| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Regular Articles |
From the Clinical Cancer Genetics and Human Cancer
Genetics Programs,*
Ohio State University Comprehensive
Cancer Center, Columbus, Ohio; the Department of
Pathology,
University of Zürich,
Zürich, Switzerland; the Charles A. Dana Human Cancer Genetics
Unit,
Dana-Farber Cancer Institute, Boston,
Massachusetts; the Massachusetts Institute of
Technology,§
Boston, Massachusetts; the
Departments of Pathology and Surgery,¶
Martin-Luther-University of Halle-Wittenberg, Halle/Saale, Germany; the
Kolling Institute for Medical Research and Department of
Surgery,||
Royal North Shore Hospital, University of
Sydney, St. Leonards, New South Wales, Australia; the Department of
Pathology,**
Brigham and Women’s Hospital and
Harvard Medical School, Boston, Massachusetts; and the Cancer Research
Campaign Human Cancer Genetics Research
Group,
University of Cambridge,
Cambridge, United Kingdom
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Paraffin blocks from 139 unselected benign and malignant nonmedullary thyroid tumors were ascertained from Germany, Australia, and Switzerland. Histological classification of the thyroid tumors was in accordance with the World Health Organization.28 Of note, five papillary tumors were classified as follicular type (Lindsay tumor), and 13 tumors (seven FAs, five FTCs, one PTC) had a prominent granular eosinophilic-appearing cytoplasm (also known as oxyphilic or Hürthle cell).
Anti-PTEN Antibody Specificity
The monoclonal antibody 6H2.1 raised against the last 100
C-terminal amino acids of PTEN29
was used in all
immunohistochemical analyses. As biochemical proof of antibody
specificity for PTEN, total protein lysates were
obtained10,15
from a series of thyroid cell lines for
which PTEN status is known: NPA-87, K-1, FTC-133, and WRO-82–1 (gifts
from D. V. Canlapan and D. Wynford-Thomas). Further, as an
additional positive control, the wild-type full-length human
PTEN cDNA sequence was cloned into the expression vector
pcDNA3 and transfected into the PTEN null line FTC-133. Western blot
analysis was performed as previously described10
except
that 6H2.1 was used at a 1:250 dilution. Thyroid lines with
endogenously expressing or exogenously introduced PTEN all demonstrated
a single band at 55 kd, the molecular weight predicted for PTEN,
although the PTEN null lines did not cross-react with 6H2.1. No other
nonspecific bands were noted, thus proving antibody-specificity (Figure 1)
. Control antibody against 
-tubulin
(Sigma, St. Louis, MO), used at 1:10,000 dilution, immunoreacted evenly
across protein lysates from all cell lines (Figure 1)
. The specificity
of the antibody 6H2.1 and its suitability for immunohistochemistry in
paraffin-embedded tissue has been demonstrated
previously.29
In brief, we used the antibody against
embedded PTEN-transfected U2OS cells, BALBc/3T3, Nalm6, and
DU145 as positive controls; MDA-MB-468 with hemizygous deletion of
PTEN and a truncation of the remaining allele; A172 which
has loss of one PTEN allele, and a truncating mutation in
exon 2 of the remaining allele; and PC3, which is null for
PTEN.29
Further, commercially available peptide
corresponding to PTEN has been used to successfully compete away 6H2.1
immunostaining in paraffin-embedded tissue (GL M, unpublished data).
