| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Advances in Brief |
Centro Medicina Nucleare, Consiglio Nazionale delle Ricerche, Dipartimento di Scienze Biomorfologiche e Funzionali, Università "Federico II", 80131 Naples [A. Z., S. D. V., R. F., M. S.]; Istituto Nazionale per lo Studio e la Cura dei Tumori, 80131 Naples [M. V. C., G. B., G. D.]; and Istituto Internazionale di Genetica e Biofisica, 80125 Naples [P. F., M. P. S.], Italy
 |
ABSTRACT |
|---|
 Top ABSTRACT IntroductionMaterials and MethodsResultsDiscussionREFERENCES |
|---|
|
Introduction |
|---|
|
TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
|---|
The uPAR is a highly glycosylated Mr 55,000–60,000 glycosylphosphatidylinositol-anchored protein that comprises three structural domains including the NH2-terminal uPA -binding site (3) . Many malignant cultured cell lines and human neoplasms have been characterized by their increased uPA and uPAR expression (4) . Accordingly, high levels of uPA and uPAR in malignant tumors are reported to be significantly associated to a poor prognosis, which suggests that the inhibition of uPAR activity could be a promising strategy to prevent cancer invasion and metastasis (5) .
In a previous study (6) , we reported a coordinate overexpression of uPA and uPAR in breast carcinomas leading to a net enhancement of cell invasiveness. This finding raises an interesting question concerning the mechanisms responsible for the modulation of uPAR expression, which is also controlled by a variety of hormones and growth factors (4) .
Soravia et al. (7) recently identified a minimal promoter region required for the basal transcription of the human uPAR gene. This region lacks TATA and CAAT boxes and contains GC-rich proximal sequences that are specifically bound by the transcription factor Sp1. The uPAR gene is transcriptionally regulated by Src activity via an upstream sequence (-152/-135) bound with Sp1 (8) . The transcription factor Sp1 is a member of the C2-H2 zinc finger family, which acts in the absence of TATA boxes and regulates the transcription of a wide variety of different genes including those involved in general cellular metabolism such as the housekeeping genes (9) and a number of growth factor and growth factor receptor genes (10 , 11) . Traditionally considered as a constitutive transcription factor, it is becoming increasingly clear that Sp1 activity may be induced by many oncoproteins such as v-Rel, v-Ras, v-Src, c-Fes, and the human retinoblastoma gene product (12, 13, 14) . Furthermore, Sp1 -binding activity is decreased by phosphorylation (15) , whereas it is increased by dephosphorylation mediated by protein phosphatase 1 (16) .
Despite the proven ability of Sp1 to regulate the transcriptional
activity of a variety of genes involved in cell differentiation and
proliferation (17
, 18)
, little is known about its role in
tumor growth and progression. High levels of Sp1 have been reported in
human gastric carcinomas (19)
, and a coordinate
overexpression of Sp1 and laminin-
1 was found in human
hepatocellular carcinomas (20)
.
In an effort to identify the transcriptional activators involved in the regulation of uPAR, we investigated whether there is a relationship between uPAR expression and Sp1 activity in invasive breast carcinomas. Therefore, we determined the levels of uPAR and the DNA -binding activity of Sp1 in 4 malignant tumor cell lines, 14 breast carcinomas, and 5 benign breast lesions. In addition, the ability of uPA or its catalytically inactive ATF to regulate both uPAR levels and Sp1 activity was tested in MDA-MB-231 and MCF-7 mammary carcinoma cell lines.
|
Materials and Methods |
|---|
|
TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
|---|
Patients and Tissue Samples.
Fourteen patients with breast carcinoma (mean age, 68 ± 13 years) and 5 with benign breast lesions (mean age, 43 ± 16 years) were studied. Malignant tumors included nine invasive
ductal carcinomas, four invasive lobular carcinomas, and one
duct-lobular carcinoma with a diameter ranging between 1.7 and 5 cm.
The benign lesions included three fibroadenomas and two fibrocystic
diseases. Tumor biopsy specimens were immediately frozen in liquid
nitrogen after surgical removal and stored at -80°C.
Nuclear Extracts from Cells and Tissues.
