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Cedars-Sinai Research Institute-UCLA School of Medicine
(X.Z., G.A.H., T.R.P., A.V., M.N., S.M.) Los Angeles, California
90048
Neuroendocrine Unit (M.D.B.) Division of Functional
Neurosurgery University of São Paulo Medical School
São Paulo, SP, Brazil 01406-100
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ABSTRACT |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Pituitary tumors are well differentiated adenomas accounting for
10% of intracranial neoplasms, and clinically silent pituitary
microadenomas are encountered in up to 23% of unselected adult
autopsies (11, 12). These monoclonal adenomas are either nonfunctioning
and do not secrete pituitary trophic hormones or are functioning and
secrete one or more hormones including PRL, GH, ACTH, or rarely,
glycoprotein hormones. These hypersecretory syndromes are associated
with hypogonadism, infertility, acromegaly, Cushing’s disease, or
rarely, hyperthyroidism (13). Most pituitary tumors are histologically
benign. True pituitary carcinomas are extremely rare, and documentation
of distant metastasis is the sole diagnostic criterion for malignancy
(14).
Pituitary tumor pathogenesis has been extensively studied (15). Several
intrinsic mutations resulting in activation of tumor-promoting genes as
well as inactivation of tumor suppressor genes have been described,
including G protein (Gs
) mutations (16, 17), rarely
occurring ras mutations in invasive tumors (18, 19), loss of
heterozygosity involving the 11q13 region (20), loss of purine-binding
factor gene (nm23) expression (21), and, in mouse models, disruption of
RB (22) and cyclin-dependent kinase inhibitors (23, 24). However, only
G protein mutations have reproducibly been identified in a subset of
sporadic GH-secreting pituitary adenomas (25). The molecular etiology
of these tumors remains elusive, and other mechanisms may be invoked in
pituitary tumorigenesis. Recently, a novel pituitary tumor-transforming
cDNA (PTTG) was isolated in our laboratory from rat GH4 pituitary tumor
cells (26). Overexpression of rat PTTG resulted in cell transformation
in vitro and induced in vivo tumor formation in
athymic mice.
We now characterize the human pituitary tumor-transforming gene (PTTG). It is abundantly expressed in malignant tumor cells, as well as in some normal tissues, and potently transforms cells both in vitro and in vivo. Overexpression of PTTG in transfected NIH 3T3 cells increases basic FGF mRNA level as well as stimulates its secretion. As point mutations in a proline-rich region near the PTTG C terminus abrogate its transforming ability and block basic FGF production, PTTG function in tumorigenesis may involve intracellular SH3 signals and growth factor production.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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). The presence of an in-frame stop
codon before the predicted initiation codon suggests that it is
complete. The homology between DNA sequences of this open reading frame
and the coding region of rat PTTG is 85%. Amino acid sequence
comparison between the translated product of this cDNA and rat PTTG
protein reveals 77% identity and 89% homology. Since all positive
clones were sequenced and no other cDNA fragment with higher homology
was detected in the library, it appears that these cDNA clones
represent human homologs of rat PTTG.
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). This proline-rich region contains two PXXP
motifs consistent with the previously identified SH3-binding site (27).
The presence of these functional motifs suggests that human PTTG
protein may be involved in SH3 domain-mediated signal transduction
pathways (28, 29).
The human PTTG cDNA was used to screen a human genomic library, and
positive genomic clones were subjected to sequence analysis. The
results were compared with the cDNA sequence of human PTTG and revealed
four introns within the coding region (Fig. 1a).
Chromosomal Localization of Human PTTG
DNA from the Stanford Human-Hamster G3 Radiation Hybrid Mapping
Panel was used as template in PCR reactions with PTTG-specific primers.
The amplified products were sequenced to confirm that they indeed
contain human PTTG sequences. By electronic analysis at the Stanford
Human Genome Center website, PTTG was localized to 21.01
centirads from the marker D5S2576 with a LOD score of
8.48. According to neighboring Genethon markers in the SCIENCE96
Transcription Map, this marker is most likely located within the
interval 5q32–34 of chromosome 5.
