| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Tumor Biology |
UroGenesys Inc., Santa Monica, California 90404
 |
ABSTRACT |
|---|
 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
|
INTRODUCTION |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
To understand the molecular events surrounding the progression of prostate cancer to androgen independence, we used LAPC-9, a human prostate cancer xenograft derived from a bone metastasis, which can mimic the transition from androgen dependence to androgen independence (5) . A subtractive hybridization method (6) was used to identify androgen-regulated genes by subtracting cDNAs from the LAPC-9 AI subline from cDNAs derived from the original LAPC-9 AD xenograft. This strategy resulted in the identification of the TMPRSS2 gene, which encodes a putative transmembrane serine protease (7) .
TMPRSS2 was predicted to be a type II transmembrane protein with an extracellular COOH terminus containing the protease domain and an intracellular NH2 terminus. TMPRSS2 was recently shown to be regulated by androgens in the LNCaP prostate cancer cell model (8) . To characterize the TMPRSS2 protein in prostate and prostate cancer, we generated MAbs toward the protease domain. Using these MAbs, we demonstrate that TMPRSS2 protein is highly expressed in prostate secretory epithelium and in prostate cancer and that the protein expression is also dependent on an androgen signal. The protease domain is released by an autocatalytic cleavage mechanism, resulting in its secretion into the extracellular space.
|
MATERIALS AND METHODS |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
The AD LAPC-4 and LAPC-9 xenografts were routinely passaged as small tissue chunks in SCID male mice (5 , 9) . AI sublines of the xenografts were derived as described previously (5 , 9) and passaged in castrated males or in female SCID mice.
Human tissues for RNA and protein analyses were obtained from the Human Tissue Resource Center at the University of California Los Angeles (Los Angeles, CA), from the National Disease Research Interchange (Philadelphia, PA), and from QualTek, Inc. (Santa Barbara, CA).
SSH.
Tumor tissue and cell lines were homogenized in Trizol reagent (Life
Technologies, Inc.) using 10 ml/gram tissue or 10
ml/108 cells to isolate total RNA. Polyadenylated
RNA was purified from total RNA using Qiagen’s Oligotex mRNA Mini and
Midi kits. SSH was performed using the PCR-Select cDNA Subtraction Kit
(Clontech, Palo Alto, CA; Ref. 6
). Tester cDNA was
derived from the AD LAPC-9 xenograft, whereas driver cDNA was obtained
from the AI subline of LAPC-9. SSH-derived gene fragments were
processed and analyzed as described previously (10)
.
Expression Analysis.
Northern blotting was performed on 10 µg of total RNA prepared from
cell lines and LAPC xenografts using random hexamer-labeled (Boehringer
Mannheim) TMPRSS2 cDNA. The human multitissue mRNA blots
containing 2 µg of mRNA per lane were purchased from Clontech and
probed with TMPRSS2 cDNA.
Constructs.
TMPRSS2 cDNA was isolated by screening a human prostate cDNA
library (Life Technologies, Inc.) using clone 20P1F12, a
TMPRSS2 SSH-derived fragment, as a probe. For protein
expression in 293T cells, TMPRSS2 was cloned into pcDNA 3.1
Myc-His (Invitrogen, Carlsbad, CA) and retroviral vector pSR
tkneo
(11)
. Cells were transfected with either
pSRtkneo-expressing TMPRSS2 or a COOH-terminal His-tagged
TMPRSS2.
