Cancer Research Infection and Cancer: Biology, Therapeutics, and Prevention Tumor Immunology: New Perspectives
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
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Jin, W.
Right arrow Articles by Cote, G. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Jin, W.
Right arrow Articles by Cote, G. J.
[Cancer Research 60, 1221-1224, March 1, 2000]
© 2000 American Association for Cancer Research

Advances in Brief

Fibroblast Growth Factor Receptor-1 {alpha}-Exon Exclusion and Polypyrimidine Tract-binding Protein in Glioblastoma Multiforme Tumors1

Wei Jin, Ian E. McCutcheon, Gregory N. Fuller, Eileen S-C. Huang and Gilbert J. Cote2

Departments of Medical Specialties [W. J., E. S-C. H., G. J. C.], Neurosurgery [I. E. M.], and Pathology [G. N. F.], The University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results and Discussion
 REFERENCES
 
Neoplastictransformation of glial cells alters inclusion of the {alpha} exon in human fibroblast growth factor receptor-1 (FGFR-1) mRNA transcripts. Although normal cells predominantly include the {alpha} exon, this exon is excluded in most glioblastoma cell transcripts, creating a high-affinity receptor form. In this study, we identified polypyrimidine tract-binding protein (PTB) as a regulator of FGFR-1 splicing. PTB interacted in a sequence-specific manner with the ISS-1 regulatory element in the intron upstream of the {alpha} exon. PTB expression was also strongly increased in seven malignant glioblastoma multiforme tumors relative to adjacent normal tissue, but not in a low-grade astrocytoma. These results suggest that increased expression of PTB may contribute to glial cell malignancy.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results and Discussion
 REFERENCES
 
Alternative recognition of the {alpha} exon during processing of FGFR-13 RNA produces receptor forms that vary in their affinity for fibroblast growth factor (1 , 2) . Because FGFR-1 plays a primary role in many cell growth and differentiation pathways, precise regulation of its RNA splicing is critical. However, normal recognition of the {alpha} exon is altered during the malignant progression of glial cells, producing a receptor form lacking the {alpha} exon and with enhanced affinity for fibroblast growth factor (3 , 4) . Expression of this form of FGFR-1 in glial cells is believed to provide a cell-growth advantage and possibly to contribute to glial cell malignancy (3) . Using a cell culture model, we previously identified two intronic RNA sequences flanking the {alpha} exon, ISS-1 and ISS-2, that are required for glioblastoma cell-specific FGFR-1 RNA splicing (5 , 6) . Deletion or mutation of either of these elements reverses the splicing phenotype observed in glioblastoma cells so that the FGFR-1 mRNA includes the {alpha} exon. In this study, we found that the trans-acting factor PTB specifically bound to the upstream element ISS-1 and was overexpressed in patient glioblastomas, suggesting that PTB may regulate glioblastoma-specific FGFR-1 RNA splicing.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results and Discussion
 REFERENCES
 
Cell Culture and Tissue Specimens.
The human astrocytoma cell line SNB-19 and the human choriocarcinoma cell line JEG-3 were maintained as described previously (7) . Tissue samples were obtained from 10 patients who underwent therapeutic removal of primary or recurrent brain tumors at M. D. Anderson Cancer Center. Histopathological examination showed the samples to be glioblastoma multiforme (n = 7), anaplastic astrocytoma (n = 1), or low-grade astrocytoma (n = 1). One patient with a prior history of oligodendroglioma had radionecrosis when a lesion mimicking a tumor was resected. Tissue samples were obtained from white matter adjacent to each tumor and deemed normal based on gross histological appearance.

Plasmid Constructs.
The plasmid constructs pFGFR-17, pFGFR-D1, pFGFR-M2, and pFGFR-M4 have been described previously (5) . The plasmid constructs used for UV cross-linking were obtained by the TA cloning of inserts into the vector pGEMT Easy according to manufacturer’s protocol (Promega Corp., Madison, WI). The inserts were created by PCR amplification of pFGFR-17, pFGFR-M2, and pFGFR-M4, using primers FP109 (5'-GGAAATGAGGGCCCATCCGCTT-3') and FP110 (5'-CCTCCAAAAAGTCAAAGG-3'). The final constructs, pFGFR-67, pFGFR-68, and pFGFR-69, respectively, were obtained by an ApaI digestion and religation to remove the multilinker sequences. The ligation sites of plasmid constructs were sequenced to confirm the identity of each clone.