This mapping result was further confirmed by fluorescence in
situ hybridization (FISH), using a 16-kb human genomic fragment
containing PTTG as a probe. The initial experiment resulted in specific
labeling of the distal long arm of a group B chromosome, which was
believed to be chromosome 5 based on its size, morphology, and banding
pattern. In a second experiment, a probe previously mapped to 5q21 was
cohybridized with PTTG, resulting in specific labeling of the middle
and distal long arm of chromosome 5, respectively (Fig. 2a). Among a total of 80 metaphase cells
analyzed, 63 exhibited specific labeling, showing that human PTTG is
located at a position that is 84% the distance from the centromere to
the telomere of chromosome arm 5q, an area corresponding to band 5q33
according to the International System for Human Cytogenetic
Nomenclature 1995. Thus, the results concur and localize PTTG to 5q33
(Fig. 2b).
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. A strong mRNA signal of
approximately 0.8 kb was detected in human fetal liver (Fig. 3b). In
normal human adult tissues, abundant PTTG expression was evident in
testis. Strong expression was also observed in thymus, and weak
expression signals were seen in colon, small intestine, brain,
placenta, and pancreas (Fig. 3a). Interestingly, when human malignant
tumor cells were tested, PTTG was found to be highly expressed in all
cell lines examined (Fig. 3c). PTTG mRNA was also detected in several
human pituitary tumors, including nonfunctioning, PRL-secreting, and
ACTH-secreting tumors (Fig. 3d). No mutations of the PTTG-coding region
in tumors were detected by RT-PCR followed by sequence analysis (data
not shown).
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). The point mutations did not change
protein expression or susceptibility to proteolysis, since PTTG protein
with the same molecular weight was expressed in each transfected cell
type at similar levels, as shown by Western blot (Fig. 4c). The
transforming ability of these cells was tested in an
anchorage-independent growth assay. We found that NIH 3T3 cells
overexpressing PTTG formed large colonies (numbers ranged from 198
± 6 to 267 ± 23 colonies per plate, mean ± SD)
on soft agar, while control NIH 3T3 cells containing the same
expression vector but lacking PTTG cDNA insert did not induce
significant colony foci under the same conditions (22 ± 1
colonies per plate) (Table 1). In
contrast, the number and size of colonies formed from NIH 3T3 cells
expressing mutant PTTG were greatly reduced (ranging from 57 ± 6
to 60 ± 5 colonies per plate) (Table 1 and Fig. 5). Furthermore, when these cells were
injected subcutaneously into athymic nude mice, PTTG-overexpressing
cells caused tumor formation within 2 weeks in all five injected
animals (tumor weights ranged from 560 to 1000 mg) (Fig. 6). In five mice injected with control
transfectants (expression vector alone), only one developed a much
smaller tumor weighing only 100 mg. As expected, when cells expressing
mutant PTTG were injected into nude mice, no tumor formation was
observed even after 3 weeks of injection (Fig. 6), consistent with the
results obtained in the anchorage-independent growth assay. These
results thus demonstrate the in vitro transforming activity
and in vivo tumor-inducing potential of human PTTG and also
strongly suggest that signaling protein(s) containing SH3 domain(s)
mediate PTTG action.
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). In the cells
transfected with mutant PTTG, the abundance of bFGF mRNA transcripts
was low, similar to that observed in the control cells.
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, bFGF levels
were markedly higher in the conditioned medium collected from wild-type
human PTTG transfectants cultured for 72 h than those from control
and mutant transfectants. Differences of total protein concentrations
in these cultures were less than 10%. Therefore, PTTG not only
enhances bFGF mRNA levels, but also stimulates bFGF secretion. The PTTG
proline-rich region containing two SH3-binding motifs appears critical
for this function. |
DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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In normal adult rat tissues, PTTG expression is restricted to the testis (26). The normal tissue distribution of human PTTG is also limited; however, it is not restricted to testis but is also expressed in thymus, colon, small intestine, and, weakly, in brain and placenta, indicating that it may also play a role in certain normal cellular functions. The expression of human PTTG in fetal liver, but not in adult liver, suggests that it is differentially regulated and possibly functions during development. Interestingly, PTTG is highly expressed in all carcinoma cell lines tested, suggesting that it is a common and important factor for most malignant tumor types.
