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Molecular and Cellular Biology, January 2000, p. 672-683, Vol. 20, No. 2
Department of Developmental and Molecular
Biology and Department of Medicine, The Albert Einstein Cancer Center,
Albert Einstein College of Medicine, Bronx, New York
104611; Department of Anatomy,
Physiological Sciences, and Radiology, College of Veterinary Medicine,
North Carolina State University, Raleigh, North Carolina
276062; Department of Pathology,
Northwestern University Medical School, Chicago, Illinois
606113; Department of Pathology,
McMaster University, West Hamilton, Ontario L8S 4K1,
Canada4; Department of Tumor Biology,
University of Texas M. D. Anderson Cancer Center, Houston, Texas
770305; and Department of Bioregulation,
The Weizmann Institute of Science, Rehovot 76100, Israel6
Received 16 June 1999/Returned for modification 9 August
1999/Accepted 11 October 1999
The neu (c-erbB-2) proto-oncogene encodes a
tyrosine kinase receptor that is overexpressed in 20 to 30% of human
breast tumors. Herein, cyclin D1 protein levels were increased in
mammary tumors induced by overexpression of wild-type Neu or activating
mutants of Neu in transgenic mice and in MCF7 cells overexpressing
transforming Neu. Analyses of 12 Neu mutants in MCF7 cells indicated
important roles for specific C-terminal autophosphorylation sites and
the extracellular domain in cyclin D1 promoter activation. Induction of
cyclin D1 by NeuT involved Ras, Rac, Rho, extracellular
signal-regulated kinase, c-Jun N-terminal kinase, and p38, but not
phosphatidylinositol 3-kinase. NeuT induction of the cyclin D1 promoter
required the E2F and Sp1 DNA binding sites and was inhibited by
dominant negative E2F-1 or DP-1. Neu-induced transformation was
inhibited by a cyclin D1 antisense or dominant negative E2F-1 construct
in Rat-1 cells. Growth of NeuT-transformed mammary adenocarcinoma cells
in nude mice was blocked by the cyclin D1 antisense construct. These
results demonstrate that E2F-1 mediates a Neu-signaling cascade to
cyclin D1 and identify cyclin D1 as a critical downstream
target of neu-induced transformation.
The neu
(c-erbB-2, HER-2) proto-oncogene encodes a
receptor tyrosine kinase that is a member of a growth factor receptor
family, which includes the epidermal growth factor (EGF) receptor
(ErbB-1), ErbB-3, and ErbB-4. neu is overexpressed in 20 to
30% of human breast tumors (64). Both Neu and the EGF
receptor stimulate proliferation of breast cancer cells, and
overexpression of these two proteins correlates with progression of
human breast cancer and poor patient prognosis (28, 31, 47).
A substitution point mutation at residue 664 (Val In mammary tumors of mice transgenic for the wild-type Neu receptor
(MMTV-neu mice), the receptor's intrinsic tyrosine kinase activity was increased in association with in-frame somatic mutations of the transgene (61). Introduction of these extracellular
domain deletion (ECD) mutations into the wild-type Neu cDNA enhanced neu transforming potential (61). Transgenic mice
expressing these Neu deletion mutants in the mammary gland (MMTV-NDL
mice) developed multifocal mammary adenocarcinomas with high frequency and shorter latency compared with mice transgenic for the wild-type neu. In primary human breast tumors, a splice variant of
ErbB-2 encoding a similar ECD deletion which can also transform Rat-1 fibroblasts has been detected, suggesting that such activating mutants
of ErbB-2 may similarly have a critical role in human breast cancer
induction and progression (62).
The mitogenic activity of the ErbB family, induced by ligand addition,
is initiated through the formation of heterodimeric and homodimeric
receptor signaling complexes (49). ErbB-2 is capable of
heterodimerizing with other family members, and induction of ErbB-2
tyrosine phosphorylation stimulates mitogenesis (21, 49).
Overexpression of ErbB-2 results in autophosphorylation and induction
of signaling pathways involving Ras and c-Src (27, 43, 51).
Mitogenic intracellular signaling mediators induced through ErbB
proteins include the p42 and p44 extracellular signal-regulated kinases
(ERKs) (5), the stress-activated protein kinases
(49), and a wortmannin-sensitive phosphoinositide 3-OH
kinase (PI 3-kinase) activity (68). The mitogenic and
transforming potential of Neu is well documented and raises the
possibility that Neu directly affects components of the cell cycle
regulatory apparatus implicated in cellular transformation.
The functional inactivation of the retinoblastoma tumor suppressor
protein (pRB) is a common finding in many tumor types (74). Phosphorylation and inactivation of pRB by cyclin-dependent kinase (Cdk) holoenzymes, consisting of D-type cyclins and the catalytic subunits including Cdk4 or Cdk6, block the growth suppressive function
of pRB (reviewed in references 57 and
74). Cyclin D1 overexpression in cultured cells
hyperphosphorylates pRB (54), and in cells containing pRB,
the abundance of cyclin D1 is rate limiting in progression through the
first gap (G1) phase of the cell cycle. Aberrant
overexpression of cyclin D1 is associated with breast cancer formation,
with cyclin D1 mRNA overexpressed in 70 to 100% of breast tumor cell
lines (32, 56) and the majority of breast cancers
(75). Targeted overexpression of cyclin D1 induced mammary
adenocarcinoma (69), and transgenic mice lacking both
cyclin D1 alleles failed to develop normal mammary glands
(59). These studies, though consistent with a role for cyclin D1 in both oncogenesis and breast development, also demonstrate the limited utility of the cyclin D1 Cyclin D1 abundance is induced transcriptionally, and the protein is
degraded rapidly upon the withdrawal of growth factors via the
proteasome pathway (20). It has been proposed that induction of cyclin D1 by growth factors and oncogenes may contribute to the
transformed phenotype (reviewed in references 57 and
74). Cyclin D1 is induced by several proteins
involved in proliferative signaling and transformation, including Ras
(1), Rac (76), Src (33), STATs
(11, 38), and simian virus 40 (SV40) small t antigen
(71). Further, cyclin D1 collaborates with Ras and Myc in
tumor formation (10). Transformation by Ras in certain cell
types requires the GTPase Rac1 and RhoA (52, 53). Rac induced cyclin D1 (29, 76), while a cyclin D1 antisense
construct reduced Ras-induced colony-forming activity (35),
suggesting that cyclin D1 is a downstream target of Ras- and perhaps
Rac-induced transformation. In the present study, we examined the role
of cyclin D1 in neu-induced transformation and identified
the intracellular signaling pathway by which NeuT induces cyclin D1.