Single point mutants of TMPRSS2 were generated using a
two-step PCR method. Arg-240, Arg-252, and Arg-255 were mutated to
glutamines, and Ser-441 was mutated to alanine. Using a full-length
cDNA clone as template, a 5'-TMPRSS2 PCR fragment was generated using
one mutagenic primer (5'-GGCCCTCCAGCGTCACCC-3' for S441A mutant,
5'-CCGCAGGCTATACATTGTAAAGAAACC-3' for R240Q,
5'-TCCTGCTCTGTTGGCTTGAGTTCA-3' for R252Q, and
5'-CCCACAATCTGGCTCTGGCG-3' for R255Q) and one 5'-specific
TMPRSS2 primer containing the start codon, a kozak sequence, and an
EcoRI site for cloning (5'CGAATTCGCAAGATGGCTTTGAAC-3'). The
3' fragment was generated by PCR using the reverse complement of the
mutagenic primer (5'-GGGTGACGCTGGAGGGCC-3' for S441A,
5'-GGTTTCTTTACAATGTATAGCCTGCGG-3' for R240Q,
5'-TGAACTCAAGCCAACAGAGCAGGA-3' for R252Q mutant, and
5'-CGCCAGAGCCAGATTGTGGG-3' for R255Q) and a 3'-specific TMPRSS2 primer
containing the stop codon and a XbaI site for cloning
(5'CGTCTAGATTAGCCGTCTGCCCTCA-3'). For the second round of PCR, the 3'
and 5' fragments were used as templates. The final PCR product was
digested with EcoRI and XbaI and cloned into
pSRMSV-tkNeo. Protein expression was analyzed after transfection
into 293T cells.
To generate PC-3 AR cells, AR cDNA was cloned into pSRMSV-tkNeo.
Retrovirus was generated (11)
by cotransfection of
retroviral expression plasmid with psi(-) amphotropic packaging
plasmid and used to infect PC-3 cells. Stable cell lines were generated
by selection in G418-containing media for 1–2 weeks.
Protein Analysis.
In vitro transcription/translation was performed using the
TNT Coupled Reticulocyte Lysate System (Promega, Madison, WI). Two µg
of DNA (luciferase or TMPRSS2 cDNA in pCMV-Sport-6) were
incubated with 40 µg of TNT lysate and 20 µCi of
[35S]methionine Trans-label (ICN,
Costa Mesa, CA). The reaction was terminated with SDS sample buffer and
analyzed by SDS-PAGE and autoradiography.
Mouse MAbs were generated toward a COOH-terminal region of the protease (residues 362–440) fused to bacterial GST. The GST-fusion protein was generated by PCR using the following primers to amplify the TMPRSS2 sequence: 5'-TTGAATTCCAAACCAGTGTGTCTGCCC-3' and 5'-AAGCTCGAGTCGTCACCCTGGCAAGAAT-3'. The PCR product was inserted into pGEX-4T-3 (Amersham Pharmacia Biotech) using the EcoRI and XhoI cloning sites. GST-fusion protein was purified and used to immunize mice. Hybridoma supernatants were screened by Western blotting using cell extracts from 293T cells expressing TMPRSS2-mycHis-tagged protein. 1F9, a hybridoma clone that specifically recognizes TMPRSS2 protein, was used for all subsequent studies. Western blotting of tissue, xenograft, and cancer cell line lysates was performed on 20 µg of cell lysate protein. Normalization of extracts was achieved by probing cell extracts with anti-GRB-2 antibodies (Transduction Laboratories, San Diego, CA).
TMPRSS2 Detection in Medium and Serum Samples.
Media was collected from TMPRSS2-expressing cells and analyzed directly
(20 µl) by Western blotting using 1F9 MAb. For immunoprecipitations,
1F9 MAb was covalently coupled to protein G beads using the
homobifunctional cross-linking reagent dimethyl pimelimidate (Pierce,
Rockford, IL). SCID mouse serum (100 µl) was diluted to 1 ml with
radioimmunoprecipitation assay buffer [25 mM Tris (pH
7.5), 150 mM NaCl, 0.5% sodium deoxycholate, 1% Triton
X-100, 1% SDS, and 2 mM EDTA], incubated with 50 µl of
a 50% (w/v) 1F9-coupled protein G bead slurry, and immunoprecipitated
at 4°C overnight. Immunoprecipitates were washed with
radioimmunoprecipitation assay buffer, eluted in SDS-sample buffer, and
analyzed by Western blotting.
