shown). We also noticed a 2–3-fold increase in the level of c-jun and c-myc mRNAs in the liver of AUF1–1 Tg mice, the only strain which expressed the Tg in this organ (Figs. 2
and 5D
). Overall, these results showed that AUF1 overexpression was able to increase the expression of class I and class III ARE-containing mRNA in vivo.
|
.
|
. This suggests a clonal origin of the tumor and a direct correlation between Tg expression and neoplasia. The staining was mostly in the nucleus of neoplastic cells although a weak cytoplasmic staining was also noted (Fig. 6, C and D
and data not shown). Except for S100 protein, which was found to be positive in a proportion of neoplastic cells, all of the other antibodies directed against muscle actin (HHF-35), vimentin, neurone-specific enolase, and cytokeratin were unreactive with neoplastic cells. A weak but significant staining of some cells was noted with anti- smooth muscle actin 1A5 antibody. Together with the lack of morphological features characteristic of an established category of malignant tumors, negative staining with a panel of specific antibodies led us to make the diagnosis of "undifferentiated sarcoma, possibly of smooth muscle cell origin."
Modulation of AUF1 Target mRNA Expression in Different Tissues of Mice Developing Tumors and in Tumors.
We analyzed by quantitative RT-PCR the level of expression of representative ARE-containing mRNAs in apparently normal tissues (heart, spleen, and liver) of sick or dead animals, as well as in their tumors. Because we observed previously a synchronous expression of AUF1 and HuR, we checked whether HuR level of expression could have been modified on p37AUF1 overexpression. However, we observed no change neither in the muscle of healthy Tg mice nor in the five tumors analyzed (from testis, neck, or bladder). Because most tumors were highly vascularized, we also studied VEGF expression, a class III ARE mRNA (8)
. However, we did not observe significant difference in VEGF mRNA level of expression between tumors and muscle (data not shown). By contrast, we noticed a 4- and 2-fold decrease in the level of expression of TNF and GM-CSF mRNAs, respectively, and a 2-fold increase in c-fos mRNA expression in the spleen of sick mice compared with the spleen of WT or healthy mice (Fig. 5E)
. In addition, c-myc expression was increased 2–3-fold in the heart (data not shown), and c-fos and c-jun mRNA expression was also considerably increased in the liver of tumor-bearing animals (mean of 12 and 7 times, respectively; Figs. 4B
and 5D
). This increase was directly correlated with a high AUF1 Tg mRNA expression. Indeed, as revealed by S1 nuclease analysis, the liver of the two animals analyzed in this experiment that developed tumors (F0 n° 1 and F2 n° 563), and contained high amounts of myc-tagged AUF1 mRNA, also abundantly expressed c-fos and c-jun mRNAs (Fig. 4, A and B)
.
Cyclin D1 overexpression has been described in various neoplasia (reviewed in Ref. 41
). Because cyclin D1 mRNA contains in its 3' UTR an ARE which could be a target for AUF1 (7)
, we quantified by RTQ RT-PCR analysis the level of cyclin D1 mRNA in the AUF1 tumors and observed a considerable increase (20–50-fold) in its expression compared with WT and AUF1–1 muscle (Fig. 5C)
. This increase was accompanied by a strong expression of Cyclin D1 protein, as revealed by immunostaining (Fig. 6, E and F)
. No comparable staining was observed on adjacent healthy tissue nor on other tissues of healthy Tg or WT mice (data not shown). This overexpression was not observed in healthy liver, spleen, and muscle of AUF1–1 Tg mice nor in hepatocarcinomas obtained in L-PK-c-myc Tg mice, which overexpressed c-myc in the livers (Fig. 5, C and D
and data not shown). Cyclin D1 overexpression in AUF1–1 tumors was not because of cyclin D1 gene rearrangement or deletion as revealed by Southern blot analysis using 5' and 3' cyclin D1 probes (data not shown).
