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Department of Carcinogenesis, University of Texas M. D. Anderson Cancer Center, Science Park Research Division, Smithville, Texas 78957
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ABSTRACT |
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 Top ABSTRACT IntroductionMaterials and MethodsResultsDiscussionNote Added in ProofREFERENCES |
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Introduction |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionNote Added in ProofREFERENCES |
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In this report we describe the physical map of the region of interest between STS markers D16S518 and D16S516 and the cloning of a novel protein from within this area.
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Materials and Methods |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionNote Added in ProofREFERENCES |
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Genomic DNA shotgun sequencing was performed using DNaseI BAC DNA digestion and subsequent cloning into pZErO-1 vector (Invitrogen). Inserts were amplified with vector-specific primers. Cycle sequencing reactions were performed using ABI PRISM BigDye Terminator cycle sequencing chemistry (Perkin-Elmer/Applied Biosystems) and analyzed on an ABI 377 automated fluorescent sequencer (Perkin-Elmer/Applied Biosystems). When necessary, clones were sequenced manually with 32P-labeled primers.
Isolation of Candidate cDNAs from the Region of Interest.
cDNA clones were isolated following a modification of a solution hybrid
capture method described by Futreal et al.
(12)
, using BAC clones from the region of interest, as
selector DNA, and isolating cDNA clones from a human mammary gland cDNA
library (5'-STRECH; Clontech Laboratories, Inc.). All cloned cDNAs were
sequenced and analyzed using the BLAST algorithm, searching all
available GenBank human databases. The isolated cDNA clones were mapped
back to the corresponding BAC (selector) DNAs and compared with the
genomic DNA sequence.
WWOX cDNA Isolation and Exon-Intron Structure
Determination.
A consensus sequence was generated by alignment of the primary cloned
cDNA sequence and matching ESTs. From this sequence primers were
prepared to isolate the full-length cDNA. Two independent clones were
isolated from a placenta cDNA library panel (Rapid Screen, OriGene
Technologies, Inc.). Additionally, a second strategy was followed using
the 5'- and 3'-rapid amplification of cDNA ends PCR method on a human
mammary gland cDNA library (Marathon-Ready; Clontech) according to the
manufacturer’s protocol. The cDNAs isolated by this last method were
cloned, sequenced, aligned, and compared with the clones isolated from
the placenta library to determine the full-length cDNA. Primers for the
5' and 3' ends of WWOX cDNA were used as a first step to
isolate additional BAC genomic clones. After the intron-exon junctions
for a specific exon were determined, primers for the next exon were
designed. The whole-length cDNA sequence was compared with the genomic
sequence to determine the genomic structure of WWOX.
Protein Sequence Analysis.
The WWOX amino acid sequence was analyzed using the BLASTP and
PSI-BLAST algorithms in search for matches or homologies in the GenBank
protein databases. The identification of protein family domains was
determined by using the Pfam domain models (PFAM: multiple alignments
and profile HMMs of protein domains, release 4.3, The Pfam
Consortium, http://pfam.wustl.edu/).
Northern Analysis.
Northern blots using 2 µg of poly(A) RNA from breast cancer cell
lines and normal human breast epithelium were prepared using standard
procedures. The multitissue Northern blot was purchased from Clontech.
A 1553-bp EcoRI restriction fragment of WWOX
clone, spanning the 5' end and amino acid-coding region, was used as
probe after labeling with [32P]dCTP using
random priming (Prime It II; Stratagene, La Jolla, CA). The membranes
were hybridized in Rapid-hyb buffer (Amersham), followed by washing
according to the manufacturer’s protocol.
In Vitro Translation.
In vitro translation was performed using an in
vitro transcription-translation reticulocyte lysate assay (TNT T7
Quick Coupled Transcription/Translation System; Promega) with
full-length WWOX cDNA as template.
[35S]Methionine-labeled products were analyzed
by SDS-PAGE followed by phosphorimager detection.
Mutation Screening.
Genomic DNA isolated from a panel of 27 breast cancer cell lines was
used to resequence each of the exons of WWOX. Primers for
individual exon amplification and sequencing are specified in Table 1
.
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Results |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionNote Added in ProofREFERENCES |
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We followed two main approaches to characterize the chromosomal region of interest to isolate the putative tumor suppressor gene(s). After building a YAC and BAC contig spanning the D16S518–D16S516 region, we used conventional shotgun sequencing and cDNA isolation.