Immunohistochemistry.
Immunohistochemical analysis of formalin-fixed, paraffin-embedded
tissues with 1F9 MAb was performed on 4-µm tissue sections. After
steam treatment in sodium citrate (10 mM, pH 6.0), slides
were incubated with 10 µg/ml 1F9 MAb followed by an incubation with
biotinylated rabbit antimouse IgG. Competitive inhibition studies
were carried out in the presence of 50 µg/ml GST or GST-TMPRSS2
fusion protein. The reactions were visualized using avidin-conjugated
horseradish peroxidase (Vector Laboratories, Burlingame, CA).
|
RESULTS |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
. All six differences were confirmed by sequencing additional
TMPRSS2 cDNA clones and gene fragments derived from normal
prostate and LAPC-4 and LAPC-9 xenograft cDNA libraries. All of these
differences occur in the putative extracellular domain; two of them
(amino acids 160 and 242) reside in the SRCR domain, whereas the others
are all located within the protease domain.
|
. Similar expression levels were detected in prostate, LAPC-4 AD,
LAPC-4 AI, LAPC-9 AD, and LNCaP cells. Lower levels of
TMPRSS2 were seen in LAPC-9 AI and PC-3 cells, with no
expression seen in DU145. High levels of TMPRSS2 expression
were also detected in three of four colon cancer cell lines, including
LoVo, T84, and Colo-205 (Fig. 2)
. Analysis of other cancer cell lines,
including breast, testicular, ovarian, pancreatic and cervical showed
no detectable expression (data not shown).
|
, confirming the results
obtained by Lin et al. (8)
. Lower expression
levels were also detected in pancreas, kidney, and lung. No significant
expression was detected in small intestine.
TMPRSS2 Protein Is Proteolytically Cleaved in Tissues and Cell
Lines.
In vitro-translated TMPRSS2 appears predominantly as the
predicted Mr 54,000 protein, with a
minor breakdown product of Mr 32,000
(Fig. 3A)
. Mouse MAbs were generated toward the protease domain of
TMPRSS2 to study its expression pattern in cells and tissues. Western
blotting of protein extracts from 293T cells using the 1F9 MAb showed
equal expression of two protein species with apparent molecular weights
of 70,000 and 32,000 only in TMPRSS2-transfected cells and
not in control vector-transfected cells (Fig. 3)
. Similar results were
obtained using other MAbs directed against TMPRSS2 (data not shown).
The Mr 70,000 cellular isoform of
TMPRSS2 is larger than the predicted and in vitro-translated
full-length protein, suggesting that it is modified, possibly by
glycosylation. The TMPRSS2 protein sequence contains three
possible N-linked glycosylation sites at residues 128, 213, and 249.
Preliminary studies using N-glycosidase F-treated TMPRSS2 protein
indicate that the protein is indeed glycosylated and that glycosylation
accounts for some of the difference between the predicted and observed
molecular weight of cellular TMPRSS2 (data not shown). The
Mr 32,000 form may be a
proteolytically cleaved fragment containing the COOH-terminal epitopes
recognized by the antibody.
|
. Analysis of three prostate cancer
specimens and the matched adjacent tissue with apparently normal
morphology showed significant expression of TMPRSS2 protein in all
samples (Fig. 3D)
. High expression was also detected in the
colon cancer cell line Colo-205 (Fig. 3B)
.
TMPRSS2 Protein Expression Is Dependent on the AR Signal.
Our analysis above shows that expression of TMPRSS2 protein
is undetectable in the AI LAPC-9, PC-3, and DU145 cell lines. To extend
these findings, as well as the observation by Lin et al.