RNA Isolation and RT-PCR.
The transfection of cell lines, RNA isolation, and RT-PCR analysis were performed as described previously (7) . Total RNA was isolated from ~100 mg of normal and tumor tissue by sonication in Catrimox-14 (Qiagen, Chatworth, CA) as described previously (8) . Because of the presence of nonspecific amplification bands, the RT-PCR protocol used to amplify tissue-derived RNA was modified from a previously described procedure to include two amplification steps (9) . Briefly, reverse transcription was performed with the FGFR-1-specific primer Endo-R using 5 µg of total RNA in a 20-µl reaction volume. A first round of 11 cycles of PCR (1 min at 94°C, 1 min at 55°C, and 2 min at 72°C) was performed with 10 µl of the cDNA and the primers Endo-F and Endo-R (9) in a final volume of 50 µl. This was followed by a second round of 17 cycles of PCR (1 min at 94°C, 1 min at 66°C, and 2 min at 72°C) with 0.1 µl of the first-round PCR mixture and primers FP183 (5'-CTTCTGGGCTGTGCTGGTCA-3') and a mixture of unlabeled plus 0.08 pmol of 32P end-labeled FP184 primer (5'-TCTTTTCTGGGGATGTCCAA-3'). A single pair of RNA samples (Fig. 3Citation , Lanes 5 and 6) failed to amplify under these conditions and required 1 µl of the first-round PCR mixture. These RT-PCR conditions were found to be within the linear amplification range for RNA isolated from SNB-19 and JEG-3 cell lines (data not shown).



View larger version (102K):
[in this window]
[in a new window]
  		Fig. 3. Western analysis of PTB expression in human brain samples (top two panels). Total cellular protein was prepared from tumor (T) and adjacent normal (N) tissue obtained from patients diagnosed with low-grade astrocytoma (LGA), anaplastic astrocytoma (AA), or glioblastoma multiforme (GBM). One patient with a prior history of oligodendroglioma (Rec), had radionecrosis with a lesion mimicking a tumor (R). Western analysis was performed as described in "Materials and Methods" using ~50 µg of protein in each lane. Actin antibody was included with the PTB antibody during the primary incubation to provide an additional control for protein sample integrity and loading. RT-PCR analysis of FGFR-1 transcripts was performed on total RNA isolated from the tissue pairs in the middle panel as described in "Materials and Methods" (bottom panel). Arrows indicate the {alpha}-exon inclusion (I) and exclusion (E) products.

 
UV Cross-Linking and Immunoprecipitation.
In preliminary experiments, nuclear extracts from SNB-19 and JEG-3 cells were prepared using the small-scale preparation method of Lee et al. (10) . However, we then determined that the JEG-3 cell line had high endogenous protease activity and switched to a protocol described by Dyer and Herzog (11) . The JEG-3 cells were grown in monolayer culture to ~80% confluence for extract preparation. Proteolysis was inhibited by the addition of 5 mM DTT, 1 mM phenylmethylsulfonyl fluoride, 10 µg/ml leupeptin, 2 µg/ml aprotinin, and 1 µM pepstatin to the lysis, wash, and extraction buffers. The final protein concentration of the nuclear extracts ranged from 2 to 6 mg/ml. The UV cross-linking experiments were performed using in vitro splicing conditions described previously (12) . Capped RNA transcripts were prepared from EcoRI-digested pFGFR-67, -68, or -69 (Fig. 2Citation , WT, M2, and M4, respectively). The 32P[UTP]-labeled RNA transcripts were incubated with 30% cell nuclear extract, 1% polyethylene glycol, 0.625 mM ATP, 25 mM creatine phosphate, 1 mM MgCl2 and 20% buffer D at 30°C for 10 min. For competition assays, unlabeled RNA was incubated with the splicing mixture for 10 min on ice before the addition of labeled RNA. After RNase treatment, the UV cross-linked RNA/protein complexes were immunoprecipitated with the PTB-specific monoclonal antibody DH3 (a gift from David Helfman, Cold Spring Harbor Laboratories) as described previously (13 , 14) .