Cyclin D1 immune-complex assays.
Cyclin D1
immunoprecipitation kinase assays were performed as previously
described (33, 72). Tissues from MMTV-neu and MMTV-NDL transgenic mice (25, 62) were Dounce homogenized in
lysis buffer (150 mM NaCl, 50 mM HEPES pH 7.2, 1 mM EDTA, 1 mM EGTA, 1 mM dithiothreitol, 0.1% Tween 20, 0.1 mM phenylmethylsulfonyl fluoride, 2.5 µg of leupeptin per ml, 0.1 mM sodium orthovanadate [Sigma, St. Louis, Mo.]) at 4°C. Lysates (100 µg) were
precipitated with protein A-agarose beads precoated with the cyclin D1
antibody DCS-11 (NeoMarkers, Fremont, Calif.). Phosphorylated proteins were separated by electrophoresis and quantified after exposure to
autoradiographic film (Labscientific, Inc., Livingston, N.J.) by
densitometry using ImageQuant version 1.11 (Molecular Dynamics, Sunnyvale, Calif.).
Western blots.
The abundance of cyclin D1 and Neu proteins
in 50 µg of lysate was determined by Western analysis as previously
described (33, 72), using a cyclin D1 antibody (DCS-6;
NeoMarkers), a c-Neu antibody (Ab-3; Oncogene Research Products,
Cambridge, Mass.), a keratin-8 antibody (M20; ICN Biomedicals, Inc.,
Aurora, Ohio), an Immunohistochemistry.
Immunostaining of the mammary tissue
from seven transgenic animals was performed as previously described
(33). In each tumor, 500 cells were scored for nuclear
cyclin D1 staining. Tissues were fixed in 4% paraformaldehyde, blocked
in paraffin, sectioned at 5 µm, and stained with hematoxylin and
eosin or used for immunohistochemistry. Cyclin D1 was detected by using
antibody DCS-6 with the Vectastain ABC system (Vector Laboratories,
Burlingame, Calif.).
Construction of reporter and expression vectors.
The human
cyclin D1 promoter reporter constructions, the c-fos
promoter, the (UAS)5E1BTATALUC reporter, and the PALUC
reporter, which contains 7 kb of the human cyclin A promoter (1,
33, 70), were previously described. The E2F site of the cyclin D1 promoter was mutated from TTTGGCGCC to TTTcttGaC
(mutated bases are in lowercase) in the context of the
0270-7306/0/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Cyclin D1 Is Required for Transformation by
Activated Neu and Is Induced through an E2F-Dependent Signaling
Pathway
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
Glu) in the
transmembrane domain of rat Neu (referred to as NeuT) encodes an
activated transforming tyrosine kinase (7). Overexpression
of either wild-type Neu or NeuT in transgenic mice under the control of
the murine mammary tumor virus (MMTV) long terminal repeat induces
mammary adenocarcinoma with high frequency (25, 41). Several
independent transgenic strains bearing the identical
MMTV-neuT transgene developed synchronous, multifocal
mammary tumors involving all mammary glands (24), providing
strong evidence that activated neu requires few if any additional genetic events to transform the epithelial cell.
/
animals for analysis of cyclin D1's role in mammary tumorigenesis.
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
-tubulin antibody (5H1) (13), and a
guanine nucleotide dissociation inhibitor (GDI) antibody (a generous
gift from Perry Bickel, Washington University, St. Louis, Mo.)
(55).
163 bp
fragment, using PCR to form 163E2FmtCD1LUC. The serum response
element from the c-fos promoter from 332 to 277 was
linked to the minimal TATA region of the E4 promoter and cloned into
the reporter pA3LUC.
NeuN and pSV2NeuN), NeuT
(pJ4NeuT and pSV2NeuT), the ECD mutants of Neu (8142, 8340, 8342, and 8567) (61), the carboxy-terminal deletion of NeuT (
CT), and the CT mutants pLSV P1, P1F, P2,3, P4, P5, and
Y1253F (9) were previously described. RSV (Rous
sarcoma virus)-RasN17, RSV-RasL61, RSV-RasL61S186 (1),
pEXV3N19Rho, pEXV3N17Rac, and the dominant negative MEK1 plasmid
pEXVMEKC (MEKAla-218/Ala-222) (52, 71), and
c-Jun N-terminal kinase (JNK) inhibitor JIP-1 (JNK-interacting protein
1) (18, 33) were previously described. The cDNAs encoding
N17Rac and N19Rho were cloned into the tetracycline-regulated vector
pBPSTR-1 (46). The human cyclin D1 cDNA antisense construct from the tetracycline-regulated plasmid pUHD10.3 CD1AS (shown to reduce
cyclin D1 protein levels in rat H19-7 cells [79]) was
recloned into pBPSTR-1 to form pBPSTR-1CD1AS.
103-126 were
previously described (70, 80). The Sp1, Sp3, and E2F-1
activation domains were linked to the GAL4 DNA binding domain to form
GAL4-Sp1(83-621) (63), GAL4-Sp3(1-382),
GAL4-E2F-1(368-437), and GAL4-E2F-1(413-417), which is defective
in regulation by pRB. GAL4-PAG236 encodes the constitutively active
transactivation domain.
Reporter assays and cell culture.
