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• W1986863816 abstract "The GP1G gene codes for three of the four abundant androgen-regulated secretory proteins produced by the guinea pig seminal vesicle. Sequencing of the entire 6.3-kilobase gene and comparison with other mammalian seminal vesicle secretory protein genes reveals a common three-exon, two-intron organization. However, significant sequence similarity between this group of genes is largely limited to their 5′-flanking regions and first exons, which code almost exclusively for signal peptides in each case. The first intron of GP1G does contain a region with high similarity to the coding exon of a human seminal vesicle secretory protein gene, semenogelin II. The 3′ half of the GP1G gene appears to share a common ancestry with the human SKALP/elafin gene. Sequences related to the elafin promoter, coding, untranslated regions, and introns are clearly identifiable within the GP1G sequence. The elafin gene codes for a serine protease inhibitor and is expressed in a variety of different human tissues. To determine if the GP1G gene was also active outside of the seminal vesicle, RNA from a variety of guinea pig tissues was hybridized to a GP1G cDNA probe. At least three novel RNA bands hybridizing to the GP1G probe were detected in testis RNA samples, and GP1G-related mRNAs were also found in other tissues. These data suggest that these seminal vesicle secretory proteins may have functional roles outside the reproductive system. The GP1G gene codes for three of the four abundant androgen-regulated secretory proteins produced by the guinea pig seminal vesicle. Sequencing of the entire 6.3-kilobase gene and comparison with other mammalian seminal vesicle secretory protein genes reveals a common three-exon, two-intron organization. However, significant sequence similarity between this group of genes is largely limited to their 5′-flanking regions and first exons, which code almost exclusively for signal peptides in each case. The first intron of GP1G does contain a region with high similarity to the coding exon of a human seminal vesicle secretory protein gene, semenogelin II. The 3′ half of the GP1G gene appears to share a common ancestry with the human SKALP/elafin gene. Sequences related to the elafin promoter, coding, untranslated regions, and introns are clearly identifiable within the GP1G sequence. The elafin gene codes for a serine protease inhibitor and is expressed in a variety of different human tissues. To determine if the GP1G gene was also active outside of the seminal vesicle, RNA from a variety of guinea pig tissues was hybridized to a GP1G cDNA probe. At least three novel RNA bands hybridizing to the GP1G probe were detected in testis RNA samples, and GP1G-related mRNAs were also found in other tissues. These data suggest that these seminal vesicle secretory proteins may have functional roles outside the reproductive system. The seminal vesicle is an androgen-dependent male reproductive organ that synthesizes and secretes a protein-filled fluid that makes up a major portion of the ejaculated semen. Although some of these secretions appear to be capable of maintaining the integrity, motility, and/or transport of spermatozoa, the role of the seminal vesicle in reproduction is not well understood (reviewed in Ref. 1Aumuller G. Steitz J. Int. Rev. Cytol. 1990; 121: 127-231Crossref PubMed Scopus (123) Google Scholar). In guinea pigs, the seminal vesicle synthesizes and secretes four abundant seminal vesicle secretory proteins (SVSPs) 1The abbreviations used are: SVSPseminal vesicle secretory proteinUTRuntranslated regionkbkilobase pairsbpbase pair(s)ntnucleotidesSGsemenogelin. called SVP-1-4. Biochemical studies have indicated that the copulatory plug in the guinea pig is formed by the action of a prostate-secreted transglutaminase on SVP-1 (2Veneziale C.M. Deering N.C. Andrologia. 1976; 8: 73-82Crossref PubMed Scopus (16) Google Scholar, 3Notides A.C. Williams-Ashman H.G. Proc. Natl. Acad. Sci. U. S. A. 1967; 58: 1991-1995Crossref PubMed Scopus (43) Google Scholar, 4Moore J.T. Hagstrom J. McCormick D.J. Harvey S. Madden B. Holicky E. Stanford D.R. Wieben E.D. Proc. Natl. Acad. Sci. U. S. A. 1987; 84: 6712-6714Crossref PubMed Scopus (22) Google Scholar, 5Hagstrom J.E. Harvey S. Madden B. McCormick D. Wieben E.D. Mol. Endocrinol. 1989; 3: 1797-1806Crossref PubMed Scopus (14) Google Scholar). SVP-1 contains 8.5 repeats of a 24-amino acid glutamine- and lysine-rich clotting domain and is therefore ideally suited for a role as a transglutaminase substrate (4Moore J.T. Hagstrom J. McCormick D.J. Harvey S. Madden B. Holicky E. Stanford D.R. Wieben E.D. Proc. Natl. Acad. Sci. U. S. A. 1987; 84: 6712-6714Crossref PubMed Scopus (22) Google Scholar). Mature SVP-1 is a 22-kDa protein that is cleaved from the carboxyl terminus of a 45-kDa polypeptide precursor. The amino terminus of the 45-kDa precursor codes for both SVP-3 and SVP-4. These two acidic SVSPs can be distinguished on the basis of net charge, but partial sequencing at the protein level indicates that they share an identical primary sequence (5Hagstrom J.E. Harvey S. Madden B. McCormick D. Wieben E.D. Mol. Endocrinol. 