View larger version (43K):
[in this window]
[in a new window]
  		Fig. 2. PTB specifically bound ISS-1. A, UV cross-linking of SNB-19 and JEG-3 cell nuclear extract to labeled wild-type (WT), M2 mutant, or M4 mutant probes (see "Materials and Methods" and Fig. 1Citation B). B, UV cross-linking to wild-type probe was performed with SNB-19 cell nuclear extract that was preincubated with increasing amounts (20-, 50-, 100-, and 175-fold molar excesses) of unlabeled self competitor or with M2 mutant competitor. Cross-linking in the absence of competitor (NC) served as a control. C, immunoprecipitation (IP) with PTB antibody or antimouse immunoglobulin antibody (Ig) after UV cross-linking of SNB-19 cell nuclear extract to wild-type (WT) and M2 mutant RNA. Total UV cross-linking of SNB-19 cell nuclear extract is provided as a control (T). In A and B, masses of molecular markers are on the left.

 
Western Blot Analysis.
Protein extracts were prepared by sonicating tissue in lysis buffer containing 50 mM HEPES (pH 7.0), 150 mM NaCl, 1.5 mM MgCl2, 1 mM EGTA, 100 mM NaF, 10 mM sodium PPi, 1 mM sodium orthovanadate, 10% glycerol, 1 mM phenylmethylsulfonyl fluoride, 10 µg/ml aprotinin, and 1% Triton X-100. The protein concentration was determined using the dye-based Bio-Rad Protein Assay. Proteins (50 µg/lane) were separated on 10% (v/v) polyacrylamide gels containing 0.1% SDS and transferred to nitrocellulose membrane; antigens were detected using an ECL kit (Amersham Life Sciences, Arlington Heights, IL) with monoclonal antibody against PTB (diluted 1:200) and actin (diluted 1:3000; Amersham Life Sciences).


   Results and Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results and Discussion
REFERENCES
 
Failure to include the {alpha} exon during processing of the FGFR-1 primary transcript has been correlated with glial cell malignancy (3) . Our DNA sequence analysis of the FGFR-1 gene and studies of cell-culture models of {alpha} exon splicing suggested that changes in the expression of trans-acting factors cause this aberrant RNA splicing (9) . We previously identified a series of RNA sequence elements that are required to maintain regulated FGFR-1 splicing in a cell culture model system that mimics the patterns observed in normal brain glial cells and glioblastomas (9) . The reporter construct (pFGFR-17) contains a 3.8-kb fragment of the FGFR-1 genomic sequence inserted into intron 1 of the human metallothionein IIA gene (Fig. 1A)Citation . In RNA transcripts derived from pFGFR-17, the {alpha} exon was included in a cell-specific manner: the exon was predominantly excluded (71%) in the glioblastoma cell line SNB-19, but predominantly included in JEG-3 cells (83%; Fig. 1BCitation ). Two intronic sequences flanking the {alpha} exon, ISS-1 and ISS-2, inhibit {alpha}-exon inclusion in SNB-19 cells (5 , 6) . The ISS-1 element was mapped by the deletion construct, pFGFR-D1, to a 40-nt sequence 241 nt upstream of the {alpha} exon. The deletion of this short sequence had a dramatic effect on exon inclusion in SNB-19 cells, increasing it from 29% to 70%, with little effect on exon inclusion in JEG-3 cells (83% versus 86%; Fig. 1BCitation ). Within this 40-nt region are two YUGCYYYY elements that resemble the regulatory sequences found to inhibit exon recognition in the {alpha}-tropomyosin gene (15 , 16) . These sequences were mutated to determine whether they played a similar role in {alpha}-exon recognition. Mutation of the first element to create pFGFR-M2 increased {alpha}-exon inclusion to a level similar to that of pFGFR-D1, whereas mutation of the second element (pFGFR-M4) only partially increased inclusion. Both mutations had only a small effect on splicing in JEG-3 cells (Fig. 1B)Citation .