Cell culture,
transfections, and luciferase assays were performed as previously
described (1). MCF7 cells were maintained in Dulbecco
modified Eagle medium (DMEM) with 10% (vol/vol) calf serum and 1%
penicillin-streptomycin. Rat-1, MDA-MB-231, MDA-MB-453, HBL-100, and
BT-483 cells were grown in DMEM-Ham's F12 (1:1) with 10% calf serum
and 1% penicillin-streptomycin. The MCF7 stable cell line 1745CD1LUC
was established by selection with G418 in the presence of pcDNA3. The
NIH 3T3 stable cell lines DHFR/G8 (overexpressing wild-type
neu), B104-1-1, and neuC-1 have been described
elsewhere (78). The NAFA cell line from the
MMTV-neuT mouse (41) was grown in DMEM with 10%
fetal bovine serum and 1% penicillin-streptomycin.
Oligodeoxyribonucleotides.
The oligonucleotide sequences
used in electrophoretic mobility shift assays (EMSAs) were as follows:
for the adenovirus E2F site, 5' GCC GTC CAG TTT CGC GCC CTT TCT CAA ATT
TAA GCA GCT CGA; for the cyclin D1 E2F site, 5' TCC CGG CGT TTG GCG CCC
GCG CCC; for the cyclin D1 Sp1 site (130 to 99), 5' TCC CCC TGC GCC
CGC CCC CGC CCC CCT CCC GC; and for the consensus Sp1 site, 5' ATT CGA
TCG GGG CGG GGC GAG C. For the mutant cyclin D1 E2F oligonucleotide, the wild-type TTT GGC GCC CG sequence was changed to cga Gct GCC CG.
The sequence of the primer used to mutate the cyclin D1 E2F site
(TTTGGCGCC) was 5' GGT ACC TCG CTG CTC CCG GCG TTT ctt gaC CGC G. (Mutated bases are shown in lowercase.) The primers used for PCR
in chromatin immunoprecipitation (CHIP) assays were 349CD1 (5' CTC
CAC CTC ACC CCC TAA AT) and 112CD1 (5' GGG GGC GGG CGC AGG GGG A).
PCR primers for neu from the NAFA cell tumors were 5' CGG
AAC CCA CAT CAG GCC and 5' TTT CCT GCA GCC TAC GC.
EMSAs. EMSAs using the Sp1 sequence with MCF7 nuclear extracts were performed as described previously (1, 72). Extracts were incubated in a mixture containing 20 mM HEPES (pH 7.9), 80 mM KCl, 5 mM MgCl2, 0.2 mM dithiothreitol, 2% Ficoll, 5% glycerol, 0.1 mM EDTA, and 500 ng of poly(dI-dC) on ice for 30 min. 32P-labeled oligonucleotides (100 fmol, 50,000 cpm) were added to the reaction mix and incubated at room temperature for 30 min. The protein-DNA complexes were electrophoresed through a 5% polyacrylamide gel with 0.5× TBE (0.5× TBE is 0.045 M Tris-borate plus 0.001 M EDTA) buffer and 2.5% glycerol. The gels were dried and exposed to autoradiographic film.
EMSAs using the E2F sequences were performed essentially as previously described (66). Sf9 cells were infected with equal amounts (PFU) of baculoviruses encoding E2F-1, E2F-4, DP-1, or DP-2. Equal amounts of 32P-labeled probes (10,000 to 20,000 cpm) were incubated with equal volumes of extracts from baculovirus-infected Sf9 cells. Antisera to E2F and DP proteins (Santa Cruz Biotechnology, Inc., Santa Cruz, Calif.) were used to confirm the components of each protein-DNA complex (not shown). To determine relative binding activities of the individual complexes, radioactivity in each complex was calculated with a phosphorimager (Packard Instant Imager), and the counts in the cyclin D1 complexes were normalized to the value for the corresponding adenovirus E2F complexes. The mean of two independent experiments was used for each complex.CHIP.
The CHIP method was described elsewhere
(65). Briefly, 2 × 107 MCF7 cells were
fixed by addition of formaldehyde to the tissue culture media (final
concentration, 1%). Isolated chromatin was sonicated to an average
length of 0.5 to 1 kb and treated with 1 µg of rabbit anti-E2F-1
antibody (C-20; Santa Cruz Biotechnology) or control rabbit
immunoglobulin G (IgG) for 16 h at 4°C. The complexes were
immunoprecipitated with 10 µl of blocked Staph A cells and washed
with immunoprecipitation buffer (100 mM Tris-Cl [pH 9.0], 500 mM
LiCl, 1% NP-40, 1% deoxycholate). After elution and reversal of
cross-links, DNA was isolated and analyzed by PCR; 10 ng of
1745CD1LUC plasmid DNA, sterile water, and immunoprecipitation buffer
were included as controls. PCR products were visualized on a 2%
agarose gel with ethidium bromide.
Transformation assays. Transformation assays were conducted exactly as previously described (16). Rat-1 cells (105/60-mm-diameter dish) were transfected by calcium phosphate precipitation, with a 45-s glycerol shock performed after 5 to 8 h. After 3 days, the cells were trypsinized and passed into 100-mm-diameter dishes. The medium was changed twice weekly for 3 weeks. For colony counting, cells were washed twice with phosphate-buffered saline (PBS), fixed (10 min, 10% acetic acid), and stained (10 min, 0.4% crystal violet in 10% ethanol). The dishes were rinsed, inverted, and dried at room temperature.
Tumorigenicity in immunodeficient mice. Nude mice injections were performed as described previously (23). Male, 6- to 8-week-old nude mice (strain BALB/cAnNCr-nuBR) were obtained from the National Cancer Institute. NAFA cells were transfected by calcium phosphate precipitation with plasmid pMACS4.1 (Miltenyi Biotec Inc., Auburn, Calif.) and either pBPSTR-1 or pBPSTR-1CD1AS. Transfected cells were enriched by magnetic bead-activated cell sorting (autoMACS; Miltenyi Biotec) (6) according to the manufacturer's protocol. Transfected cells were washed twice, suspended in 0.1 ml of PBS, and injected subcutaneously. For each mouse, the left flank was injected with NAFA cells transfected with cyclin D1 antisense, while the right flank received NAFA cells transfected with the control vector. Thus, each mouse received two injections of at least 3 × 105 cells. Tumor growth localized to the site of injection was monitored for 3 to 5 weeks, at which time mice were sacrificed. Tumors that formed were measured, excised, and analyzed for presence of neuT by PCR, expression of NeuT by Western blotting (not shown), and histopathology. Injections into nude mice were performed on four separate occasions, with similar results.