|
Immunohistochemistry
The tissue samples were fixed by immersion in 10% buffered formalin and subsequently embedded in paraffin according to standard protocols. Four-mm sections were cut, mounted on Superfrost plus slides, and baked for 2 hours at 60°C. Subsequently, the sections were deparaffinized and rehydrated by passing through xylene and a graded series of ethanol solutions. Antigen retrieval was performed by boiling at 98°C in 0.01 mol/L sodium citrate buffer, pH 6.4, in a microwave oven for 20 minutes. To block endogenous peroxidase activity, the sections were incubated with 0.3% hydrogen peroxide in methanol for 30 minutes after cooling to room temperature. After blocking for 30 minutes in 0.75% horse serum, the sections were incubated with a PTEN monoclonal antibody 6H2.1 (dilution 1:100) for 1 hour at room temperature. Primary antibody binding was localized by using an avidin-biotin-peroxidase kit (Vector Laboratories, Burlingame, CA) according to the manufacturer’s instruction. The chromogenic reaction was carried out with 0.05% 3,3'diaminobenzidine (Sigma, St. Louis, MO) using nickel cobalt amplification which gives a black product.31 After counterstaining with Nuclear Fast Red (Rowley Biochemical Institute, Danvers, MA) and mounting, the slides were independently evaluated under a light microscope by two investigators (OG and AP) and randomly spot evaluated by a third investigator (CE). Intensity of staining was classified separately for the nucleus/nuclear membrane and the cytoplasm and graded strong (+++), moderate (++), weak (+), or absent (-). These independent assessments did not differ by more than one grading level.
LOH Analysis
In 95 samples, tumor tissue and blood or corresponding normal tissue (either normal thyroid tissue or adjacent muscle tissue) were available for extraction of paired somatic and germline DNA to study LOH. DNA extraction after microdissection was performed using standard protocols.32 All subsequent polymerase chain reactions were carried out using 0.6 µM each of forward and reverse primer in 1x polymerase chain reaction buffer (Qiagen, Valencia, CA), 4.5 mmol/L MgCl2 (Qiagen), 1x Q-buffer (Qiagen), 2.5 U HotStarTaq polymerase (Qiagen), and 200 µmol/L dNTP (Gibco, Gaithersburg, MD) in a final volume of 50 µl. Reactions were subjected to 35 cycles of 94°C for 1 minute, 55°C to 60°C for 1 minute, and 72°C for 1 minute followed by 10 minutes at 72°C. Potential hemizygosity at the PTEN locus was assessed by screening for a T/G polymorphism within PTEN intron 8 (IVS8 + 32G/T) detected by differential digestion with the restriction endonuclease HincII as previously described25 except for using the primers PTEN-E8-F (5'-GCGTGCAGATAATGACAAGG-3') and PTEN-I8-R (5'-TGTCAAGCAAGTTCTTCATCG-3'). If the result of the digestion was not informative, LOH analysis was performed using markers flanking PTEN, D10S541 (telomeric) and D10S579 (centromeric)1,16 as well as the marker D10S2491 that lies within PTEN.33 All forward primers were 5'-labeled with either HEX or 6-FAM fluorescent dye (Research Genetics, Huntsville, AL). Polymerase chain reactions were carried out as described above and separated by electrophoresis through 6% denaturing polyacrylamide gels using an Applied Biosystems model 377 automated DNA sequencer (Applied Biosystems, Perkin-Elmer Corp., Norwalk, CT). The results were analyzed by automated fluorescence detection using the GeneScan collection and analysis software (GeneScan, Applied Biosystems). Scoring of LOH was performed by inspection of the GeneScan analysis output. A double peak, observed in the microsatellite marker that was amplified from DNA extracted from the germline sample, indicated heterozygosity. A single peak in DNA extracted and amplified from the corresponding tumor sample indicated a loss of one allele. If normal cells were admixed with tumor cells, a ratio of 1.5:1 or greater of germline DNA peak to tumor DNA peak was also considered LOH.24
To examine the correlative trend between PTEN staining intensity and LOH, we performed a Mantel-Haenszel test34 for trend in the association between the row and column variables. A P < 0.05 was considered statistically significant.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Of the total 139 thyroid tumor samples examined for PTEN
expression using the monoclonal antibody 6H2.1, 50 had accompanying
normal thyroid tissue. Normal follicular thyroid cells showed a uniform
strong (+++) to moderate (++) nuclear or nuclear membrane (hereafter
referred to as nuclear) signal whereas the cytoplasmic staining was
less strong, + to ++ (Figure 2A)
.