The chromosomal location of human PTTG, 5q33, is associated with reports of recurrent neoplastic abnormalities, including myeloid leukemia, chronic myeloproliferative disorder, myelodysplastic syndrome, squamous cell carcinoma, and lipoma (30). Using RT-PCR and direct sequencing, we examined PTTG in several human carcinoma cell lines, including cervix carcinoma HeLa cell, choriocarcinomas JEG-3 and JAR, breast adenocarcinoma MCF-7, osteogenic sarcoma U-2 OS, hepatocellular carcinoma Hep 3B, lung carcinoma EY, and thyroid carcinoma TC-1. Although no mutation was detected within the PTTG coding region, PTTG expression levels were high in all carcinoma cell lines tested. Thus, putative mutations in the gene-regulatory regions may cause PTTG dysregulation, and enhanced PTTG expression may mediate neoplastic cell transformation. We also found that PTTG mRNA was expressed in several pituitary tumors, indicating that it may be involved in pituitary tumorigenesis. Interestingly, PTTG mRNA levels in benign pituitary tumors, in general, were much lower than in malignant carcinomas (31). Therefore, although it seems that tumor PTTG expression correlates with malignancy, further confirmation is needed.
The transforming ability and high level of PTTG expression in malignant tumors demonstrate its involvement in tumorigenesis, although mechanisms of PTTG action and its relationship to other oncogene or tumor suppressor gene products is yet unclear. The presence of a basic amino acid-rich region and a proline-rich region in PTTG protein provide insights regarding its function. Basic amino acid-rich domains have been suggested as a nuclear localization signal (31, 32, 33), although the subcellular localization of PTTG is still undetermined. The proline-rich region of the human PTTG protein contains two PXXP motifs, which are potential binding sites for SH3-domains (27), important mediators of intracellular signal transduction (28, 34). Several proteins have recently been identified to contain PXXP motifs and bind to SH3 domains, such as GDP/GTP exchange factor SOS (35, 36), protein kinases JNK and phosphatidylinositol 3-kinase (37, 38), and the Abl oncogene product (39, 40). We report here that point mutations in the PXXP motif of human PTTG abrogated its transforming and tumor-inducing activity, despite expression of PTTG mRNA and protein in these mutants. Thus, this PXXP motif is important for PTTG-mediated transformation. Alternatively, another mechanism for the function of this region could involve serine phosphorylation of adjacent regions (41).
Interestingly, PTTG induces bFGF production at both the mRNA and protein levels. bFGF is a major activating factor for angiogenesis (42, 43), a necessary process for the expansion of the primary tumor mass as well as tumor metastasis (9, 44, 45). This is also in concurrence with our finding that transfected cells overexpressing PTTG cause formation of solid tumors in nude mice. Increased bFGF expression has been reported in several human tumors, such as pancreatic carcinoma (46), endometrial adenocarcinoma (47), advanced renal cell carcinoma (48), primary breast cancer (49), and pituitary tumors (50), in which it is considered a stimulating growth factor (51). Considering that the bFGF receptor is a protein tyrosine kinase and that PTTG increases bFGF production, we propose that one of the mechanisms of tumorigenesis by PTTG involves an SH3 protein interacting with PTTG, stimulating gene transcription and secretion of bFGF, and resulting in cell transformation and tumor formation. This hypothesis is supported by our observation that mutations of the proline-rich region, the potential SH3-binding site, abrogate bFGF production as well as cell transformation. These results establish human PTTG as a potent tumor-promoting factor whose functions involve bFGF production and cell transformation.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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A human genomic library (Stratagene, La Jolla, CA) was screened according to the manufacturer’s protocol, using the radioactively labeled human cDNA clone containing the complete coding region as a probe. DNA from each positive phage clone was purified using Lambda DNA preparation kit (Qiagen, Valencia, CA) and sequenced with a thermocycle sequencing kit (Amersham, Arlington Heights, IL) and SequaGel System (National Diagnostics).