(8)
that TMPRSS2 message is androgen regulated
in LNCaP cells, we androgen-deprived LNCaP cells and an LAPC-9 AD cell
line derived from the LAPC-9 AD xenograft, which expresses the
wild-type AR and PSA (data not shown). TMPRSS2 protein expression in
the androgen-deprived cells was compared with expression in LNCaP cells
(Fig. 4A)
and LAPC-9 AD cells (Fig. 4B)
after treatment
with mibolerone, a synthetic androgen. The results show that TMPRSS2
expression was significantly reduced during androgen deprivation in
both cell lines and reappeared during mibolerone treatment. PSA protein
levels were measured in parallel, showing a similar regulation (data
not shown).
|
. However, PC-3
cells that have been engineered to express the wild-type AR (PC-3 AR)
express significant levels of TMPRSS2 when treated with mibolerone
(Fig. 4C)
. Interestingly, only the full-length TMPRSS2
protein is detected in untreated PC-3 AR cells and control PC-3 neo
cells. Treatment with mibolerone not only increases total TMPRSS2
expression but also induces expression of the
Mr 32,000 cleavage product. This
indicates that TMPRSS2 expression in prostate cancer cells is dependent
on an androgen signal and that cleavage may be a function of expression
level.
TMPRSS2 Protease Is Released into Cell Culture Medium and Mouse
Serum by Prostate Cancer Cells.
Structural predictions for TMPRSS2 suggest that it is a type II
transmembrane protein with an extracellular protease domain (Fig. 1)
.
The size of the cleaved Mr 32,000
TMPRSS2 fragment suggests that it contains the entire protease region.
Cleavage of this domain is thus predicted to result in the release of
the protease into the extracellular space. To test this hypothesis,
media were collected from androgen-starved and androgen-stimulated
LNCaP cells. The media were then analyzed for the presence of TMPRSS2
protein by Western blotting using anti-TMPRSS2 MAb. The results show a
clear detection of cleaved TMPRSS2 protein in the media of
androgen-stimulated cells, but not in androgen-deprived cells (Fig. 4D)
. The amount of protease present in the media is directly
correlated to the amount of TMPRSS2 protein present in the cell
extracts, which increases with an increased dose of mibolerone (Fig. 4D)
. Similar release of protease into cell media was also
observed for PC-3 AR cells that were treated with mibolerone (Fig. 4D)
. Secreted TMPRSS2 protease is also detected in the sera
of male mice that harbor LNCaP tumors, but not in sera derived from
naïve males (Fig. 4D)
. The
Mr 70,000 form of TMPRSS2 is not
detected in the cell media of TMPRSS2-expressing cells or in the sera
of LNCaP tumor-bearing mice.
TMPRSS2 Cleavage Is a Consequence of Autocatalytic Activity.
To determine whether the cleavage of TMPRSS2 is dependent on its own
catalytic activity, Ser-441 of the catalytic triad in the protease
domain was mutated to alanine (S441A). Mutant TMPRSS2 cDNA was cloned
into a retroviral vector for expression in 293T cells. Western blot
analysis of cell extracts of 293T cells transfected with either
wild-type or S441A mutant TMPRSS2 showed that in contrast to wild-type
protein, TMPRSS2 S441A appeared as a single protein species with an
apparent molecular weight of 70,000 (Fig. 5)
. Cell media analysis shows the presence of the cleaved
Mr 32,000 protease domain only in
media collected from cells transfected with wild-type TMPRSS2 and not
in media from S441A-transfected cells (data not shown). TMPRSS2 with a
COOH-terminal myc-His tag also showed predominant expression of the
full-length tagged protein, although some cleavage product is detected
(Fig. 5)
. The myc-His tag at the COOH terminus of the protease domain
may exert some inhibitory activity on the proteolytic cleavage. These
results suggest that the proteolytic cleavage of TMPRSS2 in cells and
tissues is a consequence of autocatalytic activity.
|
TMPRSS2 Is Expressed in the Secretory Epithelia of Prostate and
Prostate Cancer Cells.