Endothelial cells showed strong (+++) to moderate (++) PTEN expression
with a nuclear predominance and were useful as internal positive
controls (Figure 2
, B and E). In contrast, nuclear and cytoplasmic
staining intensity of fibrocytes was very heterogeneous and varied from
weak (Figure 2A)
to strong (Figure 2
F).
|
for purposes of this study.
|
. In thyroid carcinomas
(FTC, PTC, and undifferentiated thyroid carcinoma [UTC]) as a group,
nuclear PTEN immunostaining was mostly weak in comparison with normal
thyroid follicular cells and FAs. Among the three classes of
carcinomas, FTCs had the strongest immunostaining in both the nucleus
and cytoplasm and UTCs the weakest (Figures 2, C–E, and 3)
. A few
carcinomas, in particular UTCs, showed no PTEN staining in the nucleus
(FTC, 3 of 28; PTC, 3 of 37; UTC, 8 of 26) or in the cytoplasm (one
FTC, two PTCs, five UTCs; Figure 2
E); eight carcinomas (one FTC, two
PTCs, five UTCs) had no immunoreactivity in the nucleus or in the
cytoplasm. In almost half of all thyroid carcinomas (FTC, 46%; PTC,
49%; UTC, 35%), the cytoplasmic staining was more intense than the
nuclear staining (Figures 2, F and G, and 3)
. In contrast, the more
intense cytoplasmic over nuclear staining was observed in only 7% of
FAs. In other words, the stepwise decrease in PTEN immunoreactivity in
the nucleus seemed to precede that in the cytoplasm from normal thyroid
tissue to FA to carcinomas and finally to UTC (Figure 3)
. There was no
obvious difference in PTEN staining pattern and intensity in
Hürthle cell tumors compared to non-Hürthle cell tumors.
Fibrocytes seemed to stain a little more intensely in tumor stroma
(Figure 2
F) compared to normal thyroid stroma (Figure 2A)
.
Seven carcinomas (four UTCs, two PTCs, one FTC), but no adenomas,
showed dichotomous regional PTEN staining within each sample. These
were characterized either by islands of strongly immunopositive cells
among sheets of cells staining more weakly (Figure 2
, H and I) or by
single cells staining weakly randomly distributed among cells staining
strongly. In one UTC, the positive cells (graded +) were small and more
regular whereas the PTEN-negative cells were larger, pleiomorphic, and
had a more undifferentiated appearance. This correlation, however, was
not seen in the other three UTCs. This pattern of immunostaining in the
former UTC was replicated several times, thus indicating that this was
not an artifact.
Comparison of Immunohistochemical and LOH Data
In 95 tumors, normal and tumor tissue samples were available for
LOH analysis. Similar to the immunohistochemical analysis, the four
available carcinomas with dichotomous staining intensity within each
sample, which had paired normal and tumor tissue, were considered as
eight samples. Therefore, 99 total samples were considered. For
purposes of this study, which was to compare the immunohistochemical
data to the LOH data, one copy of PTEN was considered to be
physically deleted only when one or more of the markers, which lie
within or closely flanking the gene, showed LOH. Using this definition
for monoallelic PTEN deletion, LOH data from 92 tumors were
informative. Of the 92 informative tumors, 27 tumors (29%) were shown
to have loss of one allele of PTEN and 65 tumors were
classified as having no LOH (Table 1)
.