|
DISCUSSION |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
AUF1/hnRNPD has been described ex vivo and in vitro as a protein able to bind to the AREs contained in the 3' UTR of a broad variety of functionally different mRNAs (40)
and participate in their destabilization (1
, 4
, 10
, 11
, 42, 43, 44)
. Therefore, it was surprising to observe that, in vivo, in various tissues of overexpressing AUF1 Tg mice, there is an increase in the level of accumulation of mRNAs containing either a class I ARE, such as c-fos and c-myc, or a class III ARE, like c-jun. The only mRNAs whose expression is significantly decreased are the GM-CSF and TNF, which both contain a class II ARE. The importance of the class II ARE in the control of mRNA stability in vivo has been demonstrated recently by the analysis of Tg mice in which the ARE of the TNF and GM-CSF was deleted (23
, 45)
. This deletion leads to an accumulation of TNF and GM-CSF mRNAs, which in turn results in immune disorders leading in the case of GM-CSF to embryonic death (45)
. The inverse correlation observed between the level of GM-CSF mRNA accumulation and that of AUF1 led to the postulate that AUF1 could play a major role in the control of GM-CSF mRNA level of expression (45)
. Our results indeed support this conclusion. It would now be interesting to test whether the destabilizing activity of AUF1 is restricted to GM-CSF and TNF or if it affects also other class II ARE-containing RNAs, such as those encoding interleukins, IFNs, or hematopoetic cell growth factors (8)
. These experiments are in progress.
Our results indicate that depending on the class of ARE, the level of p37AUF1 overexpression relative to the other isoforms and the abundance and/or activity of the auxiliary factors with which it interacts, AUF1 may act either as a stabilizing or a destabilizing factor. Several lines of evidence show a direct correlation between p37AUF1 overexpression and modulation of target mRNA expression: (a) the modulation is only observed in tissues where the Tg expression is high compared with endogenous AUF1; e.g., in muscle cells, where endogenous AUF1 expression is very low (29) and the ß-actin regulatory sequences are highly active, we found a significant and reproducible increase in the level of c-myc, c-fos, and c-jun mRNA expression; (b) this increase is independent of the Tg integration site as it is observed in the three independent Tg lines; (c) in the liver of AUF1 tumor-bearing animals, the higher expression of the tested target mRNAs correlates with the high level of p37AUF1 expression; and (d) finally, none of the modifications observed in Tg normal or tumoral tissues were found in WT tissues or in other models of tumors proved to have normal AUF1 expression. In effect, we did not find any modification of c-fos, c-jun, and cyclin D1 mRNA expression in the hepatocarcinoma obtained in L-PK-c-myc Tg mice, which constitutively express very high levels of c-myc in their liver (46) . Although we have not analyzed in depth the effect of AUF1 on target mRNA expression, we believe that it is likely post-transcriptional, because there are many reports showing that AUF1 is an RNA-binding protein affecting mRNA stability (1 , 4 , 9, 10, 11 , 42, 43, 44 , 47) .
Despite various types of investigations, the precise classification of the AUF1-associated tumors has proven to be difficult. Although we made the diagnosis of undifferentiated sarcoma, the weak staining for muscle-specific actin could indicate an undifferentiated leiomyosarcoma. This hypothesis is supported by the strong activity of the ß-actin regulatory sequences in muscle cells from which these tumors are supposed to develop and which exhibit a strong expression of the Tg.
In the AUF1 tumors, beside an accumulation of c-myc and c-fos mRNA similar to that found in the muscle, there is a considerable increase in cyclin D1 mRNA and protein expression. The correlation between overexpression of a key regulator of the G1 phase of the cell cycle and tumorigenesis has already been established not only in mouse mammary tumor virus-cyclin D1 Tg mice, which develop mammary adenocarcinomas (48) , but also in various human neoplasia, including breast cancers, malignant lymphomas, and chronic lymphocytic leukemia (reviewed in Ref. 41 ). In the latter malignancies, Cyclin D1 overexpression is associated with DNA rearrangement, corresponding either to a translocation, as documented in 40–70% of cases of mantle cell lymphomas (reviewed in Ref. 49 ), or a small deletion in the 3' UTR of cyclin D1 mRNA (50) . Interestingly, it was shown recently that this long 3' UTR contains a 390-base element that binds AUF1 (7) . We cannot formally exclude the hypothesis of a transcriptional up-regulation of cyclin D1 expression. However, because Cyclin D1 overexpression was detected in all tested AUF1 tumors, a clonal regulatory mutation is unlikely, and we favor the hypothesis of a trans-acting regulatory disturbance mediated by AUF1 overexpression. Accumulation of this cell regulator could favor rapid cell division, progressive loss of differentiation markers, and tumorigenesis.