The expression of TMPRSS2 in prostate cancer biopsies and surgical
samples was examined by immunohistochemical analysis. Specific staining
of TMPRSS2 protein was validated using LNCaP cells that were androgen
deprived for 1 week and then either left untreated or stimulated with
mibolerone for 9 h. The cells were then fixed, embedded in
paraffin, and stained with the 1F9 MAb. TMPRSS2 staining of
androgen-deprived LNCaP showed very little staining of the cells. In
contrast, the majority of androgen-stimulated cells showed strong
intracellular staining (Fig. 6, a and b)
. LNCaP cells growing in regular media
exhibited staining similar to that seen in androgen-stimulated cells
(data not shown). The majority of staining appeared to be localized to
granular structures within the cell.
|
; Table 1
). The signal appeared to be strongest at the apical side of the
secretory cells, and in most cases granular staining was seen, as
observed in LNCaP. The prostate tissue staining was specific because
GST-TMPRSS2 immunogen could competitively inhibit staining of prostate
cancer tissue, whereas GST alone could not (Fig. 6, e and f)
. Similar to PSA, TMPRSS2 protein was found to accumulate
within the lumen of the epithelial glands (Fig. 6, g and h)
, indicating that TMPRSS2 protein is secreted by the
secretory epithelia. This staining pattern is in contrast to the RNA
in situ hybridization analysis, which showed expression of
TMPRSS2 RNA primarily in the basal cell layer of normal
prostate glands and not in the secretory epithelium (8)
.
It is possible that TMPRSS2 RNA is present in both
compartments, but that basal cell RNA is more stable.
|
, including kidney and lung, which express some
TMPRSS2 message. Protein expression was detected in normal
pancreas samples and normal colon and colon cancer tissues (Table 1)
.
The pancreatic staining was restricted to the pyramidal exocrine acinar
cells, with no staining detected in the islets of Langerhans (data not
shown). The staining in normal colon appeared primarily within crypts
of the mucosal lining but was significantly less intense than normal
prostate staining (data not shown). The staining in colon cancer seemed
to concentrate in luminal areas, indicating possible secretion of the
antigen by colon cancer cells. |
DISCUSSION |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
In prostate cancer cells and tissues, TMPRSS2 is regulated by an androgen signal. Androgen deprivation and stimulation experiments in LAPC-9 xenograft and LAPC-9 cell line, which express the wild-type AR (5) , and in LNCaP cells show that TMPRSS2 protein expression is increased with androgen stimulation. PC-3 cells, which do not normally express the AR (12) and grow in an AI manner, express little TMPRSS2. However, constitutive expression of the wild-type AR in PC-3 cells and simultaneous stimulation with androgen induce the expression of TMPRSS2 protein. PSA expression in PC-3 cells can also be induced by heterologous expression of the AR and concomitant androgen stimulation (13) . These studies demonstrate that, similar to PSA, TMPRSS2 protein expression is critically dependent on the AR pathway.
Prostate tissue expresses a number of androgen-regulated proteases, including PSA, human glandular kallikrein and prostase/KLK-L1 (14, 15, 16) . TMPRSS2 is unique among these proteases due to its structural features. It is a putative type II transmembrane protease with a SRCR and a LDLRA domain (7) . The protease domain is located at the COOH terminus, which is postulated to be extracellular. These features suggested that TMPRSS2 protein is expressed at the cell membrane and could function as a receptor for other proteins or small molecules. The TMPRSS2 protease domain is most homologous to hepsin (also a type II transmembrane protease), which lacks the SRCR and LDLRA domains (17) and is up-regulated in ovarian cancer (18) . Subcellular fractionation studies localized hepsin to the membraneous fraction of cultured HepG2 cells (19) . Our studies show that a significant fraction of TMPRSS2 protein is proteolytically cleaved and secreted. The remaining regions, including the LDLRA and the SRCR domains, are possibly still membrane associated and could function as receptors independent of the protease domain.