Nuclear extracts were prepared according to the method of Dignam
et al. (22)
. Briefly, cells were washed in cold
PBS and collected by centrifugation. The cell pellet was resuspended in
10 mM HEPES (pH 7.9), 1.5
mM MgCl2, 10
mM KCl, 0.5 mM DTT, and 0.1
mM EGTA (homogenization buffer); homogenized by
passage through a 26-gauge needle; and centrifuged for 5 min at 1,500
rpm. The pellet representing nuclei was resuspended in 10
mM HEPES (pH 7.9), 5% glycerol, 1.5
mM MgCl2, 0.5
mM DTT, 0.4 M NaCl, and 0.1
mM EGTA (extraction buffer). The protease
inhibitors leupeptin (5 mM), aprotinin (1.5
mM), phenylmethylsulfonyl fluoride (2
mM), and benzamidine (1 mM)
were used throughout the extraction procedure. The suspension
was rocked at 4°C for 30 min, cleared by centrifugation for 30 min at
12,000 rpm, and stored at -80°C.
Frozen samples of benign and malignant human breast tissues (500–1000 mg) were pulverized in a Mikro-Dismembrator (Braun, Melsungen, Germany). The resulting powder was suspended at 1:10 (w/v) in the homogenization buffer supplemented with 0.25 M sucrose (buffer A), homogenized, and centrifuged for 15 min at 2,300 rpm. The pellet was resuspended in buffer A, mixed with two volumes of homogenization buffer containing 2.5 M sucrose (buffer B), layered on top of 3:1 (v/v) buffer B, and finally centrifuged at 27,000 rpm for 1 h at 4°C. Nuclear proteins were then extracted as described above for cells. Protein concentration was determined by the method of Bradford (Bio-Rad Laboratories, Richmond CA).
Electrophoretic Mobility Shift Assay.
The double-stranded DNA oligonucleotide containing Sp1 consensus
sequence (5'-ATT CGATCGGGGCGGG-GCGAGC-3') was from Promega,
Madison, WI. The oligonucleotide was end-labeled with T4 polynucleotide
kinase and [-32P]ATP and purified by gel
electrophoresis. Ten and 40 µg of nuclear extracts from cells and
tissues, respectively, were preincubated in a binding buffer containing
20 mM HEPES (pH 7.5), 40 mM KCl, 5% glycerol,
2 µg of poly(dI·dC) for 10 min at 22°C. The radiolabeled DNA
probe (100,000 cpm/0.1 ng) was added in the presence or absence of a
large molar excess (300-fold) of unlabeled Sp1 oligonucleotide, and the
incubation was continued for an additional 20 min at 22°C. An excess
of unlabeled AP1 oligonucleotide (Promega) was also used as
competitor when indicated. Free and bound probes were separated on a
8% nondenaturating polyacrylamide gel followed by autoradiography.
Sp1-binding activity was quantitated by morphodensitometric scanning of autoradiograms using an image analysis system (Sistemi Avanzati, Milan, Italy) including a high resolution charge coupled device camera (High Technology Holland) and the Micro Computer Imaging Device (Imaging Research, Inc, Ontario, Canada). Each gel included a nuclear extract sample from HeLa cells as a control. For each sample, the product of absorbance and the area of the band was calculated and normalized against the Sp1 signal and protein content of HeLa cells, which were taken as 100%.
Cross-linking of uPAR.
Human recombinant ATF of urokinase (amino acids 1–135), obtained from
Dr. J. Wang (Abbot laboratories, Abbot Park, IL), was labeled with
Na125I using Iodo-Gen method as described
previously (6)
.
Membrane fractions from cultured cell lines and benign and malignant human breast tissues were prepared and treated with an acidic buffer (pH 3) to remove bound uPA. After washing with PBS they were incubated with 125I-ATF (7 nM) and cross-linked using disuccinimidyl suberate as reported elsewhere (6) . uPAR expression was determined by morphodensitometric scanning of autoradiograms as described above using HT1080 cells as an internal control for each gel.
Western Blotting and Immunoperoxidase Staining.
Western blot analysis of proteins from nuclear extracts and whole cell
lysates was carried out using a standard procedure (23)
.
Sp1 was detected using 1 µg/ml anti-Sp1 polyclonal antibody (Santa
Cruz Biotechnology, Santa Cruz, CA), and uPAR was detected with 5
µg/ml anti-uPAR R4 monoclonal antibody, generously provided by Dr. G.
Hoyer-Hansen (the Finsen Laboratory, Righospitalet, Copenhagen,
Denmark). The immunoreaction was revealed by the enhanced
chemiluminiscence detection system (ECL) according to the
manufacturer’s recommendations.