An analysis of the human ARE-containing mRNA database suggests that the proportion of mRNAs with AREs could be as high as 8% (8) . Thus, there are many candidates for post-transcriptional regulation by AUF1. Using the p37AUF1 Tg mice, we have now shown for the first time that this heterogeneous nuclear ribonucleoprotein acts as a trans-acting factor in vivo and that its overexpression is associated with tumors. This Tg model thus constitutes an invaluable tool to identify which of the potential AUF1 target mRNAs are involved in physiological processes and/or in tumorigenesis.
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
1 Supported by ARC (Association pour la Recherche sur le Cancer) contract n° 9842, ARECA network "Pôle protéomique et Cancer," Conseil Régional, and CNRS. S. Grazide and A. Gouble are doctoral students supported by the ARC. 
2 To whom requests for reprints should be addressed, at Centre de Biologie du Développement, CNRS-UMR5547, Université Paul Sabatier, Bâtiment 4R3, 118 Route de Narbonne, 31062 Toulouse, Cedex 4, France. Phone: 33 5 61 55 64 73; Fax: 33 5 61 55 65 07; E-mail: morello{at}cict.fr.
3 The abbreviations used are: GM-CSF, granulocyte macrophage colony-stimulating factor; RT-PCR, reverse transcription-PCR; TCR, T-cell receptor; VEGF, vascular endothelial growth factor; TNF, tumor necrosis factor; ARE, adenylate uridylate-rich element; RTQ, real-time quantitative; WT, wild-type; UTR, untranslated region; Endo, endogeneous; AUBP, adenylate uridylate-rich element-RNA-binding proteins; Tg, transgene; HE, hematoxylin-eosin; hnRNPD, heterogeneous nuclear ribonucleoprotein D.
4 A-B. Shyu, personal communication.
Received 8/15/01. Accepted 1/ 3/02.
|
REFERENCES |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
mRNA. Mol. Cell. Biol., 19: 4311-4323, 1999.This article has been cited by other articles:
|
|
 |
|
  S. E. Brennan, Y. Kuwano, N. Alkharouf, P. J. Blackshear, M. Gorospe, and G. M. Wilson The mRNA-Destabilizing Protein Tristetraprolin Is Suppressed in Many Cancers, Altering Tumorigenic Phenotypes and Patient Prognosis Cancer Res., June 15, 2009; 69(12): 5168 - 5176. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Mazan-Mamczarz, Y. Kuwano, M. Zhan, E. J. White, J. L. Martindale, A. Lal, and M. Gorospe Identification of a signature motif in target mRNAs of RNA-binding protein AUF1 Nucleic Acids Res., January 1, 2009; 37(1): 204 - 214. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Mazan-Mamczarz, P. R. Hagner, B. Dai, W. H. Wood, Y. Zhang, K. G. Becker, Z. Liu, and R. B. Gartenhaus Identification of Transformation-Related Pathways in a Breast Epithelial Cell Model Using a Ribonomics Approach Cancer Res., October 1, 2008; 68(19): 7730 - 7735. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. H. Ing, D. A. Massuto, and L. A. Jaeger Estradiol Up-regulates AUF1p45 Binding to Stabilizing Regions within the 3'-Untranslated Region of Estrogen Receptor {alpha} mRNA J. Biol. Chem., January 18, 2008; 283(3): 1764 - 1772. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Torrisani, A. Unterberger, S. R. Tendulkar, K. Shikimi, and M. Szyf AUF1 Cell Cycle Variations Define Genomic DNA Methylation by Regulation of DNMT1 mRNA Stability Mol. Cell. Biol., January 1, 2007; 27(1): 395 - 410. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Paschoud, A. M. Dogar, C. Kuntz, B. Grisoni-Neupert, L. Richman, and L. C. Kuhn Destabilization of Interleukin-6 mRNA Requires a Putative RNA Stem-Loop Structure, an AU-Rich Element, and the RNA-Binding Protein AUF1 Mol. Cell. Biol., November 15, 2006; 26(22): 8228 - 8241. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. W. Morris ALK-mediated oncogenesis: mechanisms that matter Blood, October 15, 2006; 108(8): 2500 - 2501. [Full Text] [PDF]
|
|
|
|
|
|