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RESULTS |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Neu induces cyclin D1 abundance in the mammary gland tumors of
transgenic mice and stable cell lines.
To examine a possible role
for Neu in regulating cyclin D1, we assessed stable NIH 3T3 cell lines
overexpressing wild-type or transforming neu (shown
schematically in Fig. 1A). Stable
overexpression of wild-type neu in NIH 3T3 cells did not
induce the transformed phenotype. A stable NIH 3T3 cell line (B104-1-1)
expressing NeuT exhibited a transformed phenotype associated with Shc
tyrosine phosphorylation and Shc-Grb2 complex formation
(78). The NIH 3T3 stable cell line neuC-1
contains an internal carboxy-terminal deletion (amino acids 1007 to
1248) of NeuT which removes most of the Neu autophosphorylation sites
but maintains transforming potential. In the transformed cell lines
B104-1-1 (Fig. 1A, lane 3) and neuC-1 (Fig. 1A, lane 2),
cyclin D1 levels were increased 7- and 6.5-fold, respectively, compared
with the cells expressing wild-type Neu (Fig. 1A, lane 1).
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-tubulin
confirmed equal protein loading in both lanes (Fig. 1C).
To determine if Neu induces cyclin D1 levels in vivo, cyclin D1 protein
levels were assessed in the mammary tumor tissue from 18 independent
MMTV-neu (wild-type Neu-expressing) (25) and MMTV-NDL (Neu deletion mutants-expressing) (62) transgenic
mice, and comparison was made with normal mammary gland tissue from three nontransgenic animals (Fig. 1D). Equal amounts of protein loading
were confirmed by Ponceau S staining and -tubulin abundance (not
shown). Cyclin D1 protein levels were increased up to 12.9-fold in all
tumor samples examined except one (Fig. 1E). Cyclin D1 kinase (CD1K)
activity was also assessed in each tumor, using a cyclin D1
immunoprecipitation kinase assay and glutathione
S-transferase (GST)-pRB as the substrate (70,
72). The phosphorylated pRB band was dependent on the addition of
pRB substrate and was inhibited by the addition of
p16INK4a protein (not shown), consistent with
the specificity of the kinase assays (12). Equal amounts of
total protein were assessed in the assay, with comparison made between
the activity generated by mammary tumor tissue from the transgenic mice
and the mean mammary gland tissue CD1K activity from three
nontransgenic animals (Fig. 1D). CD1K activity was increased in each
tumor examined, from 1.5- to 17.7-fold (Fig. 1E, MMTV-neu
[blue] and MMTV-NDL [red]).
Because the subcellular distribution of cyclin D1 varies with cell
cycle progression and the nuclear location of cyclin D1 is important
for its ability to inactivate pRB (19, 37), we assessed the
distribution of cyclin D1 within the tumors by immunohistochemistry. Immunostaining of mammary tumors from both MMTV-neu and
MMTV-NDL transgenic animals demonstrated increased nuclear abundance of cyclin D1 in the adenocarcinoma (Fig. 1F, top) compared with normal mammary tissue from the same animal (Fig. 1F, bottom), shown at higher
magnification to demonstrate the absence of cyclin D1 staining. Analyses were performed on separate tumors from seven animals. The mean
percentage of cells positively staining for nuclear cyclin D1 in the
mammary gland tumors was 55% (range, 10 to 85%) compared with 2 to
5% nuclear staining in adjacent normal mammary epithelium.
NeuT activates the cyclin D1 promoter in MCF7 cells.
To
determine whether the cyclin D1 gene is a direct
transcriptional target of Neu, the human cyclin D1 promoter linked to a
luciferase reporter was examined in MCF7 cells. Overexpression of NeuT
induced cyclin D1 promoter activity in a dose-dependent manner (Fig.
2A). Wild-type Neu induced the cyclin D1
promoter (1.4-fold [not shown]). The induction was observed whether
wild-type Neu was driven from the SV40 or pJ4 expression vector. The
cyclin D1 promoter was induced a mean of 26-fold by NeuT when expressed from the SV40 promoter, which is highly active in MCF7 cells (Fig. 2B).
To examine the specificity of the NeuT induction of cyclin D1, we
examined several other gene promoters, including those for the
c-fos gene and the cyclin A gene. The
c-fos promoter was induced 14-fold, and the serum response
element of the c-fos promoter was induced 39-fold. In
contrast, the cyclin A promoter was not induced by NeuT in MCF7 cells
(Fig. 2B).
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NeuT). This promoter is less active in MCF7 cells; however, the cyclin
D1 promoter was induced 6.7-fold (Fig. 2C), compared with 1.5-fold
induction by wild-type Neu. To determine whether the transforming Neu
ECD mutants found in the MMTV-neu mice (61) could
directly activate the cyclin D1 promoter, cotransfection experiments
were conducted with MCF7 cells. The most transforming mutant (Neu 8142)
induced the cyclin D1 promoter 5.4-fold (Fig. 2C). For each of the ECD
mutants, the magnitude of cyclin D1 promoter induction corresponded
well with the previously published transforming ability of these
mutants in Rat-1 cells (61).
The carboxy-terminal domain of Neu includes five autophosphorylation
sites. The autophosphorylation capacity of Neu is linked to its
transforming capacity in focus-forming assays in fibroblasts and in the
formation of tumors in athymic mice (9). The mutants examined in Fig. 2D included a carboxy-terminal deletion mutant (CT)
and a series of mutants in which the carboxy-terminal 12 amino acids of
Neu were linked to the CT, to serve as a functional docking site for
SH2-containing proteins, with phosphorylation sites sequentially added.