View larger version (35K):
[in this window]
[in a new window]
  		Fig. 1. Inhibition of {alpha}-exon inclusion in SNB-19 cells was mediated through the ISS-1 element. A, the pFGFR-17 splicing construct and the cell-specific RNA splicing pathways. The FGFR-1 genomic sequence was inserted into intron 1 of the human metallothionein IIA gene. The numbers indicate the lengths of the exons and introns in bp. The positions of the oligonucleotide primers and the sizes of the RT-PCR products are indicated. RSV, Rous sarcoma virus promoter. B, examination of {alpha}-exon inclusion in RNA isolated from transfected cells. The specific deletions (-) and mutations (uppercase letters) in the constructs containing modifications of the ISS-1 element are depicted on the right. A representative autoradiograph is shown on the left; arrows indicate the RT-PCR products that include (I) or exclude (E) the {alpha} exon. The percentages of {alpha}-exon inclusion ± the SD were derived from phosphor counts from three independent transfections.

 
To identify factors associated with ISS-1, we performed UV cross-linking experiments. The RNA probes used all contain the core 40-nt region and 28 additional nt of flanking sequence (see "Materials and Methods"). Both SNB-19 and JEG-3 extracts were capable of forming splicing complexes on an adenovirus substrate (Ref. 17 , and data not shown). Several proteins were found to UV cross-link to the wild-type sequence in both SNB-19 and JEG-3 extracts (Fig. 2A)Citation . Prominent bands of ~40, 44, and 60 kDa were observed in both extracts, and additional ~50- and 130-kDa bands were specific to JEG-3 cells. Introduction of the M2 or M4 mutations into the RNA probe reduced the cross-linking of the 60-kDa protein to both SNB-19 and JEG-3 nuclear extracts, but the reduction was consistently greater in SNB-19 extract (Fig. 2ACitation , and data not shown). No reduction in the cross-linking of other major bands was observed, but additional proteins were seen to bind the mutant RNA. To examine the specificity of the 60-kDa binding protein, we performed competition experiments with SNB-19 extract (Fig. 2B)Citation . The wild-type but not the M2 sequence was able to specifically compete for binding with the 60-kDa protein, whereas the wild-type and mutant sequences competed equally for binding with the other proteins (Fig. 2B)Citation .

The UV cross-linking results provided evidence that a 60-kDa protein interacts specifically with the ISS-1 regulatory region. The protein’s molecular mass and proposed role as a splicing inhibitor suggested that the protein might be PTB (18 , 19) . PTB has been shown to mediate exon skipping for a growing number of mammalian genes, including GABAA receptor {gamma}2, c-src, fibronectin, and {alpha}- and ß-tropomyosin (15 , 16 , 18 , 19) . To test whether the 60-kDa protein is PTB, we immunoprecipitated UV cross-linked complexes with PTB antibody (a generous gift from David Helfman). The 60-kDa UV cross-linked protein was indeed precipitated by PTB antibody (Fig. 2C)Citation . As observed previously, significantly more protein was associated with the wild-type sequence than with the M2 mutant RNA. No immunoprecipitated protein was seen when a control antibody was used (Fig. 2C)Citation .

Our results clearly demonstrated that PTB can specifically bind to the 40-nt ISS-1 regulatory element, although in vitro binding was not cell specific. This raises questions about the in vivo function of PTB. To better address whether PTB plays a role in the dysregulation of FGFR-1 splicing in glioblastomas, we examined the expression of PTB in a series of graded brain tumors. Total cellular protein was prepared from tumor and adjacent normal tissue obtained from patients diagnosed with low-grade astrocytoma, anaplastic astrocytoma, or glioblastoma multiforme. These data clearly indicated that the level of PTB was significantly elevated in tumor samples relative to adjacent normal tissue in all seven glioblastoma multiforme patients (Fig. 3)Citation . Elevated PTB expression was also observed in the single patient with anaplastic astrocytoma, but not in a patient with low-grade astrocytoma. The level of PTB expression in normal brain varied between patient samples and may reflect infiltration of tumor cells. One patient with a prior history of oligodendroglioma was found to have radionecrosis with a lesion mimicking a tumor. Interestingly, no difference was seen in the level of PTB expression in the tissues obtained from this patient.