Determination of Human PTTG Chromosomal Location
Chromosomal localization of human PTTG was determined by PCR
analysis of the Stanford Human-Hamster G3 Radiation Hybrid (RH) Mapping
Panel (Research Genetics, Huntsville, AL) as well as by FISH. DNA from
83 samples in the G3 RH mapping panel were amplified in 20-µl
reactions containing 50 ng DNA, 1.75 U Expand High Fidelity enzyme
(Boehringer-Mannheim, Indianapolis, IN), 1x reaction buffer with 1.5
mM MgCl2, 0.2 mM deoxynucleoside
triphosphates (dNTPs), and 300 nM human PTTG-specific
primers, 5'-CTGCCT-CAGATGATGCCTATCCAG-3'and
5'-CAAGCTCTCTCTCCTCGTCAAGG-3'. The PCR reactions were performed for
35 cycles of 94 C, 15 sec; 60 C, 30 sec; 68 C, 2.5 min. PCR products
were visualized in 1% agarose gels stained with ethidium bromide and
scored as positive ("1") if a strong (3.5-kb PCR product) was
visualized, negative ("0") if the band was not visualized, or
ambiguous if a weak band was observed. The same results were obtained
when the panel was again amplified with GIBCO-BRL (Gaithersburg, MD)
Taq DNA polymerase. These data were submitted electronically
to the Stanford Human Genome Center website to determine linkage to
previously mapped markers. The FISH was performed at GenomeSystem, Inc.
(St. Louis, MO). Briefly, a 16-kb human genomic fragment containing
PTTG was labeled with digoxigenin dUTP by nick translation. Labeled
probe was combined with sheared human DNA and hybridized to normal
metaphase chromosomes derived from phytohemagglutinin-stimulated
peripheral blood lymphocytes. Specific hybridization signals were
detected by incubating the hybridized slides in fluoresceinated
antidigoxigenin antibodies followed by counterstaining with
4,6-diamidino-2-phenylindole (DAPI).
Northern Blot Analysis
RNA blots (CLONTECH, Palo Alto, CA) derived from normal human
adult and fetal tissue, as well as from malignant tumor cell lines and
fresh pituitary tumor specimens, were hybridized with a 0.7-kb
radiolabeled human cDNA fragment containing the complete coding region.
Northern blot analysis was performed using ExpressHyb Solution
(CLONTECH) or QuickHyb Solution (Stratagene, La Jolla, CA) according to
the manufacturer’s protocol.
Western Blot Analysis
An antirat PTTG polyclonal antibody was developed as described
previously (26). This antibody was purified by a PTTG affinity column
that couples 10 mg synthetic antigenic peptide with HiTrap
N-hydroxysuccinimide-activated column (Pharmacia,
Piscataway, NJ) according to manufacturer’s protocol. The affinity
column was washed with 75 mM Tris-HCl, pH 8.0, until no
protein appeared in the eluent. The purified antibody was eluted with
0.1 M glycine, 0.5 M NaOH, pH 2.7, and
neutralized with each volume of 2 N Tris-HCl, pH 8.0.
Western blot was performed as described previously (26) using this
purified antibody (1:100 dilution).
Stable Transfection of Human PTTG into NIH 3T3 Cells
The complete coding region of human PTTG cDNA was subcloned in
frame into mammalian expression vectors pBK-CMV (Stratagene) or pCI-neo
(Promega, Madison, WI) and transfected into NIH 3T3 fibroblast cells
with Lipofectamine (GIBCO-BRL) according to the manufacturer’s
protocol. Twenty-four hours after transfection, cells were serially
diluted and grown in selection medium containing 1 mg/ml G418 for 2
weeks. Individual clones were isolated and maintained in selection
medium. Total RNA was isolated from human PTTG-transfected cell lines
as well as from control cells in which the vector pBK-CMV or pCI-neo
had been transfected. Overexpression of human PTTG in each transfected
cell line was confirmed by Northern blotting.
Site-Directed Mutagenesis
Point mutations on the proline-rich domain of PTTG peptide were
generated by PCR-based site-directed mutagenesis. Two synthetic
oligonucleotides, 5'-GATGCTCTCCGCACTCTGGGAATCCAATCTG-3' and
5'-TTCACAAGTTGAGGGGCGCCCAGCTGAAACAG-3', which would cause amino acid
changes P163A, P170L, P172A, and P173L, were used to amplify human PTTG
cDNA cloned into pBlueScript-SK vector (Stratagene). The amplified cDNA
containing these mutations was then cloned into pCI-neo (Promega) and
used in stable transfection. Expression of mutated PTTG product in
transfected cells was confirmed by Northern analysis and RT-PCR
followed by direct sequence analysis.