The mutant P1 includes the carboxy-terminal Neu phosphorylation site
(tyrosine 1253). In this series of mutants, the cyclin D1 promoter was
induced 3.6-fold by NeuT and 4.4-fold by the P1 mutant. The P1F mutant,
which has a substitution of the terminal tyrosine for phenylalanine,
was poorly transforming in Rat-1 cells and in athymic mice and was
defective in activation of the cyclin D1 promoter. The induction of
cyclin D1 by P1F was 37% of the value for P1 (Fig. 2D), and in athymic
mice its transforming capacity was 25% of that of P1 (9).
Mutation of tyrosine 1253 to phenylalanine (Y1253F) in the context of
NeuT reduced transforming ability to 17% (9). This mutant
induced the cyclin D1 promoter 50% compared with P1.
Previous studies had suggested that additional phosphorylation sites
within the carboxy terminus contribute to the transforming capacity of
NeuT. We assessed whether additional phosphorylation sites contribute
to the induction of cyclin D1. The P2/3 mutant induced the cyclin D1
promoter 2.9-fold. The P4 and P5 mutants had displayed 2 to 3%
transforming ability in NIH 3T3 cells and induced the cyclin D1
promoter 1.4- and 1.2-fold, respectively (Fig. 2D). Thus, full
induction of the cyclin D1 promoter could be induced through the same
carboxy-terminal phosphorylation events as previously shown to
correlate with Neu's transforming ability.
Intracellular signaling pathways governing neuT induction of cyclin D1. Due to its potent transforming capacity, which correlated with its induction of the cyclin D1 promoter, we focused on NeuT to determine the signaling pathway governing cyclin D1 regulation downstream of activated Neu. In previous studies, neutralizing Ras antibodies inhibited Neu-induced DNA synthesis (9). Ras is known to induce cyclin D1 (1, 38). We therefore assessed whether NeuT induction of cyclin D1 required Ras. NeuT-induced promoter activity was reduced 80 to 90% by N17Ras (Fig. 3A). The inhibition by N17Ras of NeuT induction of the cyclin D1 promoter was dose dependent and was observed with similar concentrations of N17Ras as shown previously to inhibit JNK activation by EGF (40). The RasL61S186 mutant, which is incapable of inserting in the plasma membrane, did not affect activity of cyclin D1 in the presence of NeuT (not shown).
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1745CD1LUC by pEXVN19Rho, activating
mutants of Rho (RhoAL63) further induced the cyclin D1 promoter (not
shown). In addition, plasmids pEXVN19Rho and pEXVN17Rac inhibited
RasL61 induction of the collagenase AP-1 site reporter (p3TPLUX)
(71) in a dose-dependent manner in MCF7 cells (not shown),
consistent with previous studies of these same mutant plasmids
performed in fibroblasts and HeLa cells (40, 52, 71).
NeuT induced ERK activity in cultured cells (9), and
induction of the cyclin D1 promoter in MCF7 cells by another oncogenic tyrosine kinase, pp60v-src, involved the ERK,
p38, and JNK pathways (33). The MEK inhibitor PD098059,
which inhibits induction of the MEK/ERK pathway (3), reduced
the NeuT induction of the cyclin D1 promoter by 30% compared with the
DMSO control (n = 8, P < 0.05) (Fig. 3B). The p38
mitogen-activated protein kinase (MAPK) pathway chemical inhibitor
SB203580 reduced the NeuT induction of the cyclin D1 promoter by 40 to
50% (n = 8, P < 0.05) at concentrations
previously shown to inhibit p38 MAPK activity (Fig. 3B). Finally,
introduction of JIP-1 (18), which sequesters JNK in the
cytoplasm and therefore inhibits its activity, reduced NeuT-induced
cyclin D1 promoter activation by 70% (n = 4, P < 0.05) (Fig. 3B).
Wortmannin, which blocks PI 3-kinase activation, added at
concentrations from 20 to 100 nM (previously shown to inhibit PI 3-kinase but not PI 4-kinase, protein kinase A [PKA], PKC, or PKG
[77]) did not affect cyclin D1 induction by NeuT (not
shown), consistent with recent studies showing that the cyclin D1
promoter is not directly induced by the PI 3-kinase pathway
(38). The pp70S6k pathway has been implicated in
promoting cell cycle progression (50) and, like cyclin D1,
is induced by activating Rac1 (15). Addition of rapamycin,
which prevents induction of pp70S6k, from 100 pM to 20 nM
did not reduce NeuT induction of cyclin D1 but caused an induction
(60%, not shown), suggesting that the pp70S6k pathway may
inhibit cyclin D1 in the presence of activating NeuT. These studies
suggest that NeuT induction of cyclin D1 involves a Ras/Rac/Rho pathway
in which ERK, JNK, and p38 MAPK but neither PI 3-kinase nor
pp70S6k is a distal mediator.
Sp1 and E2F binding sites are required for full induction of the
cyclin D1 promoter by NeuT.
To determine the sequences of the
cyclin D1 promoter required for full induction by NeuT, cotransfection
experiments were conducted with a series of 5' promoter deletion
constructions. Deletion of the promoter from 1745 to 163 retained
25-fold induction by NeuT (compared to the vector control [Fig.
4B]). Within the proximal promoter, we
had recently identified functional sequences resembling an E2F binding
site and an Sp1 binding site (70) (Fig. 4A). Mutation of the
E2F site in the context of the 163 bp promoter fragment (163E2Fmt)
reduced NeuT induction from 25- to 3-fold (Fig. 4B). Deletion of the
Sp1 site (163Sp-1) reduced NeuT induction from 25- to 13.6-fold,
suggesting that the Sp1 site may also contribute to full induction of
cyclin D1 by Neu (Fig. 4B). The cyclin D1 E2F and Sp1 sequences were
linked to the minimal thymidine kinase (TK) promoter to form
heterologous reporters and were examined for NeuT responsiveness. The
cyclin D1 Sp1 site was induced 10.5-fold by NeuT, and the cyclin D1 E2F site reporter was induced 15.6-fold (Fig. 4C). In contrast, the TK
promoter was not responsive to NeuT (Fig. 4C).