To correlate PTB expression with {alpha}-exon skipping, we examined FGFR-1 splicing in tissues from which sufficient sample was available to isolate RNA (Fig. 3)Citation . As reported previously (3) , we found a high level of {alpha}-exon exclusion (~70–90%) in the RNA samples from glioblastomas. In normal tissue, the level of FGFR-1 expression was consistently lower than in the tumor samples, but the methodology used did not allow us to directly quantitate these differences. However, the level of {alpha}-exon inclusion in normal tissue was clearly higher (~30–55%) than that observed in tumor samples. Therefore, elevated PTB expression correlated with {alpha}-exon exclusion in tumors. In normal tissues, however, the relationship was less clear. Decreased levels of PTB correlated with increased {alpha}-exon inclusion. However, normal samples expressing high PTB levels did not necessarily have high levels of {alpha}-exon exclusion. This may reflect differences in the cell composition of the normal tissue or may indicate that additional factors are involved in the regulation of FGFR-1 {alpha}-exon splicing. Tumor cells and gray matter express significantly higher levels of FGFR-1 than does normal white matter (3) , and contamination with these cells types could contribute to an artificially high level of exon skipping. Alternatively, the observed increase in PTB expression in glioblastomas may be coupled with a loss of factors required for {alpha}-exon inclusion. We previously have reported the identification of exonic sequences that are required for {alpha}-exon inclusion in JEG-3 cells (7) . The UV cross-linking results suggest that in JEG-3 cells, an inclusion pathway may be the dominant splicing pathway or that PTB alone is not sufficient to cause {alpha}-exon skipping. However, it is clear from this study that PTB interacts with the ISS-1, an element required for {alpha}-exon skipping, and that PTB protein levels are markedly elevated in glioblastomas. Given the ability of PTB to affect RNA processing decisions, our results suggest that in addition to FGFR-1, a number of other pre-mRNAs may undergo changes in alternative splicing during the early and intermediate stages of brain cancer.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported by Public Health Service Grant CA-67946 awarded to G. J. C. by the National Cancer Institute. Back

2 To whom requests for reprints should be addressed, at Section of Endocrine Neoplasia and Hormonal Disorders, Box 015, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: (713) 792-2840; Fax: (713) 794-4065; E-mail: gcote{at}mdanderson.org Back

3 The abbreviations used are: FGFR-1, fibroblast growth factor receptor-1; PTB, polypyrimidine tract-binding protein; RT-PCR, reverse transcription-PCR; nt, nucleotide. Back

Received 10/29/99. Accepted 1/17/00.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results and Discussion
 REFERENCES
 