Mutational inactivation of the TMPRSS2 protease shows that the cleavage
of the protease is a consequence of its own catalytic activity,
suggesting that TMPRSS2 may be its own substrate. Alternatively,
TMPRSS2 activates a secondary protease that then cleaves the
TMPRSS2 protease. Both interpretations require an active TMPRSS2
protease. Similar autocatalytic cleavage has also been observed for
hepsin (20)
. Site-directed mutagenesis shows that the
cleavage of TMPRSS2 occurs at Arg-255 and results in the release of the
protease domain. Western blot analysis using anti-TMPRSS2 MAb, directed
to the protease domain, demonstrated that only the
Mr 32,000 protease fragment is
secreted by prostate cancer cells and xenografts into the media or
sera, respectively (Fig. 4D)
. These findings suggest that
the protein accumulated in the glandular lumen of normal and cancerous
prostate tissues is the cleaved protease fragment. Proliferation and
metastasis of cancer cells, associated with destruction of the normal
tissue architecture, may cause a rise in serum TMPRSS2 levels
that would signify the presence of cancer cells. These data suggest
that released TMPRSS2 protease may be useful as a potential serum
diagnostic or prognostic marker for prostate and possibly colon
cancer.
Secreted TMPRSS2 protease may be involved in processing and activating growth factors present in the extracellular space. Recent work with PSA and human glandular kallikrein have shown that they may play a role in activating growth factors important in the osteoblastic response of bone-metastasized prostate cancer (21) . One of these factors, parathyroid hormone-related protein, has been shown to increase the rate of prostate tumor growth in vivo and protect LNCaP cells from apoptosis (22) . IGFBP-3, an inhibitor of insulin-like growth factor I, has also recently been shown to be a substrate for PSA (23 , 24) . Cleavage of IGFBP-3 results in an increase in active insulin-like growth factor I, a growth factor implicated in prostate cancer cell growth (23 , 25) . It remains to be seen whether TMPRSS2 is capable of acting on parathyroid hormone-related protein, IGFBP-3, and/or other factors that could influence prostate cancer growth. The expression pattern and localization of TMPRSS2 make it a potential target for therapy in cancers of the prostate.
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
1 Present address: EOS Biotechnology, South San
Francisco, CA 94080. 
2 To whom requests for reprints should be
addressed, at UroGenesys Inc., 1701 Colorado Avenue, Santa Monica, CA
90404. Phone: (310) 820-8029, ext. 216; Fax: (310) 820-8489; E-mail: ajakobovits{at}urogenesys.com
3 The abbreviations used are: PSA,
prostate-specific antigen; MAb, monoclonal antibody; GST, glutathione
S-transferase; AD, androgen-dependent; AI,
androgen-independent; SCID, severe combined immunodeficient; SSH,
suppression subtractive hybridization; AR, androgen receptor; SRCR,
scavenger receptor cysteine-rich; LDLRA, low-density lipoprotein
receptor A; IGFBP-3, insulin-like growth factor-binding protein 3; CSS,
charcoal-stripped serum.
Received 7/ 5/00. Accepted 12/15/00.