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E2F-1 and Sp1/Sp3 bind the cyclin D1 promoter in MCF7 cells. To determine which proteins bind the cyclin D1 Sp1 site in MCF7 cells, EMSAs were performed (Fig. 5A). The cyclin D1 Sp1 sequences formed three complexes with MCF7 nuclear extracts (Fig. 5A, lane 1, arrows A to C). These complexes were competed with 100-fold molar excess of the cold cognate oligonucleotide probe or a consensus Sp1 site probe (Fig. 5A, lanes 2 and 3) but not by an unrelated sequence (Fig. 5A, lane 4). Supershifting antibodies to members of the Sp family demonstrated that band A consisted of Sp1 (Fig. 5A, lanes 6 and 7). Bands B and C were inhibited with the addition of Sp3 antibody (Fig. 5A, lane 9). Control IgG (Fig. 5A, lane 5) or antibodies to Sp2 and Sp4 (Fig. 5A, lanes 8 and 10) had no effect. The inhibition of binding by the Sp3 antibody was not observed with other DNA sequences (not shown) and was associated with a partial supershift, consistent with the presence of Sp3 binding to this site.
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Sp1, Sp3, and E2F-1 transactivation function is induced by
NeuT.
To determine whether E2F-1 is critical for NeuT induction of
cyclin D1 promoter activity, experiments were conducted with DNA-binding-defective mutant E2F-1 E132 or activation-defective mutant
E2F-1 Y411C. E2F-1 E132 functions as a dominant inhibitor of E2F
activity by dimerizing with DP proteins and thereby blocking the DNA
binding of the active E2F-DP complex. E2F-1 Y411C binds competitively
to E2F binding sites and thereby blocks activation by wild-type E2F-1.
Overexpression of E2F-1 E132 or E2F-1 Y411C reduced the NeuT induction
of cyclin D1 by 33 or 30%, respectively (Fig.
6A). Similarly, the DP-1 dominant
negative (DP-1 103-126) reduced NeuT induction of cyclin D1 by 43%
(Fig. 6A). In contrast, overexpression of the wild-type E2F-1 further
induced cyclin D1 promoter activity 2.6-fold (Fig. 6A). These results
are consistent with a requirement for E2F-1 for optimal induction of
cyclin D1 by NeuT.
|
1745CD1LUC reporter in MCF7 cells. E2F-1 induced the cyclin D1 promoter in MCF7 cells 3.8-fold (Fig. 6B).
Overexpression of either the E2F-1 E132 mutant or the DP-1 dominant
negative inhibited the cyclin D1 promoter by 36 or 34%, respectively
(Fig. 6B), whereas the E2F-1 Y411C mutant had no effect (not shown). To
identify the DNA sequences required for induction of the cyclin D1
promoter by E2F-1, cotransfection experiments were conducted with the
cyclin D1 promoter deletion constructs (Fig. 6C). The induction by
E2F-1 was maintained in the 163 bp fragment but was lost upon point
mutation of the E2F site (163 E2FmutLUC), suggesting that the E2F
site is the region required for optimal induction by E2F-1
overexpression (Fig. 6C). E2F-1 is therefore a positive regulator of
cyclin D1 in MCF7 cells.
The results presented above indicated that NeuT induced the cyclin D1
promoter through an E2F binding site that bound E2F-1 and was required
for E2F-1 induction in MCF7 cells and through an Sp1 binding site that
bound Sp1 and Sp3. To understand how NeuT may induce cyclin D1 through
the E2F-1 and Sp1/Sp3 binding sequences, we tested whether NeuT
regulates E2F-1, Sp1, and Sp3 transactivation function. The
transactivation domains of these proteins were linked to the GAL4 DNA
binding domain. The NeuT-regulated activity of Sp1 and E2F-1 was
examined in conjunction with a heterologous reporter construction,
(UAS)5E1BTATALUC, consisting of multimeric GAL4 DNA binding
sites linked to a luciferase reporter gene (Fig. 6D). E2F-1, Sp1, and
Sp3 conveyed basal enhancer function in MCF7 cells, and overexpression
of NeuT enhanced E2F-1 activity 6.3-fold. E2F-1 transactivation
function is regulated by the relative abundance of pRB, and selected
deletions within the carboxy-terminal pRB binding domain abolish
transcriptional regulation by pRB (22). In contrast with
GAL4-E2F-1, the carboxy-terminal E2F-1 mutant GAL4-E2F-1(413-417)
was not induced by NeuT. Overexpression of NeuT induced Sp1 activity
37.5-fold and Sp3 activity 11-fold. In contrast, the constitutively
active GAL4 construct PAG236 was not induced by NeuT. Thus, NeuT
induces transactivation function of the transcription factors binding
to the neuT-responsive regions of the cyclin D1 promoter.
Cyclin D1 antisense blocks NeuT-induced transformation. The findings that cyclin D1 levels were induced in neu-induced mammary gland tumors and that NeuT potently induced the cyclin D1 promoter raised the possibility that cyclin D1 is required for NeuT-induced transformation. Transformation assays were therefore performed with Rat-1 cells. NeuT (Fig. 7A) and RasL61 (not shown) both induced focus formation as previously described (61). Experiments were conducted to assess the involvement of cyclin D1 and several intracellular signaling proteins involved in mitogenic signaling in NeuT-induced transformation. Either a 1:1 or a 1:2 molar ratio of NeuT plasmid (2.5 µg) to antisense or dominant negative expression plasmid was used (Fig. 7). In previous studies of V12Ras-induced focus formation, the N17Rac plasmid was used in the ratio of 1:250 (V12Ras:N17Rac) for 70% inhibition of focus formation (53). Thus, our experiments used relatively small amounts of dominant negative or antisense expression plasmid in conjunction with the NeuT expression plasmid.