To determine the rate of proliferation, immunoperoxidase staining was performed as described previously (6) using the antibody Ki67 directed against a nuclear antigen expressed in G1, S, G2, or M phases of the cell cycle.
Statistics.
The uPAR levels, Sp1 activity, and rate of proliferation were compared
using simple regression analysis and Pearson’s coefficient of
correlation. A probability value (P) lower than 0.05 was
considered significant.
|
Results |
|---|
|
TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
|---|
summarizes the clinical data and pathological findings of the patients
with breast cancer and benign breast lesions that we have analyzed.
|
, a major specific complex was observed in two invasive
breast carcinoma samples (T2 and T8), whereas
only a barely detectable Sp1 signal resulted from one of the
fibroadenoma specimens (B15). The remaining two benign
fibroadenomas (samples 18 and 19) and two fibrocystic diseases (samples
16 and 17) did not exhibit any Sp1 activity (not shown). Nuclear
extracts from control HeLa cells subjected to the same procedure
resulted in a specific complex with similar electrophoretic mobility
(Fig. 1A)
. In a separate experiment, doubling the amount of
HeLa nuclear extract produced a parallel increase in the resulting
complex, which showed that the assay was indeed quantitative (not
shown).
|
, a selection of samples
representing the spectrum of Sp1 activity in the breast carcinomas
examined includes those with low (T7), intermediate
(T4, T5), and high signal (T2,
T3). Western blot analysis with anti-Sp1 antibody on nuclear
extracts from seven malignant specimens (samples 2–5 and 8–10) and
three benign breast lesions (samples 17–19) confirmed the presence of
varying nuclear levels of Sp1 protein in malignant tumors and the
absence of a detectable signal in benign breast lesions (not shown).
We have previously shown (6
, 24)
that malignant breast
lesions overexpress uPARs and that the relative abundance of uPAR can
be estimated by quantitative cross-linking using
125I-ATF. In agreement with previous findings
(25)
, in all of the tissue samples, a single and specific
band at Mr 70,000 with varying
intensity was detected (Fig. 1, C and D)
. The
electrophoretic mobility of the 125I-ATF-uPAR
complex was similar to that exhibited by HT1080 cells, and
125I-ATF binding was competed for by an excess of
unlabeled urokinase in both cell and tissue samples (Fig. 1, C and D)
. A detectable, although low, amount of
125I-ATF-uPAR complex was found in the B15
fibroadenoma specimen (Fig. 1C)
and a fibrocystic disease
sample (sample 16; not shown).
Table 2
summarizes the results of the cross-linking experiments and
electrophoretic mobility shift assays, as obtained by
morphodensitometric analysis of autoradiograms. The levels of uPAR and
Sp1 activity were expressed as a percentage of the HT1080 and HeLa
cells content, respectively. This quantitative analysis could not be
applied to a few cases because of the low intensity of the signal
(samples 13 and 14) or an unsuitable internal standard (samples 1 and
6). A positive and significant correlation was found between uPAR
levels and Sp1 activity in breast carcinomas (Pearson’s coefficient of
correlation, r, 0.94; P < 0.001).
|
. Furthermore, although
high levels of Sp1 activity were observed in highly proliferative
breast carcinomas, the correlation between Sp1 activity and the rate of
proliferation was not statistically significant (r, 0.71;
P = 0.07). On the contrary, a direct and
significant correlation was found between uPAR levels and the rate of
proliferation (r, 0.82; P < 0.01).
Coordinate Up-Regulation of Sp1 Activity and uPAR Expression by
uPA.
To test the possibility that uPA may regulate the levels of uPAR and
Sp1 activity in a receptor-dependent and coordinate manner, four
malignant tumor cell lines were analyzed. First, nuclear extracts from
HeLa cells, HT1080 fibrosarcoma cells, and MDA-MB-231 and MCF-7
breast carcinoma cell lines were subjected to a gel-shift assay for the
detection of Sp1 activity. In all of the cases, this procedure resulted
in the formation of a major complex that was competed for by an excess
of unlabeled Sp1 consensus oligonucleotide. As shown in Fig. 2A
, different levels of Sp1 activity were found in the four
cell lines tested, as follows: HT1080>HeLa>MDA-MB-231>MCF-7. These
binding data reflect Sp1 protein relative levels as assessed by Western
blot analysis of the same samples (data not shown). The relative
abundance of uPA receptors was assessed by cross-linking
125I-ATF to acid-pretreated membrane fractions
from the same cell lines. According to previous findings (6
, 26)
, a single and specific band at
Mr 70,000 was detected in all of the
cell lines tested, although the amount of the complex varied among
samples, i.e., HT1080>HeLa>MDA-MB-231>MCF-7 (not shown).
|
and MCF-7 (not shown).