|
REFERENCES |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
This article has been cited by other articles:
|
|
 |
|
  T. H. Bugge, T. M. Antalis, and Q. Wu Type II Transmembrane Serine Proteases J. Biol. Chem., August 28, 2009; 284(35): 23177 - 23181. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. J. Ramsay, J. D. Hooper, A. R. Folgueras, G. Velasco, and C. Lopez-Otin Matriptase-2 (TMPRSS6): a proteolytic regulator of iron homeostasis Haematologica, June 1, 2009; 94(6): 840 - 849. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Shirogane, M. Takeda, M. Iwasaki, N. Ishiguro, H. Takeuchi, Y. Nakatsu, M. Tahara, H. Kikuta, and Y. Yanagi Efficient Multiplication of Human Metapneumovirus in Vero Cells Expressing the Transmembrane Serine Protease TMPRSS2 J. Virol., September 1, 2008; 82(17): 8942 - 8946. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. J. Ramsay, Y. Dong, M. L. Hunt, M. Linn, H. Samaratunga, J. A. Clements, and J. D. Hooper Kallikrein-related Peptidase 4 (KLK4) Initiates Intracellular Signaling via Protease-activated Receptors (PARs): KLK4 AND PAR-2 ARE CO-EXPRESSED DURING PROSTATE CANCER PROGRESSION J. Biol. Chem., May 2, 2008; 283(18): 12293 - 12304. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Bottcher, T. Matrosovich, M. Beyerle, H.-D. Klenk, W. Garten, and M. Matrosovich Proteolytic Activation of Influenza Viruses by Serine Proteases TMPRSS2 and HAT from Human Airway Epithelium J. Virol., October 1, 2006; 80(19): 9896 - 9898. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K.-i. Kiyomiya, M.-S. Lee, I-C. Tseng, H. Zuo, R. J. Barndt, M. D. Johnson, R. B. Dickson, and C.-Y. Lin Matriptase activation and shedding with HAI-1 is induced by steroid sex hormones in human prostate cancer cells, but not in breast cancer cells Am J Physiol Cell Physiol, July 1, 2006; 291(1): C40 - C49. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Tomlins, R. Mehra, D. R. Rhodes, L. R. Smith, D. Roulston, B. E. Helgeson, X. Cao, J. T. Wei, M. A. Rubin, R. B. Shah, et al. TMPRSS2:ETV4 gene fusions define a third molecular subtype of prostate cancer. Cancer Res., April 1, 2006; 66(7): 3396 - 3400. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. S. Kim, C. Heinlein, R. C. Hackman, and P. S. Nelson Phenotypic Analysis of Mice Lacking the Tmprss2-Encoded Protease Mol. Cell. Biol., February 1, 2006; 26(3): 965 - 975. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L.-Y. Luo, S. J.C. Shan, M. B. Elliott, A. Soosaipillai, and E. P. Diamandis Purification and Characterization of Human Kallikrein 11, a Candidate Prostate and Ovarian Cancer Biomarker, from Seminal Plasma Clin. Cancer Res., February 1, 2006; 12(3): 742 - 750. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Tomlins, D. R. Rhodes, S. Perner, S. M. Dhanasekaran, R. Mehra, X.-W. Sun, S. Varambally, X. Cao, J. Tchinda, R. Kuefer, et al. Recurrent Fusion of TMPRSS2 and ETS Transcription Factor Genes in Prostate Cancer Science, October 28, 2005; 310(5748): 644 - 648. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Zhang, X.-W. Wang, D. Jelovac, T. Nakanishi, M.-h. Yu, D. Akinmade, O. Goloubeva, D. D. Ross, A. Brodie, and A. W. Hamburger The ErbB3-binding protein Ebp1 suppresses androgen receptor-mediated gene transcription and tumorigenesis of prostate cancer cells PNAS, July 12, 2005; 102(28): 9890 - 9895. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A Noel, C Maillard, N Rocks, M Jost, V Chabottaux, N E Sounni, E Maquoi, D Cataldo, and J M Foidart Membrane associated proteases and their inhibitors in tumour angiogenesis J. Clin. Pathol., June 1, 2004; 57(6): 577 - 584. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Cal, V. Quesada, C. Garabaya, and C. Lopez-Otin Polyserase-I, a human polyprotease with the ability to generate independent serine protease domains from a single translation product PNAS, August 5, 2003; 100(16): 9185 - 9190. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Velasco, S. Cal, V. Quesada, L. M. Sanchez, and C. Lopez-Otin Matriptase-2, a Membrane-bound Mosaic Serine Proteinase Predominantly Expressed in Human Liver and Showing Degrading Activity against Extracellular Matrix Proteins J. Biol. Chem., September 27, 2002; 277(40): 37637 - 37646. [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 |