|
|
Cyclin D1 antisense blocks tumorigenesis of NeuT-transformed mammary cells in immunodeficient strains of mice. As cyclin D1 antisense blocked NeuT-induced transformation in fibroblasts, we assessed its effect on growth of a mammary tumor cell line (NAFA) derived from an MMTV-neuT mouse (41). NAFA cells grow rapidly and have readily detectable levels of cyclin D1 by Western blot (not shown). NAFA cells were cotransfected with a truncated human CD4-encoding plasmid and either cyclin D1 antisense or empty vector (pBPSTR-1). Transfected cells were selected by magnetic bead-activated cell sorting (39, 60) and injected subcutaneously into the flanks of the same nude mouse (Fig. 8A and B), and tumor formation was assessed. Importantly, no tumors were observed at the sites of injection of the cyclin D1 antisense-transfected cells after 3 to 5 weeks. In contrast, the control vector-transfected NAFA cells injected into the contralateral flank developed histologically confirmed adenocarcinomas consisting of solid cords and nodules of neoplastic cells in each case (Fig. 8C). Tissues from the sites of implantation were assessed for cyclin D1 levels by Western blotting (Fig. 8D). Cyclin D1 levels were lower in cells transfected with the cyclin D1 antisense construct than in cells transfected with the control vector. Equivalent protein loading was confirmed by blotting for GDI, and the tissues were confirmed to be of epithelial origin by keratin-8 blotting. After correction for equivalent protein loading using GDI, cyclin D1 levels were determined to be reduced 90% in cells transfected with the cyclin D1 antisense. Four different mice were injected on different days, as independent experiments, with similar results. These results establish that downregulation of cyclin D1 is sufficient to abolish tumorigenicity in Neu-transformed cells.
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DISCUSSION |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Oncogenic activation of neu can occur through overexpression, point mutation, or deletion of the extracellular domain (7, 61). Similar to the murine MMTV-neu model of mammary tumorigenesis, in primary human breast cancers, the overexpression of ErbB-2 (64) and the recent identification of an in-frame deletion of a portion of the extracellular domain of ErbB-2 (62) suggest an important role for ErbB-2 in induction and progression of human breast tumors. The present studies identify for the first time the role of a rate-limiting component of the cell cycle in transformation by Neu in mammary adenocarcinoma cells in vivo. Cyclin D1 abundance and kinase activity were increased in mammary gland tumors from MMTV-neu and MMTV-NDL transgenic animals. The activating ECD mutations of Neu induced cyclin D1 promoter activity in MCF7 cells in a manner that corresponded well with their transforming capacity in Rat-1 cells (61). Cyclin D1 antisense inhibited neuT-induced transformation in a dose-dependent manner and abolished the growth of NeuT-transformed mammary cells in immunodeficient mice. These results suggest a critical role for cyclin D1 in proliferative and transforming signals downstream of oncogenic Neu.
In these studies, Ras, Rac, and Rho contributed to NeuT induction of cyclin D1 promoter activity and cellular transformation. Each of these small monomeric GTPases has been implicated in promoting cell cycle progression, and activating mutants of Ras and Rac1 have been shown to induce cyclin D1 (1, 76). The MEK inhibitor PD098059, the p38 inhibitor SB203850, and the JNK pathway inhibitor JIP-1 reduced induction of cyclin D1 by NeuT. These findings are consistent with our previous studies in which ERK directly induced cyclin D1, EGF induction of the cyclin D1 promoter involved a Ras/ERK pathway (1, 71), and the ERK, p38, and JNK pathways were involved in induction of the cyclin D1 promoter in MCF7 cells downstream of another oncogenic tyrosine kinase, pp60v-src (33).
These studies identify for the first time specific transcriptional targets activated by NeuT within the cyclin D1 promoter, indicating an important role for E2F-1 in both NeuT-induced transformation and cyclin D1 promoter activation. E2F-1 can function as both an oncogene and a tumor suppressor likely dependent on cellular context, although the molecular mechanisms governing these events is poorly understood (73). NeuT induced the cyclin D1 E2F site when linked to an heterologous promoter in MCF7 cells, whereas in previous studies performed in trophoblastic cells and mouse embryo fibroblasts (70), E2F-1 inhibited cyclin D1 abundance and promoter activity. Thus, E2F-1 conveys cell-type-specific effects on the cyclin D1 promoter likely related to additional E2F/DP family members or cofactors present within a given cell type. Recent studies have indicated that in vitro, distinct E2F sites have preferential affinities for members of the E2F family (66). The cyclin D1 E2F sequence resembles most closely the consensus sequence that was found to preferentially bind pRB-E2F-1-DP-1 complexes (66). Indeed, E2F-1 bound the cyclin D1 sequence with greater affinity than E2F-4 in these studies, and pRB is a component of complexes that can bind the cyclin D1 E2F site (reference 70 and data not shown). In MCF7 cells, CHIP assays demonstrated binding of E2F-1 specifically to the cyclin D1 promoter in the context of native chromatin. Further characterization of the additional proteins binding to the cyclin D1 promoter E2F site may provide greater insight into the mechanisms of neu-mediated transformation and is the focus of ongoing studies.
The E2F-1 transactivation domain linked to the GAL4 DNA binding domain was sufficient for induction by NeuT. Cyclin D1 overexpression leads to the induction of pRB phosphorylation and the release of free E2F-1 (74), which is capable of inducing promoter activity through either Sp1 or E2F sites (30). Consistent with a role for E2F-1 in NeuT induction of cyclin D1, the DNA-binding-defective and activation-defective mutants of E2F-1 and the dominant negative mutant of DP-1 inhibited NeuT induction of cyclin D1, and E2F-1 E132 inhibited NeuT-induced transformation. Because cyclin D1 overexpression can induce promoter activity through E2F sequences (82) and overexpression of pRB inhibits E2F-1 transactivation function (22), NeuT may sustain cyclin D1-mediated autoinduction through the E2F and Sp1 sites.
The Sp1 binding site of the cyclin D1 promoter was required for optimal
induction by NeuT, and NeuT induced the Sp1 transactivation domain in
MCF7 cells. Sequences resembling Sp1 binding sites contribute to the
inducible expression of several growth factor-inducible genes (14,
44, 58). Sp1 binds to the promoters of Neu differentiation factor-inducible genes, including the acetylcholine receptor 
and
subunits and neurotrophin-3 (4). Sp1 binds several
intermediary proteins, some of which have been implicated in mitogenic
signaling, including the E2F-1 and E2F-3 proteins (30). The
Sp1 binding site of the 2-integrin gene is a site of
inhibition by ErbB-2, suggesting that the inhibition of
2-integrin abundance may contribute to loosening of
cell-cell contacts necessary for cell division (81).