|
Among the 92 informative tumors assessed for LOH and PTEN
immunostaining, there seemed to be an associative trend between
decreased or absent staining and 10q23 LOH (Table 2
, Figure 3
). The proportion of tumors
that had LOH steadily increased from tumors with +++ nuclear staining
(0% with LOH), ++ staining (21% LOH), + staining (32% LOH) to no
(-) staining (75% LOH) (P = 0.003). This trend
was also mirrored if we considered only cytoplasmic staining and LOH
status (++ cytoplasmic staining [18% with LOH], + staining [36%
LOH], to no [-] staining [67% LOH]) (Table 2
; Figure 3
;
P = 0.008). Two samples showed no PTEN staining without
evidence for LOH. One of the samples was heterozygous for IVS8 + 32G/T
whereas the other markers were not informative. The other sample showed
regions of heterozygosity at D10S579 and was not informative for the
other markers.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Because PTEN has not been shown to have a nuclear localization signal,1,2 cytoplasmic expression of PTEN is expected. In normal thyroid cells, as expected, PTEN is strongly expressed. The decrease in PTEN immunoreactivity in the cytoplasm from normal cells to differentiated carcinomas and to UTC supports our hypothesis that PTEN is inactivated and plays a role in thyroid tumorigenesis. Decreasing PTEN expression in this progression from adenoma to UTC would result in poor control of G1 arrest, apoptosis, and/or cell-cell adhesion.13,15,35,36
Given that PTEN does not have a nuclear localization signal,1 our observation of prominent and differential nuclear PTEN staining is puzzling. Our initial postulate that this represented nuclear membrane staining would appear to be more plausible, and such staining could reflect PTEN's role in regard to the cytoskeleton. Other unrelated studies have noted this nuclear staining with different PTEN antibodies, without explanation. A weak or absent intensity of nuclear PTEN staining along with a strong cytoplasmic PTEN staining was also observed in prostate cancer xenografts37 and fibroblasts.11 Together with these previous incidental observations, our immunohistochemical evidence of nuclear staining is likely real, given that the decreasing nuclear signal with less-differentiated carcinomas predominates the decreased cytoplasmic staining. The precise mechanism for our observations is yet unknown.
The equally puzzling observation that decreased nuclear staining often precedes the decreased cytoplasmic staining in thyroid cancers is intriguing. Because PTEN per se does not have a nuclear localization signal, it is possible that PTEN is shuttled into the nucleus by another molecule. Such a mechanism has been described for the tumor-suppressor TP53 which is shuttled between the nucleus and the cytoplasm via the oncoprotein MDM2.38 Other examples exist in the literature. Phosphorylated forkhead-related transcription factor is excluded from the nucleus by interaction with 14-3-3.39 When not bound to 14-3-3, forkhead-related transcription factor enters the nucleus and acts as a transcription factor for various genes, including, presumably, FAS ligand.40 VHL and ß-catenin have also been documented to play different roles depending on their subcellular localization.41,42 Based on the current state of knowledge, we would speculate that PTEN could be shuttled into the nucleus related to the cell cycle and/or as a response to cell division and cell growth. It is very well known that intracellular substrates can show a distinct distribution within different compartments (eg, cytoplasm, nucleus, microsomes), ie, differential intracellular compartmentalization. Hence, differential compartmentalization of PTEN might play some as yet undefined role in the tumorigenetic process.
As more studies are performed, it is becoming apparent that inactivation of PTEN relies on multiple diverse mechanisms and not merely structural abnormalities such as somatic mutations.10,43 In the present study, approximately one fourth of FAs and one fourth of the differentiated carcinomas had LOH. Both FAs and FTCs have a similar frequency of LOH as previously noted. The relatively high frequency of LOH in PTCs (21%) and UTCs (59%) is higher than that reported in the literature possibly because we used PTEN-specific markers. The markers in other studies were not specifically chosen for 10q23 but rather broadly covered the whole long arm of chromosome 10. Somatic intragenic mutations of PTEN are also not likely to play a major role in PTEN silencing because they have been rarely found in thyroid carcinomas.25,27 Another mechanism which has been implicated in prostate cancer and non-Hodgkin’s lymphoma is gene silencing by hypermethylation of CpG islands, presumably in the putative promoter,10,37 although the situation in prostate cancer is still controversial.33 Finally, at least in hematological malignancies, reduced or absent PTEN protein levels seem to involve either the postranscriptional, translational, or protein degradation pathways.10 Given our observations, all of these mechanisms likely come into play in the situation of epithelial thyroid tumorigenesis. We also add another possible mechanism: differential compartmentalization of PTEN. These issues need to be addressed and characterized at the functional level in the future.
|
Acknowledgements |
|---|
|
Footnotes |
|---|
Supported in part by grants RPG-98–211-01-CCE from the American Cancer Society (to C. E.) and P30CA16058 from the National Cancer Institute (Ohio State University Comprehensive Cancer Center). O. G. is a Fellow of the Deutsche Forschungsgemeinschaft, Germany, and A. P. is a Fellow of the Lydia Hochstrasser-Stiftung, Zürich, Switzerland (to P. K.)