In both of the cell lines, the elevation of Sp1 activity reached a
maximum at 30 min and returned to near baseline level by 6 h. The
same results were obtained after cell exposure to ATF, which indicated
the independence of such an effect from the uPA catalytic activity (not
shown). To test whether the enhancement of Sp1 activity indeed
corresponded to an increase in the nuclear levels of Sp1 protein, the
same nuclear extracts were analyzed by Western blotting. Two species at
Mr 97,000 and 105,000, corresponding
to the described dephosphorylated and phosphorylated forms of Sp1
(15
, 16) , respectively, were detected in all of the
samples (Fig. 2C)
. In agreement with the previous findings,
a transient increase of the dephosphorylated form of Sp1 was observed
at 30 min.
Next, whole cell lysates obtained from MDA-MB-231 cell lines exposed to
uPA were analyzed for their uPAR content by Western blotting. A marked
increase of uPAR expression was observed at 5 h after the addition
of uPA (Fig. 2D)
. Treatment with catalytically inactive
diisopropyl-fluorophosphate-inactivated uPA resulted in a similar uPAR
induction that was prevented by the addition of cycloheximide, which
indicated that uPAR up-regulation is due to neosynthesis (not shown).
Pretreatment with mithramycin, a competitive inhibitor of Sp1
DNA-binding activity, strongly reduces the extent of basal and induced
uPAR (Fig. 2D)
.
|
Discussion |
|---|
|
TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
|---|
Alteration of transcription factor function has now been established as a frequent cause of neoplastic transformation. However, little is known about how dysfunction of transcriptional activators and consequent alteration of specific transcriptomes lead to specific tumor phenotypes. In the present study, we report that uPAR ligation with uPA first enhances Sp1 activity and, subsequently, uPAR protein. This observation suggests that Sp1 may play an important role in driving induced uPAR mRNA transcription either directly or indirectly via other transcriptional activators. In any event, this finding highlights a regulatory circuitry triggered by uPA that may substantially contribute to the enhancement of cell invasiveness during breast tumor progression. The relevance of this ligand-receptor system to the malignant phenotype is shown by the finding that elevated levels of uPA and uPAR in several types of cancer are associated with a higher relapse rate and with a poor prognosis (27 , 28) . In agreement with these observations, we have previously reported that uPA and uPAR are overexpressed in breast carcinomas with respect to benign lesions (6) and that engaged uPARs are present on the surface of malignant epithelial cells (26) .
The data presented here do not exclude the contribution of other growth factor-dependent pathways to the Sp1-dependent regulation of uPAR gene, because there is great evidence for transcriptional and posttranscriptional regulation of uPAR by a variety of cytokines and tumor promoters (4 , 29) . To date, the signaling mechanisms mediating such a response have not been completely elucidated and include activation of protein kinase C, increased mRNA stability, and increased levels or activity of transcription factors (30, 31, 32, 33) . Previous studies have shown that uPAR, despite the lack of a cytoplasmic domain, is able to trigger intracellular signals by modulating the activity of some Src family kinases, such as p56/59hck and p55fgr in myeloid cells (34 , 35) . Activation of p56/59hck has been also reported in HT1080 fibrosarcoma cells on binding of catalytically inactive uPA to uPAR (36) . The strict relationship between uPAR, Src kinases, and Sp1 activity is further supported by the finding that a constitutively active Src kinase up-regulates uPAR gene expression and enhances Sp1-binding activity in the SW480 colon cancer cell line (8) . In the emerging picture, uPA may be the trigger of a signaling pathway, involving Src kinases and Sp1, that impinges on the uPAR gene and results in an amplification of the uPA/uPAR axis. The possibility to interfere at any level with this uPA-dependent auto-generating loop is of relevance for designing new antimetastatic drugs.
The use of GC-specific DNA-binding drugs that inhibit the Sp1-binding to regulatory elements (such as mithramycin) is at hand (21 , 37) . Mithramycin has been used in the treatment of acute hypercalcemia associated with malignancy (38) as an inhibitor of osteoclastic activity, especially in patients with osteolytic bone lesions of breast carcinoma and myeloma. However, the wide variety of genes that contain an Sp1 regulatory element in their promoter and the consequent limited specificity of mithramycin for the relevant target sequences have narrowed the therapeutic range of this drug and limited its clinical use. The availability of Sp1 competitors with a greater sequence specificity than mithramycin would hopefully result in a more effective and less toxic interference with the mechanisms of cancer invasion and metastasis.