We isolated numerous cDNA clones from the area using a solution hybrid cDNA capture method (12) . Thirty-five cDNAs were isolated and sequenced, of which 17 matched previously isolated ESTs, and 18 showed no matches in any of the GenBank databases. All of the isolated cDNA clones were mapped back to the corresponding BAC DNAs, and their sequences were compared with the genomic DNA sequence to identify evidence of exon-intron structure. Only one of these cDNAs showed such features and is described in the following section (i.e., WWOX).
We also sequenced approximately 400,000 bp of the region covered by the
overlapping BACs 112B7, 249B4, 286F3, and 36O22 (Fig. 1)
including a continuous sequence of 96,371 bp (accession no. AF179633).
This genomic sequence was also analyzed for matching EST clusters from
GenBank databases. Of the numerous ESTs identified and analyzed, none
showed evidence of ORF or exon-intron structure.
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Next we determined the exon structure and exon-intron boundaries of
WWOX and confirmed the chromosomal location of the gene to
the region of interest. To this end various combinations of PCR primers
were designed based on the cDNA sequence and then mapped back to the
corresponding BACs. Subsequent sequencing of the predicted exons
permitted the exon-intron boundaries to be established at the genomic
DNA level (Fig. 1)
.
WWOX is composed of nine exons, ranging in size from 58 to
1060 bp (Table 1)
. On the basis of analysis of the promoter region
(reported to GenBank under accession no. AF212843), we determined that
the first exon is localized within a CpG island starting at position
-660 and extending into the first intron at 292 bp from the ATG
translation start site. This area shows a 63% content of C + G and 8% CpG with the highest percentage within the area from -300 bp
to ATG (68 and 11%, respectively).
We also observed that the 3' end of WWOX had high sequence homology to a previous GenBank entry of a human putative oxidoreductase (U13395, locus 9621).
Interestingly, we found that the physical map of WWOX spans
the whole region of interest: we mapped exon 1 of WWOX to
the BAC containing D16S518 and exon 9 and the 3' UTR to the BAC
containing D16S516 (Fig. 1)
. We estimate that WWOX spans a
large genomic region of 
1 Mb in size. Although the exact lengths of
the intronic portions of this gene were not determined, we based this
estimate on the known size of the YAC clones, the average size of BAC
clones (150 kb), and our shotgun sequencing (described above)
wherein the 400,000 bp corresponded to the intron 8 area of
WWOX (Fig. 1)
. Interestingly, analysis of sequence contigs
from this large intronic region allowed us to identify two previously
described translocation breakpoints mapping to this same area. These
translocation breakpoints, MM.1 and JJN3, have been described in
multiple myeloma involving chromosomes 14 and 16, i.e.,
t(14;16)(q32;q23) (15)
. Further sequence analysis of this
area also identified the existence of a pseudogene for ribosomal
protein S3 matching to sequence within this intronic region (AF179633).
To our knowledge no other genes have been reported in this area
(i.e., D165518–D165516), and we have not identified any
other candidates.
WWOX Protein Structure.
The 1245-bp WWOX ORF encodes for a 414-amino acid protein
(Fig. 2)
. The BLAST and PSI-BLAST algorithms were used to search for matches in
GenBank databases. Interestingly, the NH2
terminus of the putative WWOX protein showed homology to ubiquitin
ligases such as NEDD4, YES-associated protein YAP65, and other WW
domain-containing proteins (data not shown). Further amino acid
sequence analysis using the PROSITE database identified two regions
within the putative WWOX protein (amino acids 18–47 and 59–88), which
have high homology to WW domain sequences. The first motif exhibits
typical features of a WW domain; it is 26 bp long with the two highly
conserved tryptophan and one proline residues. In the second WW domain
one tryptophan is replaced by a tyrosine residue; this is an
alternative functional replacement, which is also found in other WW
domain proteins (Fig. 2)
.
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. Due to the presence of the WW domains and the homology to SDR, we named this novel protein WWOX. Analysis using the PSORT algorithm predicts that WWOX has no NH2-terminal signal peptide, and its localization is probably in the cytoplasm (17) .
WWOX Expression Analysis.
Northern blot analysis with a probe derived from 5' end of
WWOX revealed a 2.2-kb mRNA (Fig. 3)
, which is in agreement with the length of the cDNA clone
i.e., 2264 bp.