In Vitro and in Vivo Transformation
Assay
Control and human PTTG-transfected cells were tested for
anchorage-independent growth in soft agar (53). Three milliliters of
soft agar (20% 2x DMEM, 50% DMEM, 10% FBS, and 20% 2.5% agar,
melted and mixed at 45 C) were added to 35-mm tissue culture dishes.
Ten thousand cells were mixed with 1 ml soft agar and added to each
dish. Cells were incubated for 2 weeks before colonies were counted and
photographed. For in vivo transformation, 1 x
105 control or human PTTG-transfected cells were
resuspended in 400 µl PBS and injected subcutaneously into nude mice
(five mice for each group). After two weeks, animals were photographed
and tumors were excised and weighed.
Hybridization with VEGF and bFGF cDNA Probes
The cDNA probes for VEGF and bFGF were generated by RT-PCR using
specific primers according to the published sequences (54, 55). These
cDNAs generated from PCR were cloned and confirmed by sequence
analysis. Total RNAs from cultured cells were extracted using Trizol
Reagent (GIBCO-BRL) and used in Northern analysis as described
previously (56).
ELISA of bFGF in Conditioned Medium
bFGF concentration in cell culture medium was assayed using
Quantikine HS Human FGF Basic Immunoasssay Kit (R&D Systems,
Minneapolis, MN) according to the manufacturer’s protocol. Cells
(1 x 105) were plated in 100-mm cell culture dishes.
After 72 h, the culture medium was collected, and 1 ml was
lyophilized and resuspended in 200 µl PBS for ELISA assay.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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This work was supported by NIH Grant DK-50238 (S.M.), Institutional Training Grant DK-7682 (X.Z.), and the Doris Factor Molecular Endocrinology Laboratory.
Received for publication July 23, 1998. Revision received October 5, 1998. Accepted for publication October 8, 1998.
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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J. Zhao, D. Dahle, Y. Zhou, X. Zhang, and A. Klibanski Hypermethylation of the Promoter Region Is Associated with the Loss of MEG3 Gene Expression in Human Pituitary Tumors J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 2179 - 2186. [Abstract] [Full Text] [PDF]
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 K Boelaert, R Yu, L A Tannahill, A L Stratford, F L Khanim, M C Eggo, J S Moore, L S Young, N J L Gittoes, J A Franklyn, et al. PTTG's C-terminal PXXP motifs modulate critical cellular processes in vitro J. Mol. Endocrinol., December 1, 2004; 33(3): 663 - 677. [Abstract] [Full Text] [PDF]
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J. Tfelt-Hansen, S. Yano, S. Bandyopadhyay, R. Carroll, E. M. Brown, and N. Chattopadhyay Expression of Pituitary Tumor Transforming Gene (PTTG) and Its Binding Protein in Human Astrocytes and Astrocytoma Cells: Function and Regulation of PTTG in U87 Astrocytoma Cells Endocrinology, September 1, 2004; 145(9): 4222 - 4231. [Abstract] [Full Text] [PDF]
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A. Bahar, D. J. Simpson, S. J. Cutty, J. E. Bicknell, P. R. Hoban, S. Holley, M. Mourtada-Maarabouni, G. T. Williams, R. N. Clayton, and W. E. Farrell Isolation and Characterization of a Novel Pituitary Tumor Apoptosis Gene Mol. Endocrinol., July 1, 2004; 18(7): 1827 - 1839. [Abstract] [Full Text] [PDF]
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X. Zhang, Y. Zhou, K. R. Mehta, D. C. Danila, S. Scolavino, S. R. Johnson, and A. Klibanski A Pituitary-Derived MEG3 Isoform Functions as a Growth Suppressor in Tumor Cells J. Clin. Endocrinol. Metab., November 1, 2003; 88(11): 5119 - 5126. [Abstract] [Full Text] [PDF]