Interestingly, a role for receptor-bound uPA in angiogenesis is
emerging because uPA and plasmin activities are required for the
outgrowth of capillary-like structures in a fibrin gel
(39)
. The dependence of blood-vessel formation and tumor
growth on the extracellular matrix degradation and cell migration is a
target for the development of novel anticancer strategies, as shown by
the metalloprotease inhibitors in late-stage Phase III trials
(40)
. Sp1 is also involved in tumoral angiogenesis because
it mediates the induction of vascular endothelial growth factor (VEGF)
and its receptor-2 by tumor necrosis factor 
(41
, 42)
.
It is likely that future cancer therapies will use a combination of
drugs to interfere with proteolysis, adhesion, angiogenesis, and other
mechanisms that are proven to be essential for the establishment and
the progression of tumors in vivo.
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
1 This work was supported by Associazione Italiana
Ricerca Cancro (AIRC). A. Z. was a recipient of a fellowship from
Federazione Italiana Ricerca Cancro (FIRC). 
2 To whom requests for reprints should be
addressed, at Medicina Nucleare, II Facoltà di Medicina,
Università "Federico II", Via S. Pansini, 5, 80131 Naples,
Italy. Fax: 39-081-5457081; E-mail: delvecc{at}unina.it
3 The abbreviations used are: uPA,
urokinase-type plasminogen activator; uPAR, uPA receptor; ATF,
NH2-terminal fragment of urokinase.
Received 12/ 9/99. Accepted 2/ 2/00.
|
REFERENCES |
|---|
|
TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
|---|
1 and Sp1 in human hepatocellular carcinomas. Am. J. Pathol., 151: 1663-1671, 1997.[Abstract]
vß5 vitronectin receptor promoting urokinase-dependent cell migration in breast cancer. Cancer Res., 59: 5307-5314, 1999.-related factor. J. Biol. Chem., 274: 4702-4714, 1999.1 (I) gene expression in human fibroblast. J. Clin. Invest., 92: 2916-2921, 1993.
in human glioma cells. J. Biol. Chem., 271: 28220-28228, 1996. regulates expression of vascular endothelial growth factor receptor-2 and of its co-receptor neuropilin-1 in human vascular endothelial cells. J. Biol. Chem., 273: 22128-22135, 1998.This article has been cited by other articles:
|
|
 |
|
  A. Zannetti, F. Iommelli, R. Fonti, A. Papaccioli, J. Sommella, A. Lettieri, G. Pirozzi, R. Bianco, G. Tortora, M. Salvatore, et al. Gefitinib Induction of In vivo Detectable Signals by Bcl-2/Bcl-xL Modulation of Inositol Trisphosphate Receptor Type 3 Clin. Cancer Res., August 15, 2008; 14(16): 5209 - 5219. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. G. Woo, E. S. Park, J. H. Cheon, J. H. Kim, J.-S. Lee, B. J. Park, W. Kim, S. C. Park, Y. J. Chung, B. G. Kim, et al. Gene Expression-Based Recurrence Prediction of Hepatitis B Virus-Related Human Hepatocellular Carcinoma Clin. Cancer Res., April 1, 2008; 14(7): 2056 - 2064. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Yoo and Y. J. Lee Aspirin Enhances Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Mediated Apoptosis in Hormone-Refractory Prostate Cancer Cells through Survivin Down-Regulation Mol. Pharmacol., December 1, 2007; 72(6): 1586 - 1592. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. U. Mertens-Talcott, S. Chintharlapalli, X. Li, and S. Safe The Oncogenic microRNA-27a Targets Genes That Regulate Specificity Protein Transcription Factors and the G2-M Checkpoint in MDA-MB-231 Breast Cancer Cells Cancer Res., November 15, 2007; 67(22): 11001 - 11011. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Abdelrahim, C. H. Baker, J. L. Abbruzzese, D. Sheikh-Hamad, S. Liu, S. D. Cho, K. Yoon, and S. Safe Regulation of Vascular Endothelial Growth Factor Receptor-1 Expression by Specificity Proteins 1, 3, and 4 in Pancreatic Cancer Cells Cancer Res., April 1, 2007; 67(7): 3286 - 3294. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Chintharlapalli, S. Papineni, S. K. Ramaiah, and S. Safe Betulinic Acid Inhibits Prostate Cancer Growth through Inhibition of Specificity Protein Transcription Factors Cancer Res., March 15, 2007; 67(6): 2816 - 2823. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Higashi, S. Kyo, M. Inoue, H. Tanii, and K. Saijoh Novel Functional Single Nucleotide Polymorphisms in the Latent Transforming Growth Factor-{beta} Binding Protein-1L Promoter: Effect on Latent Transforming Growth Factor-{beta} Binding Protein-1L Expression Level and Possible Prognostic Significance in Ovarian Cancer J. Mol. Diagn., July 1, 2006; 8(3): 342 - 350. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Abdelrahim, C. H. Baker, J. L. Abbruzzese, and S. Safe Tolfenamic acid and pancreatic cancer growth, angiogenesis, and Sp protein degradation. J Natl Cancer Inst, June 21, 2006; 98(12): 855 - 868. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Albertini, A. Jain, S. Vignati, S. Napoli, A. Rinaldi, I. Kwee, M. Nur-e-Alam, J. Bergant, F. Bertoni, G. M. Carbone, et al. Novel GC-rich DNA-binding compound produced by a genetically engineered mutant of the mithramycin producer Streptomyces argillaceus exhibits improved transcriptional repressor activity: implications for cancer therapy. Nucleic Acids Res., January 1, 2006; 34(6): 1721 - 1734. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Schewe, T. Biller, G. Maurer, I. A. Asangani, J. H. Leupold, E. R. Lengyel, S. Post, and H. Allgayer Combination Analysis of Activator Protein-1 Family Members, Sp1 and an Activator Protein-2{alpha}-Related Factor Binding to Different Regions of the Urokinase Receptor Gene in Resected Colorectal Cancers Clin. Cancer Res., December 15, 2005; 11(24): 8538 - 8548. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Feng and Y. W. Kan The binding of the ubiquitous transcription factor Sp1 at the locus control region represses the expression of {beta}-like globin genes PNAS, July 12, 2005; 102(28): 9896 - 9900. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Lou, S. O'Reilly, H. Liang, V. M. Maher, S. D. Sleight, and J. J. McCormick Down-Regulation of Overexpressed Sp1 Protein in Human Fibrosarcoma Cell Lines Inhibits Tumor Formation Cancer Res., February 1, 2005; 65(3): 1007 - 1017. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Wang, L. Yang, Md. S. Jamaluddin, and D. D. Boyd The Kruppel-like KLF4 Transcription Factor, a Novel Regulator of Urokinase Receptor Expression, Drives Synthesis of This Binding Site in Colonic Crypt Luminal Surface Epithelial Cells J. Biol. Chem., May 21, 2004; 279(21): 22674 - 22683. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Trisciuoglio, A. Iervolino, A. Candiloro, G. Fibbi, M. Fanciulli, U. Zangemeister-Wittke, G. Zupi, and D. Del Bufalo bcl-2 Induction of Urokinase Plasminogen Activator Receptor Expression in Human Cancer Cells through Sp1 Activation: INVOLVEMENT OF ERK1/ERK2 ACTIVITY J. Biol. Chem., February 20, 2004; 279(8): 6737 - 6745. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. D. Boyd, H. Wang, H. Avila, N. U. Parikh, H. Kessler, V. Magdolen, and G. E. Gallick Combination of an Src Kinase Inhibitor with a Novel Pharmacological Antagonist of the Urokinase Receptor Diminishes in Vitro Colon Cancer Invasiveness Clin. Cancer Res., February 15, 2004; 10(4): 1545 - 1555. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Schewe, J. H. Leupold, D. D. Boyd, E. R. Lengyel, H. Wang, K. U. Gruetzner, F. W. Schildberg, K. W. Jauch, and H. Allgayer Tumor-specific Transcription Factor Binding to an Activator Protein-2/Sp1 Element of the Urokinase-type Plasminogen Activator Receptor Promoter in a First Large Series of Resected Gastrointestinal Cancers Clin. Cancer Res., June 1, 2003; 9(6): 2267 - 2276. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. K. Rao, S. Maiti, H. N. Ananthaswamy, and M. F. Wilkinson A Highly Active Homeobox Gene Promoter Regulated by Ets and Sp1 Family Members in Normal Granulosa Cells and Diverse Tumor Cell Types J. Biol. Chem., July 12, 2002; 277(29): 26036 - 26045. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