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We also analyzed the expression of WWOX in normal mammary
epithelial cells in culture and in breast cancer cell lines. All of the
breast cancer lines analyzed showed higher WWOX expression
than normal breast tissue and normal mammary epithelial cells (HME-87;
Fig. 3, A and B
). However, among the breast
cancer lines analyzed, WWOX expression levels varied from
relatively low in T47D and MDA-MB435 to high overexpression in ZR75–1
and MCF-7 cells (Fig. 3B)
. Of these cell lines, previous
extensive allelotypic analysis using highly polymorphic STS markers
allowed us to determine that T47D, ZR-75, MDA-MB435, MDA-MB453, SKBR3,
and UACC812 were among the group of breast cancer lines with no
evidence of STS heterozygosity along most or all of 16q
(13)
. This indicated the high likelihood that they had
lost all or a large portion of one of the original parental 16q arms
including the region spanned by WWOX. However, the putative
hemizygous status of WWOX did not impede expression (Fig. 3B)
. We also found no correlation between the estrogen
receptor status of the breast cancer lines and the levels of
WWOX expression.
To examine whether the translation of the ORF of WWOX
produced the predicted protein, we used an in vitro
transcription-translation system. SDS-PAGE analysis of the translated
product revealed a single protein product of 46 kDa (Fig. 3C)
. This agrees with the predicted molecular mass of
WWOX based on its amino acid sequence (i.e., 46,676.8 Da).
Mutation Screening in Breast Cancer Cell Lines.
As mentioned above, WWOX spans the whole chromosomal area of
interest between STS markers D16S518 and D16S516. The high incidence of
LOH affecting this region led us previously to speculate on the
existence of a putative tumor suppressor gene within this area. Thus,
to investigate whether WWOX is a target for mutations in
breast cancer, we performed a mutation screening on a panel of 27
breast cancer cell lines. This panel of breast cancer cell lines was of
particular interest, because we have previously observed they exhibit a
high incidence of hemizygosity within the chromosome 16q area of
interest (13)
, i.e., cell lines in which the
majority had already lost one WWOX allele via chromosomal
rearrangements. Only one breast cancer case displayed a homozygous
deletion in this region (13)
. We now determined that this
deletion spanned part of the intron 8 region of WWOX from
STS 249B4S to D16S3029 inclusive (see Fig. 1
).
Each of the WWOX exons was amplified from the genomic DNA of
each of the 27 breast cancer lines, and the products were sequenced.
The intronic primers used for amplification and sequencing are detailed
in Table 1
.
We found no evidence of deletions or insertions in the examined DNAs. Two substitutions found appear to have a polymorphic rather than a mutational nature. The first, a C/T found at position -5 in the Kozak sequence, was observed in 50% of the tumor samples, but it was also observed that DNA isolated from normal mammary gland was polymorphic at this position. The second substitution, a G/A at position +534, results in an amino acid change, alanine to threonine, but because of the approximate frequency of 50% for either allele in the samples examined and because heterozygosity at this position was also found in normal DNA, we concluded that it also represents a polymorphism.
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Discussion |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionNote Added in ProofREFERENCES |
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The protein motif called WW or WWP was identified in very different types of proteins, including peptidyl-prolyl isomerases involved in mitosis regulation (18 , 19) , the cytoskeletal protein dystrophin (20) , spliceosome-associated proteins (21) , the ubiquitin-protein ligase NEDD4 (22) , and signal-transducing protein YAP65 (23) . This domain is characterized by the presence of very conserved proline and tryptophan residues (20 , 24 , 25) . WW domains are known to interact with the proline-rich motifs of other proteins. Thus far, four different WW binding proline-rich motifs have been identified: PPXY (23) , PPLP (26) , PGM/PPR (21) , and phosphoserine/phosphothreonine (27) . At this point it is not possible to predict which type of proline motif the WWOX protein would have affinity for.
SDRs represent a wide spectrum of enzymes. The protein domain database (PROSITE) identifies >60 different proteins from bacteria, fungi, plants, and animals that belong to this family. These are typically enzymes that metabolize different alcohols, sugars, keto-acyls, retinoids, steroids, and other hydroxy and keto substrates. One important group among the SDR proteins is the family of hydroxy-steroid dehydrogenases. The average size of SDR enzymes is 250–300 amino acids. Although overall similarity between the different SDRs can be as low as 15–30%, a small conserved substrate binding motif, YXXXK, and a coenzyme binding motif, GXXXGXG, are characteristic for these proteins (16) . Although the 414 amino acids of WWOX make it larger than the average SDR enzyme, the WWOX dehydrogenase domain exhibits the typical sequence features and distances between conserved motifs that are characteristic of SDR enzymes (28) . To our knowledge WWOX is, as yet, the only protein described that contains both binding motifs for low molecular weight ligands and substrates and WW domains.