  1. Galzie Z., Kinsella A. R., Smith J. A. Fibroblast growth factors and their receptors. Biochem. Cell Biol., 75: 669-685, 1997.[Medline]
  2. McKeehan W. L., Wang F., Kan M. The heparan sulfate-fibroblast growth factor family: diversity of structure and function. Prog. Nucleic Acid Res. Mol. Biol., 59: 135-176, 1998.[Medline]
  3. Yamaguchi F., Saya H., Bruner J., Morrison R. S. Differential expression of two fibroblast growth factor-receptor genes is associated with malignant progression in human astrocytomas. Proc. Natl. Acad. Sci. USA, 91: 484-488, 1994.[Abstract/Free Full Text]
  4. Wang F., Kan M., Yan G., Xu J., McKeehan W. L. Alternately spliced NH2-terminal immunoglobulin-like loop I in the ectodomain of the fibroblast growth factor (FGF) receptor 1 lowers affinity for both heparin and FGF-1. J. Biol. Chem., 270: 10231-10235, 1995.[Abstract/Free Full Text]
  5. Jin W., Huang E. S-C., Bi W., Cote G. J. Redundant intronic repressors function to inhibit fibroblast growth factor receptor-1 {alpha}-exon recognition in glioblastoma cells. J. Biol. Chem., 274: 28035-28041, 1999.[Abstract/Free Full Text]
  6. Jin W., Bi W., Huang E. S-C., Cote G. J. Glioblastoma cell-specific expression of fibroblast growth factor-b requires an intronic repressor of RNA splicing. Cancer Res., 59: 316-319, 1999.[Abstract/Free Full Text]
  7. Jin W., Huang E. S-C., Bi W., Cote G. J. Exon sequence is required for regulated RNA splicing of the human fibroblast growth factor receptor-1 {alpha} exon. J. Biol. Chem., 273: 16170-16176, 1998.[Abstract/Free Full Text]
  8. Dahle C. E., Macfarlane D. E. Isolating RNA with the cationic surfactant, Catrimox-14. Methods Mol. Biol., 86: 19-21, 1998.[Medline]
  9. Cote G. J., Huang E. S-C., Jin W., Morrison R. S. Sequence requirements for regulated RNA splicing of the human fibroblast growth factor receptor-1 {alpha} exon. J. Biol. Chem., 272: 1054-1060, 1997.[Abstract/Free Full Text]
  10. Lee K. A., Bindereif A., Green M. R. A small-scale procedure for preparation of nuclear extracts that support efficient transcription and pre-mRNA splicing. Gene Anal. Tech., 5: 22-31, 1988.[Medline]
  11. Dyer R. B., Herzog N. K. Isolation of intact nuclei for nuclear extract preparation from a fragile B-lymphocyte cell line. Biotechniques, 19: 192-195, 1995.[Medline]
  12. Philips A. V., Timchenko L. T., Cooper T. A. Disruption of splicing regulated by a CUG-binding protein in myotonic dystrophy. Science (Washington DC), 280: 737-741, 1998.[Abstract/Free Full Text]
  13. Grossman J. S., Meyer M. I., Wang Y. C., Mulligan G. J., Kobayashi R., Helfman D. M. The use of antibodies to the polypyrimidine tract binding protein (PTB) to analyze the protein components that assemble on alternatively spliced pre-mRNAs that use distant branch points. RNA (NY), 4: 613-625, 1998.[Abstract]
  14. Lou H., Helfman D. M., Gagel R. F., Berget S. M. Polypyrimidine tract-binding protein positively regulates inclusion of an alternative 3'-terminal exon. Mol. Cell. Biol., 19: 78-85, 1999.[Abstract/Free Full Text]
  15. Perez I., Lin C-H., McAfee J. G., Patton J. G. Mutation of the PTB binding sites causes misregulation of alternative 3' splice site selection in vivo. RNA (NY), 3: 764-778, 1997.[Abstract]
  16. Gooding C., Roberts G. C., Smith C. W. J. Role of an inhibitory element and pyrimidine tract binding protein in repression of a regulated {alpha}-tropomyosin exon. RNA (NY), 4: 85-100, 1998.[Abstract]
  17. Robberson B. L., Cote G. J., Berget S. M. Exon definition may facilitate splice site selection in multiexon RNAs. Mol. Cell. Biol., 10: 84-94, 1990.[Abstract/Free Full Text]
  18. Lopez A. J. Alternative splicing of pre-mRNA: developmental consequences and mechanisms of regulation. Annu. Rev. Genet., 32: 279-305, 1998.[Medline]
  19. Valcarcel J., Gebauer F. Post-transcriptional regulation: the dawn of PTB. Curr. Biol., 7: R705-R708, 1997.[Medline]



This article has been cited by other articles:


Home page
 J. Biol. Chem.Home page
C. Wang, J. T. Norton, S. Ghosh, J. Kim, K. Fushimi, J. Y. Wu, M. S. Stack, and S. Huang
Polypyrimidine Tract-binding Protein (PTB) Differentially Affects Malignancy in a Cell Line-dependent Manner
J. Biol. Chem., July 18, 2008; 283(29): 20277 - 20287.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
Y. Yu, X. Jiang, B. S. Schoch, R. S. Carroll, P. M. Black, and M. D. Johnson
Aberrant Splicing of Cyclin-Dependent Kinase-Associated Protein Phosphatase KAP Increases Proliferation and Migration in Glioblastoma
Cancer Res., January 1, 2007; 67(1): 130 - 138.
[Abstract] [Full Text] [PDF]