O. G. and A. P. contributed equally to this study.
Accepted for publication January 6, 2000.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  K. Sakamoto, K. Iwasaki, H. Sugiyama, and Y. Tsuji Role of the Tumor Suppressor PTEN in Antioxidant Responsive Element-mediated Transcription and Associated Histone Modifications Mol. Biol. Cell, March 15, 2009; 20(6): 1606 - 1617. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. P. Lobo, K. A. Waite, S. M. Planchon, T. Romigh, J. A. Houghton, and C. Eng ATP modulates PTEN subcellular localization in multiple cancer cell lines Hum. Mol. Genet., September 15, 2008; 17(18): 2877 - 2885. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Okada, S.-W. Jang, and K. Ye Akt phosphorylation and nuclear phosphoinositide association mediate mRNA export and cell proliferation activities by ALY PNAS, June 24, 2008; 105(25): 8649 - 8654. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Fouladkou, T. Landry, H. Kawabe, A. Neeb, C. Lu, N. Brose, V. Stambolic, and D. Rotin The ubiquitin ligase Nedd4-1 is dispensable for the regulation of PTEN stability and localization PNAS, June 24, 2008; 105(25): 8585 - 8590. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Planchon, K. A. Waite, and C. Eng The nuclear affairs of PTEN J. Cell Sci., February 1, 2008; 121(3): 249 - 253. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Riesco-Eizaguirre and P. Santisteban New insights in thyroid follicular cell biology and its impact in thyroid cancer therapy Endocr. Relat. Cancer, December 1, 2007; 14(4): 957 - 977. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Tamguney and D. Stokoe New insights into PTEN J. Cell Sci., December 1, 2007; 120(23): 4071 - 4079. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-L. Liu, Z. Mao, T. A. LaFortune, M. M. Alonso, G. E. Gallick, J. Fueyo, and W.K. A. Yung Cell Cycle Dependent Nuclear Export of Phosphatase and Tensin Homologue Tumor Suppressor Is Regulated by the Phosphoinositide-3-Kinase Signaling Cascade Cancer Res., November 15, 2007; 67(22): 11054 - 11063. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Foukakis, A. Gusnanto, A. Y. Au, A. Hoog, W.-O. Lui, C. Larsson, G. Wallin, and J. Zedenius A PCR-based expression signature of malignancy in follicular thyroid tumors Endocr. Relat. Cancer, June 1, 2007; 14(2): 381 - 391. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Yeager, A. Klein-Szanto, S. Kimura, and A. Di Cristofano Pten Loss in the Mouse Thyroid Causes Goiter and Follicular Adenomas: Insights into Thyroid Function and Cowden Disease Pathogenesis Cancer Res., February 1, 2007; 67(3): 959 - 966. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Packer, S. Pavey, A. Parker, M. Stark, P. Johansson, B. Clarke, P. Pollock, M. Ringner, and N. Hayward Osteopontin is a downstream effector of the PI3-kinase pathway in melanomas that is inversely correlated with functional PTEN Carcinogenesis, September 1, 2006; 27(9): 1778 - 1786. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Gil, A. Andres-Pons, E. Fernandez, M. Valiente, J. Torres, J. Cervera, and R. Pulido Nuclear Localization of PTEN by a Ran-dependent Mechanism Enhances Apoptosis: Involvement of an N-Terminal Nuclear Localization Domain and Multiple Nuclear Exclusion Motifs Mol. Biol. Cell, September 1, 2006; 17(9): 4002 - 4013. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Orbo, C. E. Rise, and G. L. Mutter Regression of Latent Endometrial Precancers by Progestin Infiltrated Intrauterine Device Cancer Res., June 1, 2006; 66(11): 5613 - 5617. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Garcia-Rostan, A. M. Costa, I. Pereira-Castro, G. Salvatore, R. Hernandez, M. J.A. Hermsem, A. Herrero, A. Fusco, J. Cameselle-Teijeiro, and M. Santoro Mutation of the PIK3CA Gene in Anaplastic Thyroid Cancer Cancer Res., November 15, 2005; 65(22): 10199 - 10207. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Liu, S. L. Asa, and S. Ezzat 1{alpha},25-Dihydroxyvitamin D3 Targets PTEN-Dependent Fibronectin Expression to Restore Thyroid Cancer Cell Adhesiveness Mol. Endocrinol., September 1, 2005; 19(9): 2349 - 2357. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-L. Liu, X. Sheng, Z. K. Hortobagyi, Z. Mao, G. E. Gallick, and W. K. A. Yung Nuclear PTEN-Mediated Growth Suppression Is Independent of Akt Down-Regulation Mol. Cell. Biol., July 15, 2005; 25(14): 6211 - 6224. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Mikhail, E. Velazquez, R. Shapiro, R. Berman, A. Pavlick, L. Sorhaindo, J. Spira, C. Mir, K. S. Panageas, D. Polsky, et al. PTEN Expression in Melanoma: Relationship with Patient Survival, Bcl-2 Expression, and Proliferation Clin. Cancer Res., July 15, 2005; 11(14): 5153 - 5157. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M Musat, M Korbonits, B Kola, N Borboli, M R Hanson, A M Nanzer, J Grigson, S Jordan, D G Morris, M Gueorguiev, et al. Enhanced protein kinase B/Akt signalling in pituitary tumours Endocr. Relat. Cancer, June 1, 2005; 12(2): 423 - 433. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. A. Waite, M. R. Sinden, and C. Eng Phytoestrogen exposure elevates PTEN levels Hum. Mol. Genet., June 1, 2005; 14(11): 1457 - 1463. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-H. Chung, M. E. Ginn-Pease, and C. Eng Phosphatase and Tensin Homologue Deleted on Chromosome 10 (PTEN) Has Nuclear Localization Signal-Like Sequences for Nuclear Import Mediated by Major Vault Protein Cancer Res., May 15, 2005; 65(10): 4108 - 4116. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. L. Motti, D. Califano, G. Troncone, C. De Marco, I. Migliaccio, E. Palmieri, L. Pezzullo, L. Palombini, A. Fusco, and G. Viglietto Complex Regulation of the Cyclin-Dependent Kinase Inhibitor p27kip1 in Thyroid Cancer Cells by the PI3K/AKT Pathway: Regulation of p27kip1 Expression and Localization Am. J. Pathol., March 1, 2005; 166(3): 737 - 749. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A Perren, S Schmid, T Locher, P Saremaslani, C Bonvin, P U Heitz, and P Komminoth BRAF and endocrine tumors: mutations are frequent in papillary thyroid carcinomas, rare in endocrine tumors of the gastrointestinal tract and not detected in other endocrine tumors Endocr. Relat. Cancer, December 1, 2004; 11(4): 855 - 860. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Lacalle, C. Gomez-Mouton, D. F. Barber, S. Jimenez-Baranda, E. Mira, C. Martinez-A., A. C. Carrera, and S. Manes PTEN regulates motility but not directionality during leukocyte chemotaxis J. Cell Sci., December 1, 2004; 117(25): 6207 - 6215. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Tell, A. Pines, F. Arturi, L. Cesaratto, E. Adamson, C. Puppin, I. Presta, D. Russo, S. Filetti, and G. Damante Control of Phosphatase and Tensin Homolog (PTEN) Gene Expression in Normal and Neoplastic Thyroid Cells Endocrinology, October 1, 2004; 145(10): 4660 - 4666. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Goel, C. N. Arnold, D. Niedzwiecki, J. M. Carethers, J. M. Dowell, L. Wasserman, C. Compton, R. J. Mayer, M. M. Bertagnolli, and C. R. Boland Frequent Inactivation of PTEN by Promoter Hypermethylation in Microsatellite Instability-High Sporadic Colorectal Cancers Cancer Res., May 1, 2004; 64(9): 3014 - 3021. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Musatov, J. Roberts, A. I. Brooks, J. Pena, S. Betchen, D. W. Pfaff, and M. G. Kaplitt Inhibition of neuronal phenotype by PTEN in PC12 cells PNAS, March 9, 2004; 101(10): 3627 - 3631. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. A. Orchiston, D. Bennett, N. R. Leslie, R. G. Clarke, L. Winward, C. P. Downes, and S. T. Safrany PTEN M-CBR3, a Versatile and Selective Regulator of Inositol 1,3,4,5,6-Pentakisphosphate (Ins(1,3,4,5,6)P5): EVIDENCE FOR Ins(1,3,4,5,6)P5 AS A PROLIFERATIVE SIGNAL J. Biol. Chem., January 9, 2004; 279(2): 1116 - 1122. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. C.I. Goberdhan and C. Wilson PTEN: tumour suppressor, multifunctional growth regulator and more Hum. Mol. Genet., October 15, 2003; 12(90002): R239 - 248. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Deleris, D. Bacqueville, S. Gayral, L. Carrez, J.-P. Salles, B. Perret, and M. Breton-Douillon SHIP-2 and PTEN Are Expressed and Active in Vascular Smooth Muscle Cell Nuclei, but Only SHIP-2 Is Associated with Nuclear Speckles J. Biol. Chem., October 3, 2003; 278(40): 38884 - 38891. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Choe, S. Horvath, T. F. Cloughesy, K. Crosby, D. Seligson, A. Palotie, L. Inge, B. L. Smith, C. L. Sawyers, and P. S. Mischel Analysis of the Phosphatidylinositol 3'-Kinase Signaling Pathway in Glioblastoma Patients in Vivo Cancer Res., June 1, 2003; 63(11): 2742 - 2746. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Aldred, M. E. Ginn-Pease, C. D. Morrison, A. P. Popkie, O. Gimm, C. Hoang-Vu, U. Krause, H. Dralle, S. M. Jhiang, C. Plass, et al. Caveolin-1 and Caveolin-2,Together with Three Bone Morphogenetic Protein-related Genes, May Encode Novel Tumor Suppressors Down-Regulated in Sporadic Follicular Thyroid Carcinogenesis Cancer Res., June 1, 2003; 63(11): 2864 - 2871. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. J. Halvorsen, S. A. Haukaas, and L. A. Akslen Combined Loss of PTEN and p27 Expression Is Associated with Tumor Cell Proliferation by Ki-67 and Increased Risk of Recurrent Disease in Localized Prostate Cancer Clin. Cancer Res., April 1, 2003; 9(4): 1474 - 1479. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. A. Waite and C. Eng BMP2 exposure results in decreased PTEN protein degradation and increased PTEN levels Hum. Mol. Genet., March 15, 2003; 12(6): 679 - 684. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. Ginn-Pease and C. Eng Increased Nuclear Phosphatase and Tensin Homologue Deleted on Chromosome 10 Is Associated with G0-G1 in MCF-7 Cells Cancer Res., January 15, 2003; 63(2): 282 - 286. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Yu, N. Fotouhi-Ardakani, L. Wu, M. Maoui, S. Wang, D. Banville, and S.-H. Shen PTEN Associates with the Vault Particles in HeLa Cells J. Biol. Chem., October 18, 2002; 277(43): 40247 - 40252. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. F. Irvine Nuclear Lipid Signaling Sci. Signal., September 17, 2002; 2002(150): re13 - re13. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X.-P. Zhou, A. Loukola, R. Salovaara, M. Nystrom-Lahti, P. Peltomaki, A. de la Chapelle, L. A. Aaltonen, and C. Eng PTEN Mutational Spectra, Expression Levels, and Subcellular Localization in Microsatellite Stable and Unstable Colorectal Cancers Am. J. Pathol., August 1, 2002; 161(2): 439 - 447. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. B. Knobbe, A. Merlo, and G. Reifenberger Pten signaling in gliomas Neuro-oncol, July 1, 2002; 4(3): 196 - 211. [Abstract] [PDF]