M. Fawal, F. Armstrong, S. Ollier, H. Dupont, C. Touriol, B. Monsarrat, G. Delsol, B. Payrastre, and D. Morello A "liaison dangereuse" between AUF1/hnRNPD and the oncogenic tyrosine kinase NPM-ALK Blood, October 15, 2006; 108(8): 2780 - 2788. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Pullmann Jr., K. Abdelmohsen, A. Lal, J. L. Martindale, R. D. Ladner, and M. Gorospe Differential Stability of Thymidylate Synthase 3'-Untranslated Region Polymorphic Variants Regulated by AUF1 J. Biol. Chem., August 18, 2006; 281(33): 23456 - 23463. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Spence, B. M. Duggan, C. Eckhardt, M. McClelland, and D. Mercola Messenger RNAs under Differential Translational Control in Ki-ras-Transformed Cells Mol. Cancer Res., January 1, 2006; 4(1): 47 - 60. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Linker, A. Pautz, M. Fechir, T. Hubrich, J. Greeve, and H. Kleinert Involvement of KSRP in the post-transcriptional regulation of human iNOS expression-complex interplay of KSRP with TTP and HuR Nucleic Acids Res., August 26, 2005; 33(15): 4813 - 4827. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. D. Unwin, A. Pierce, R. B. Watson, D. W. Sternberg, and A. D. Whetton Quantitative Proteomic Analysis Using Isobaric Protein Tags Enables Rapid Comparison of Changes in Transcript and Protein Levels in Transformed Cells Mol. Cell. Proteomics, July 1, 2005; 4(7): 924 - 935. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Fechir, K. Linker, A. Pautz, T. Hubrich, U. Forstermann, F. Rodriguez-Pascual, and H. Kleinert Tristetraprolin Regulates the Expression of the Human Inducible Nitric-Oxide Synthase Gene Mol. Pharmacol., June 1, 2005; 67(6): 2148 - 2161. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Bonafe, M. Gilmore-Hebert, N. L. Folk, M. Azodi, Y. Zhou, and S. K. Chambers Glyceraldehyde-3-Phosphate Dehydrogenase Binds to the AU-Rich 3' Untranslated Region of Colony-Stimulating Factor-1 (CSF-1) Messenger RNA in Human Ovarian Cancer Cells: Possible Role in CSF-1 Posttranscriptional Regulation and Tumor Phenotype Cancer Res., May 1, 2005; 65(9): 3762 - 3771. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Pio, I. Zudaire, I. Pino, Z. Castano, N. Zabalegui, S. Vicent, F. Garcia-Amigot, M. D. Odero, M. D. Lozano, J. Garcia-Foncillas, et al. {alpha}CP-4, Encoded by a Putative Tumor Suppressor Gene at 3p21, But Not Its Alternative Splice Variant {alpha}CP-4a, Is Underexpressed in Lung Cancer Cancer Res., June 15, 2004; 64(12): 4171 - 4179. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-Y. Lu and R. J. Schneider Tissue Distribution of AU-rich mRNA-binding Proteins Involved in Regulation of mRNA Decay J. Biol. Chem., March 26, 2004; 279(13): 12974 - 12979. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. A. Dixon, G. C. Balch, N. Kedersha, P. Anderson, G. A. Zimmerman, R. D. Beauchamp, and S. M. Prescott Regulation of Cyclooxygenase-2 Expression by the Translational Silencer TIA-1 J. Exp. Med., August 4, 2003; 198(3): 475 - 481. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. B. Nabors, E. Suswam, Y. Huang, X. Yang, M. J. Johnson, and P. H. King Tumor Necrosis Factor {alpha} Induces Angiogenic Factor Up-Regulation in Malignant Glioma Cells: A Role for RNA Stabilization and HuR Cancer Res., July 15, 2003; 63(14): 4181 - 4187. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. E. Frevel, T. Bakheet, A. M. Silva, J. G. Hissong, K. S. A. Khabar, and B. R. G. Williams p38 Mitogen-Activated Protein Kinase-Dependent and -Independent Signaling of mRNA Stability of AU-Rich Element-Containing Transcripts Mol. Cell. Biol., January 15, 2003; 23(2): 425 - 436. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Bakheet, B. R. G. Williams, and K. S. A. Khabar ARED 2.0: an update of AU-rich element mRNA database Nucleic Acids Res., January 1, 2003; 31(1): 421 - 423. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