WWOX has one additional putative signature, which is a serine residue 12 amino acids upstream of the YNRSK substrate binding motif. This serine is at a nearly identical location to that observed in steroid dehydrogenases (usually position -13 from Tyr), which is suggested to play an important role in the catalysis of steroid substrates (28) .
At this stage it is difficult to predict the role that WWOX may play in the metabolism of the cell. Nevertheless, its unique features make it an interesting target for further investigation. Hydroxysteroid dehydrogenases and reductases usually show a wide tissue expression profile, although some enzymes of this family are tissue specific. Northern analysis has shown that WWOX transcripts are highly represented in hormonally active tissues, with testis showing the highest expression. This tissue specificity, in addition to the SDR domain features, leads us to speculate that the WWOX substrate for dehydrogenase and reductase activity is probably a steroid. Because WWOX has the ability to interact with other proteins via the WW domains, the possibility exists that this protein may play a role in steroid-receptor interaction regulation. It is also possible to predict, on the basis of amino acid sequence analysis, that WWOX may localize to the cytoplasm of cells (17) .
We found no evidence of WWOX mutations in a variety of breast cancer lines suggesting that WWOX is not a tumor suppressor gene. However, we found that WWOX is overexpressed in breast cancer cells when compared with normal tissues. It is interesting to note that the cell line with the highest WWOX mRNA expression is the MCF7 line, which is characterized by its high dependence on estradiol for growth. This invites the speculation that perhaps WWOX plays a role in estradiol-estrogen receptor interaction regulation.
It is also intriguing that WWOX spans a chromosomal area
characterized by a very high incidence of allelic loss and chromosomal
rearrangements. Furthermore, we have mapped two previously described
chromosomal breakpoints, MM.1 and JJN3, to the last intron of
WWOX (Fig. 1)
. These specific 16q translocation breakpoints,
t(14;16)(q32;q23), were previously described in multiple myeloma
(15)
. Consequently, at least one of the alleles of
WWOX should be truncated in some multiple myeloma lines.
Hence, the potential role for WWOX inactivation in multiple myeloma
needs to be investigated. In those myeloma studies it was also observed
that other additional translocation breakpoints such as KMS11 and ANBL6
(see Ref. 15
) also map to the same region covered by YACs 933h2 and
972d3, hence, in very close vicinity of WWOX. Nevertheless,
the putative oncogenic target for transcriptional dysregulation in the
myeloma translocations was proposed to be the c-maf
oncogene, which is located telomeric of WWOX and in the
opposite 5'-3' orientation (15)
. Due to those
observations, we investigated whether the c-maf oncogene
showed any expression alterations in the breast cancer lines shown in
Fig. 3
. In short, we found no abnormalities of c-maf
expression when comparing breast cancer lines with normal breast cells
and tissues (data not shown). It is also worth mentioning that
translocations and deletions affecting ch16q23 have been described as
primary cytogenetic anomalies in several breast cancers (29
, 30)
. In our studies, we found one breast cancer case with a
homozygous deletion also mapping within the same intron 8 region in
which the translocation breakpoints were mapped. Interestingly, the
locus for the yet uncharacterized common fragile site FRA16D has been
cytogenetically mapped to this very same chromosome region,
16q23.2–23.3 (31
, 32)
.
All the evidence suggests that the whole genomic region spanned by WWOX and, in particular, the intron 8 region appear to be an area prone to chromosomal fragility. Although highly speculative, this area could be the same as the mentioned common fragile site FRA16D, because it displays features of genomic fragility similar to those observed in other better-characterized common fragile site loci (e.g., FRA3B; Refs. 31 , 32 ).
Our identification of WWOX and its possible association with cancer processes make it an interesting gene that deserves further investigation.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by the Kleberg Foundation Fund Cancer
Genetics Program, US Army Grant DAMD17-94-J-4078, and National
Institute of Environmental Health Sciences Center Grant ES07784. 
2 To whom requests for reprints should be
addressed, at University of Texas M. D. Anderson Cancer Center,
Science Park, Research Division, P.O. Box 389, Smithville, TX 78957.
Phone: (512) 237-9530; Fax: (512) 237-2475; E-mail: maldaz{at}odin.mdacc.tmc.edu
3 The abbreviations used are: LOH, loss of
heterozygosity; STS, sequence-tagged site; BAC, bacterial artificial
chromosome; YAC, yeast artificial chromosome; EST, expressed sequence
tag; poly(A), polyadenylic acid; ORF, open reading frame; UTR,
untranslated region; SDR, short-chain dehydrogenase/reductase.
Received 1/11/00. Accepted 3/ 3/00.
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