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R. Yu, W. Lu, J. Chen, C. J. McCabe, and S. Melmed Overexpressed Pituitary Tumor-Transforming Gene Causes Aneuploidy in Live Human Cells Endocrinology, November 1, 2003; 144(11): 4991 - 4998. [Abstract] [Full Text] [PDF]
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 A. Lania, G. Mantovani, and A. Spada Genetics of Pituitary Tumors: Focus on G-Protein Mutations Experimental Biology and Medicine, October 1, 2003; 228(9): 1004 - 1017. [Abstract] [Full Text] [PDF]
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 K. BOELAERT, L. A. TANNAHILL, J. N. BULMER, S. KACHILELE, S. Y. CHAN, D. KIM, N. J. L. GITTOES, J. A. FRANKLYN, M. D. KILBY, and C. J. MCCABE A potential role for PTTG/securin in the developing human fetal brain FASEB J, September 1, 2003; 17(12): 1631 - 1639. [Abstract] [Full Text] [PDF]
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H. Ying, H. Suzuki, H. Furumoto, R. Walker, P. Meltzer, M. C. Willingham, and S.-Y. Cheng Alterations in genomic profiles during tumor progression in a mouse model of follicular thyroid carcinoma Carcinogenesis, September 1, 2003; 24(9): 1467 - 1479. [Abstract] [Full Text] [PDF]
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K. Boelaert, C. J. McCabe, L. A. Tannahill, N. J. L. Gittoes, R. L. Holder, J. C. Watkinson, A. R. Bradwell, M. C. Sheppard, and J. A. Franklyn Pituitary Tumor Transforming Gene and Fibroblast Growth Factor-2 Expression: Potential Prognostic Indicators in Differentiated Thyroid Cancer J. Clin. Endocrinol. Metab., May 1, 2003; 88(5): 2341 - 2347. [Abstract] [Full Text] [PDF]
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G. A. Horwitz, I. Miklovsky, A. P. Heaney, S.-G. Ren, and S. Melmed Human Pituitary Tumor-Transforming Gene (PTTG1) Motif Suppresses Prolactin Expression Mol. Endocrinol., April 1, 2003; 17(4): 600 - 609. [Abstract] [Full Text] [PDF]
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 Y. Zhou, K. R. Mehta, A. P. Choi, S. Scolavino, and X. Zhang DNA Damage-induced Inhibition of Securin Expression Is Mediated by p53 J. Biol. Chem., January 3, 2003; 278(1): 462 - 470. [Abstract] [Full Text] [PDF]
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C. J. McCabe, K. Boelaert, L. A. Tannahill, A. P. Heaney, A. L. Stratford, J. S. Khaira, S. Hussain, M. C. Sheppard, J. A. Franklyn, and N. J. L. Gittoes Vascular Endothelial Growth Factor, Its Receptor KDR/Flk-1, and Pituitary Tumor Transforming Gene in Pituitary Tumors J. Clin. Endocrinol. Metab., September 1, 2002; 87(9): 4238 - 4244. [Abstract] [Full Text] [PDF]
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E. LaTulippe, J. Satagopan, A. Smith, H. Scher, P. Scardino, V. Reuter, and W. L. Gerald Comprehensive Gene Expression Analysis of Prostate Cancer Reveals Distinct Transcriptional Programs Associated with Metastatic Disease Cancer Res., August 1, 2002; 62(15): 4499 - 4506. [Abstract] [Full Text] [PDF]
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 Y. Shibata, N. Haruki, Y. Kuwabara, T. Nishiwaki, J. Kato, N. Shinoda, A. Sato, M. Kimura, H. Koyama, T. Toyama, et al. Expression of PTTG (Pituitary Tumor Transforming Gene) in Esophageal Cancer Jpn. J. Clin. Oncol., July 1, 2002; 32(7): 233 - 237. [Abstract] [Full Text] [PDF]
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X. Zhang, H. Sun, D. C. Danila, S. R. Johnson, Y. Zhou, B. Swearingen, and A. Klibanski Loss of Expression of GADD45{gamma}, a Growth Inhibitory Gene, in Human Pituitary Adenomas: Implications for Tumorigenesis J. Clin. Endocrinol. Metab., March 1, 2002; 87(3): 1262 - 1267. [Abstract] [Full Text] [PDF]
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 S. S. Kakar, L. Chen, R. Puri, S. E. Flynn, and L. Jennes Characterization of a Polyclonal Antibody to Human Pituitary Tumor Transforming Gene 1 (PTTG1) Protein J. Histochem. Cytochem., December 1, 2001; 49(12): 1537 - 1546. [Abstract] [Full Text] [PDF]