Together with the activation of cyclin D1, the induction of other
growth factor-regulated genes through Sp1 binding sites and the
inhibition of genes involved in cell contact may contribute to the
proliferative and transforming phenotype induced by activated Neu.
As a common downstream target of several different mitogenic signaling pathways in breast cancer cells (36), cyclin D1 represents a logical target for inactivation by gene therapy. In addition to contributing to phosphorylation and inactivation of pRB, cyclin D1 binds other proteins, including proliferating cell nuclear antigen (34), a Myb-related protein (26), and the estrogen receptor (ER) (45). Neu is capable of phosphorylating the ER on tyrosine residues (48), and phosphorylation of the ER at tyrosine and/or serine residues has been associated with functional activation. The role of cyclin D1-associated proteins in neu-induced transformation remains to be determined. Cyclin D1 antisense constructs as well as the recently characterized dominant negative mutants of cyclin D1 (19) may provide important information about the requirement for cyclin D1 in neu-induced mammary gland tumor formation in vivo. Clearly, mammary tumorigenesis is a multistep process and may involve alterations in the expression of other tumor suppressor gene products. The abundance of the p16INK4a protein is frequently reduced in the MMTV-neu tumors, and overexpression of p16INK4a but not p19ARF can inhibit NeuT-induced focus formation in Rat-1 cells, suggesting that specific tumor suppressors may inhibit Neu-induced transforming pathways (M. D'Amico and R. G. Pestell, unpublished data). The roles of these additional tumor suppressor genes in Neu-induced transformation in mammary epithelial cells are the basis of ongoing studies.
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ACKNOWLEDGMENTS |
|---|
We are grateful to S. Cook, R. Davis, N. Dyson, G. Gill, M. Gilman, E. Harlow, W. Kaelin, J. Massague, F. McCormick, J. Nevins, S. Reeves, P. Farnham, J. Wells, and L. Zhu for plasmids, antibodies, and helpful discussions. We thank R. Russell for pathological assessment of tumors.
This work was supported in part by grants R29CA70897, RO1CA75503, and 5-P30-CA13330-26 (R.G.P.), CA536340 (J.M.H.), NIH training grant T32 DK 07513 (R.J.L.), and grant CA09475-12 (M.D.). W.J.M. is supported by research grants awarded by the Canadian Breast Cancer Initiative and is a recipient of an MRC of Canada Scientist award. R.G.P. is a recipient of the Irma T. Hirschl Award and an award from the Susan G. Komen Breast Cancer Foundation. Work conducted at the Albert Einstein College of Medicine was supported by Cancer Center Core National Institutes of Health grant 5-P30-CA13330-26 and the Mortimer Harrison Foundation (R.G.P.).
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FOOTNOTES |
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* Corresponding author. Mailing address: The Albert Einstein Cancer Center, Departments of Medicine and Developmental and Molecular Biology, Albert Einstein College of Medicine, Chanin 302, 1300 Morris Park Ave., Bronx, NY 10461. Phone: (718) 430-8662. Fax: (718) 430-8674. E-mail: pestell{at}aecom.yu.edu.
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Materials and Methods
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Discussion
References
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(2003). Loss of Caveolin-1 Gene Expression Accelerates the Development of Dysplastic Mammary Lesions in Tumor-Prone Transgenic Mice. Mol. Biol. Cell
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Kirmizis, A., Bartley, S. M., Farnham, P. J.
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Page, K., Li, J., Corbit, K. C., Rumilla, K. M., Soh, J.-W., Weinstein, I. B., Albanese, C., Pestell, R. G., Rosner, M. R., Hershenson, M. B.
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Fu, M., Wang, C., Wang, J., Zhang, X., Sakamaki, T., Yeung, Y. G., Chang, C., Hopp, T., Fuqua, S. A. W., Jaffray, E., Hay, R. T., Palvimo, J. J., Janne, O. A., Pestell, R. G.
(2002). Androgen Receptor Acetylation Governs trans Activation and MEKK1-Induced Apoptosis without Affecting In Vitro Sumoylation and trans-Repression Function. Mol. Cell. Biol.
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Desai, K. V., Xiao, N., Wang, W., Gangi, L., Greene, J., Powell, J. I., Dickson, R., Furth, P., Hunter, K., Kucherlapati, R., Simon, R., Liu, E. T., Green, J. E.
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Hewitt, S. C., Bocchinfuso, W. P., Zhai, J., Harrell, C., Koonce, L., Clark, J., Myers, P., Korach, K. S.
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Muraoka, R. S., Lenferink, A. E. G., Law, B., Hamilton, E., Brantley, D. M., Roebuck, L. R., Arteaga, C. L.
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Westerheide, S. D., Mayo, M. W., Anest, V., Hanson, J. L., Baldwin, A. S. Jr.
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Kampfer, S., Windegger, M., Hochholdinger, F., Schwaiger, W., Pestell, R. G., Baier, G., Grunicke, H. H., Uberall, F.
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Lenferink, A. E. G., Busse, D., Flanagan, W. M., Yakes, F. M., Arteaga, C. L.
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Wang, C., Fu, M., D'Amico, M., Albanese, C., Zhou, J.-N., Brownlee, M., Lisanti, M. P., Chatterjee, V. K. K., Lazar, M. A., Pestell, R. G.
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Fu, M., Wang, C., Reutens, A. T., Wang, J., Angeletti, R. H., Siconolfi-Baez, L., Ogryzko, V., Avantaggiati, M.-L., Pestell, R. G.
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Wang, C., Fu, M., Angeletti, R. H., Siconolfi-Baez, L., Reutens, A. T., Albanese, C., Lisanti, M. P., Katzenellenbogen, B. S., Kato, S., Hopp, T., Fuqua, S. A. W., Lopez, G. N., Kushner, P. J., Pestell, R. G.
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