Home page
 Genome Res.Home page
I. A. Swinburne, C. A. Meyer, X. S. Liu, P. A. Silver, and A. S. Brodsky
Genomic localization of RNA binding proteins reveals links between pre-mRNA processing and transcription
Genome Res., July 1, 2006; 16(7): 912 - 921.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
D. Garneau, T. Revil, J.-F. Fisette, and B. Chabot
Heterogeneous Nuclear Ribonucleoprotein F/H Proteins Modulate the Alternative Splicing of the Apoptotic Mediator Bcl-x
J. Biol. Chem., June 17, 2005; 280(24): 22641 - 22650.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
S. W. Song, G. N. Fuller, H. Zheng, and W. Zhang
Inactivation of the Invasion Inhibitory Gene IIp45 by Alternative Splicing in Gliomas
Cancer Res., May 1, 2005; 65(9): 3562 - 3567.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
W. Jin and G. J. Cote
Enhancer-Dependent Splicing of FGFR1 {alpha}-Exon Is Repressed by RNA Interference-Mediated Down-Regulation of SRp55
Cancer Res., December 15, 2004; 64(24): 8901 - 8905.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
I. G. Bruno, W. Jin, and G. J. Cote
Correction of aberrant FGFR1 alternative RNA splicing through targeting of intronic regulatory elements
Hum. Mol. Genet., October 1, 2004; 13(20): 2409 - 2420.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
X. He, P. L. R. Ee, J. S. Coon, and W. T. Beck
Alternative Splicing of the Multidrug Resistance Protein 1/ATP Binding Cassette Transporter Subfamily Gene in Ovarian Cancer Creates Functional Splice Variants and Is Associated with Increased Expression of the Splicing Factors PTB and SRp20
Clin. Cancer Res., July 15, 2004; 10(14): 4652 - 4660.
[Abstract] [Full Text] [PDF]

Home page
 Neuro OncolHome page
I. E. McCutcheon, S. J. Hentschel, G. N. Fuller, W. Jin, and G. J. Cote
Expression of the splicing regulator polypyrimidine tract-binding protein in normal and neoplastic brain
Neuro-oncol, January 1, 2004; 6(1): 9 - 14.
[Abstract] [PDF]

Home page
 Cancer Res.Home page
W. Jin, I. G. Bruno, T.-X. Xie, L. J. Sanger, and G. J. Cote
Polypyrimidine Tract-Binding Protein Down-Regulates Fibroblast Growth Factor Receptor 1 {alpha}-Exon Inclusion
Cancer Res., October 1, 2003; 63(19): 6154 - 6157.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
L. Wang, L. Duke, P. S. Zhang, R. B. Arlinghaus, W. F. Symmans, A. Sahin, R. Mendez, and J. L. Dai
Alternative Splicing Disrupts a Nuclear Localization Signal in Spleen Tyrosine Kinase That Is Required for Invasion Suppression in Breast Cancer
Cancer Res., August 1, 2003; 63(15): 4724 - 4730.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
C. Gooding, P. Kemp, and C. W. J. Smith
A Novel Polypyrimidine Tract-binding Protein Paralog Expressed in Smooth Muscle Cells
J. Biol. Chem., April 18, 2003; 278(17): 15201 - 15207.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
E. Miriami, H. Margalit, and R. Sperling
Conserved sequence elements associated with exon skipping
Nucleic Acids Res., April 1, 2003; 31(7): 1974 - 1983.
[Abstract] [Full Text] [PDF]

Home page
 Genes Dev.Home page
N. A. Faustino and T. A. Cooper
Pre-mRNA splicing and human disease
Genes & Dev., February 15, 2003; 17(4): 419 - 437.
[Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
S. J. Muh, R. H. Hovhannisyan, and R. P. Carstens
A Non-sequence-specific Double-stranded RNA Structural Element Regulates Splicing of Two Mutually Exclusive Exons of Fibroblast Growth Factor Receptor 2 (FGFR2)
J. Biol. Chem., December 13, 2002; 277(51): 50143 - 50154.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
X. Yuan, N. Davydova, M. R. Conte, S. Curry, and S. Matthews
Chemical shift mapping of RNA interactions with the polypyrimidine tract binding protein
Nucleic Acids Res., January 15, 2002; 30(2): 456 - 462.
[Abstract] [Full Text] [PDF]

Home page
 Sci SignalHome page
T. A. Cooper
Highlights of Alternative Splicing Regulation Session: Yes, No, Maybe--A History of Paradigm Shifts
Sci. Signal., October 23, 2001; 2001(105): pe35 - pe35.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Jin, W.
Right arrow Articles by Cote, G. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Jin, W.
Right arrow Articles by Cote, G. J.

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