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Z. Wang, R. Yu, and S. Melmed Mice Lacking Pituitary Tumor Transforming Gene Show Testicular and Splenic Hypoplasia, Thymic Hyperplasia, Thrombocytopenia, Aberrant Cell Cycle Progression, and Premature Centromere Division Mol. Endocrinol., November 1, 2001; 15(11): 1870 - 1879. [Abstract] [Full Text] [PDF]
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A. P. Heaney, V. Nelson, M. Fernando, and G. Horwitz Transforming Events in Thyroid Tumorigenesis and Their Association with Follicular Lesions J. Clin. Endocrinol. Metab., October 1, 2001; 86(10): 5025 - 5032. [Abstract] [Full Text] [PDF]
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 F. Romero, M.-C. Multon, F. Ramos-Morales, A. Dominguez, J. A. Bernal, J. A. Pintor-Toro, and M. Tortolero Human securin, hPTTG, is associated with Ku heterodimer, the regulatory subunit of the DNA-dependent protein kinase Nucleic Acids Res., March 15, 2001; 29(6): 1300 - 1307. [Abstract] [Full Text] [PDF]
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H. Ishikawa, A. P. Heaney, R. Yu, G. A. Horwitz, and S. Melmed Human Pituitary Tumor-Transforming Gene Induces Angiogenesis J. Clin. Endocrinol. Metab., February 1, 2001; 86(2): 867 - 874. [Abstract] [Full Text]
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R. Yu, S.-G. Ren, G. A. Horwitz, Z. Wang, and S. Melmed Pituitary Tumor Transforming Gene (PTTG) Regulates Placental JEG-3 Cell Division and Survival: Evidence from Live Cell Imaging Mol. Endocrinol., August 1, 2000; 14(8): 1137 - 1146. [Abstract] [Full Text]
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Z. Wang and S. Melmed Pituitary Tumor Transforming Gene (PTTG) Transforming and Transactivation Activity J. Biol. Chem., March 10, 2000; 275(11): 7459 - 7461. [Abstract] [Full Text] [PDF]
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D. C. Danila, X. Zhang, Y. Zhou, G. R. Dickersin, J. A. Fletcher, E. T. Hedley-Whyte, M. K. Selig, S. R. Johnson, and A. Klibanski A Human Pituitary Tumor-Derived Folliculostellate Cell Line J. Clin. Endocrinol. Metab., March 1, 2000; 85(3): 1180 - 1187. [Abstract] [Full Text]
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Z. Wang and S. Melmed Characterization of the Murine Pituitary Tumor Transforming Gene (PTTG) and Its Promoter Endocrinology, February 1, 2000; 141(2): 763 - 771. [Abstract] [Full Text] [PDF]
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P. L. M. Dahia and A. B. Grossman The Molecular Pathogenesis of Corticotroph Tumors Endocr. Rev., April 1, 1999; 20(2): 136 - 155. [Abstract] [Full Text]
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R. Yu, A. P. Heaney, W. Lu, J. Chen, and S. Melmed Pituitary Tumor Transforming Gene Causes Aneuploidy and p53-dependent and p53-independent Apoptosis J. Biol. Chem., November 17, 2000; 275(47): 36502 - 36505. [Abstract] [Full Text] [PDF]
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L. Pei Activation of Mitogen-activated Protein Kinase Cascade Regulates Pituitary Tumor-transforming Gene Transactivation Function J. Biol. Chem., September 29, 2000; 275(40): 31191 - 31198. [Abstract] [Full Text] [PDF]
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L. Pei Identification of c-myc as a Down-stream Target for Pituitary Tumor-transforming Gene J. Biol. Chem., March 9, 2001; 276(11): 8484 - 8491. [Abstract] [Full Text] [PDF]
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W. Chien and L. Pei A Novel Binding Factor Facilitates Nuclear Translocation and Transcriptional Activation Function of the Pituitary Tumor-transforming Gene Product J. Biol. Chem., June 16, 2000; 275(25): 19422 - 19427. [Abstract] [Full Text] [PDF]
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