|
|
|
|
|
|
M. Fernandez and C. Eng The Expanding Role of PTEN in Neoplasia: A Molecule for All Seasons? : Commentary re: M. A. Davies, et al., Adenoviral-mediated Expression of MMAC/PTEN Inhibits Proliferation and Metastasis of Human Prostate Cancer Cells. Clin. Cancer Res., 8: 1904-1914, 2002. Clin. Cancer Res., June 1, 2002; 8(6): 1695 - 1698. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Liu, S. L. Asa, I. G. Fantus, P. G. Walfish, and S. Ezzat Vitamin D Arrests Thyroid Carcinoma Cell Growth and Induces p27 Dephosphorylation and Accumulation through PTEN/Akt-Dependent and -Independent Pathways Am. J. Pathol., February 1, 2002; 160(2): 511 - 519. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. L. Mutter PTEN, a Protean Tumor Suppressor Am. J. Pathol., June 1, 2001; 158(6): 1895 - 1898. [Full Text] [PDF]
|
|
|
|
|
|
K. Kurose, X.-P. Zhou, T. Araki, S. A. Cannistra, E. R. Maher, and C. Eng Frequent Loss of PTEN Expression Is Linked to Elevated Phosphorylated Akt Levels, but Not Associated with p27 and Cyclin D1 Expression, in Primary Epithelial Ovarian Carcinomas Am. J. Pathol., June 1, 2001; 158(6): 2097 - 2106. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L.-P. Weng, O. Gimm, J. B. Kum, W. M. Smith, X.-P. Zhou, D. Wynford-Thomas, G. Leone, and C. Eng Transient ectopic expression of PTEN in thyroid cancer cell lines induces cell cycle arrest and cell type-dependent cell death Hum. Mol. Genet., February 1, 2001; 10(3): 251 - 258. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Gimm, M. Armanios, H. Dziema, H. P. H. Neumann, and C. Eng Somatic and Occult Germ-line Mutations in SDHD, a Mitochondrial Complex II Gene, in Nonfamilial Pheochromocytoma Cancer Res., December 1, 2000; 60(24): 6822 - 6825. [Abstract] [Full Text]
|
|
|
|
|
|
A. Perren, P. Komminoth, P. Saremaslani, C. Matter, S. Feurer, J. A. Lees, P. U. Heitz, and C. Eng Mutation and Expression Analyses Reveal Differential Subcellular Compartmentalization of PTEN in Endocrine Pancreatic Tumors Compared to Normal Islet Cells Am. J. Pathol., October 1, 2000; 157(4): 1097 - 1103. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X.-P. Zhou, O. Gimm, H. Hampel, T. Niemann, M. J. Walker, and C. Eng Epigenetic PTEN Silencing in Malignant Melanomas without PTEN Mutation Am. J. Pathol., October 1, 2000; 157(4): 1123 - 1128. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Gimm, T. Attie-Bitach, J. A. Lees, M. Vekemans, and C. Eng Expression of the PTEN tumour suppressor protein during human development Hum. Mol. Genet., July 1, 2000; 9(11): 1633 - 1639. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Torres and R. Pulido The Tumor Suppressor PTEN Is Phosphorylated by the Protein Kinase CK2 at Its C Terminus. IMPLICATIONS FOR PTEN STABILITY TO PROTEASOME-MEDIATED DEGRADATION J. Biol. Chem., January 5, 2001; 276(2): 993 - 998. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
).
C: FTC (magnification,
x20) with mainly weak
(+) nuclear staining.
D: PTC (magnification,
x20) with weak
(+) nuclear staining.
E: UTC (magnification,
x20) with absent
(-) nuclear and
cytoplasmic staining. Note the intense immunostaining in the
endothelial cells, which serve as an internal positive control
(
, moderate 
, weak 
, and absent staining 
. NTT,
normal thyroid tissue. The y-axis represents percentage of
samples with various intensities of nuclear (top) or
cytoplasmic (bottom) staining.