1989; 3: 1797-1806Crossref PubMed Scopus (14) Google Scholar). The primary sequence of SVP-3/-4 also contains four copies of a 24-amino acid repeating domain structure, suggesting that these proteins could also be involved in clot formation. However, the amino acid repeat in SVP-3/-4 is unrelated to the SVP-1 repeat, and the function of SVP-3/-4 has yet to be determined. seminal vesicle secretory protein untranslated region kilobase pairs base pair(s) nucleotides semenogelin. The functional human homologs of guinea pig SVP-1 are the semenogelins. Semenogelin I (Sg I) is a 52-kDa protein that is cross-linked to form a clot in human semen, but the clot is rapidly digested through the action of seminal fluid proteases, including the serine protease prostate-specific antigen (6Lilja H. Abrahamsson P.-A. Lundwall AC AC AC Ao AC J. Biol. Chem. 1989; 264: 1894-1900Abstract Full Text PDF PubMed Google Scholar). Semenogelin II (Sg II) is a second secretory protein produced in both the seminal vesicle and epididymis that is approximately 80% identical to Sg I at the amino acid level (7Lilja H. Lundwall AC AC AC Ao AC Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 4559-4563Crossref PubMed Scopus (87) Google Scholar). Both semenogelin genes contain three exons. In each case, the first exon codes for the signal peptide, the second exon codes for the secreted protein, and the third exon contains a strictly 3′-untranslated region (8Ulvsbäck M. Lazure C. Lilja H. Spurr N.G. Rao V.V.N.G. Löffler C. Hansmann I. Lundwall AC AC AC Ao AC J. Biol. Chem. 1992; 267: 18080-18084PubMed Google Scholar). These two genes are greater than 80% identical within their introns and 5′- and 3′-flanking regions, suggesting that they arose by the duplication of a common ancestral gene. Although there is little coding sequence similarity between the human and rat seminal vesicle secretory protein genes, the rat genes also have a central exon coding for the secreted protein flanked by a 5′-exon coding for the signal peptide and a 3′-exon coding for the 3′-UTR (9Harris S.E. Mansson P.E. Tully D.B. Burkhart B. Proc. Natl. Acad. Sci. U. S. A. 1983; 80: 6460-6464Crossref PubMed Scopus (52) Google Scholar, 10McDonald C.J. Eliopoulos E. Higgins S.J. EMBO J. 1984; 3: 2517-2521Crossref PubMed Scopus (20) Google Scholar, 11Harris S.E. Harris M.A. Johnson C.M. Bean M.F. Dodd J.G. Matusik R.J. Carr S.A. Crabb J.W. J. Biol. Chem. 1990; 265: 9896-9903Abstract Full Text PDF PubMed Google Scholar, 12Williams L. McDonald C. Higgins S. Nucleic Acids Res. 1985; 13: 659-672Crossref PubMed Scopus (25) Google Scholar). The conservation of gene structure within the secretory protein genes of different mammals led us to determine the gene structure for the guinea pig gene (called GP1G) that yields SVP-1, SVP-3, and SVP-4. Our data indicate that sequences homologous to the coding exon of the human Sg II gene reside in the first intron of the GP1G. Furthermore, GP1G appears to be more closely related to the human SKALP/elafin gene rather than to any of the SVSP genes. The elafin gene produces a serine protease inhibitor that contains an amino-terminal transglutaminase cross-linking domain (13Alkemade J.A.C. Molhuizen H.O.F. Ponec M. Kempenaar J.A. Zeeuwen P.L.J.M. de Jongh G.J. van Vlijmen-Willems I.M.J.J. van Erp P.E.J. van de Kerkhof P.C.M. Schalkwijk J. J. Cell Sci. 1994; 107: 2335-2342Crossref PubMed Google Scholar, 14Sallenave J. Silva A. Am. J. Respir. Cell Mol. Biol. 1993; 8: 439-445Crossref PubMed Scopus (75) Google Scholar, 15Saheki T. Ito F. Hagiwara H. Saito Y. Kuroki J. Tachibana S. Hirose S. Biochem. Biophys. Res. Commun. 1992; 185: 240-245Crossref PubMed Scopus (68) Google Scholar). Based on this homology, we investigated the expression of the GP1G gene in other tissues. Northern blot analysis revealed that GP1G transcripts are present outside the seminal vesicle, including three larger hybridizing mRNAs in the testis. The presence of SVP-1 gene products in these tissues suggests that this protein has another function outside of its role in formation of the copulatory plug during reproduction. A guinea pig testis genomic library (CLONTECH) was screened with a 32P-nick-translated 1400-bp probe corresponding to the cDNA for GP1 (5Hagstrom J.E. Harvey S. Madden B. McCormick D. Wieben E.D. Mol. Endocrinol. 1989; 3: 1797-1806Crossref PubMed Scopus (14) Google Scholar). Five individual positive clones were selected and amplified. A 14.5-kb insert from one clone, 1321, was excised with SalI and subcloned into Bluescribe (+) (Stratagene). Restriction fragments were subcloned into M13mp18 and M13mp19 and sequenced in both orientations using either Sequenase version 2.0 (U. S. Biochemical Corp.) or automated sequencing performed with either an Applied Biosystems, Inc. or Pharmacia Biotech Inc. DNA sequencer. Four µg of guinea pig liver genomic DNA was digested with restriction enzymes separated on a 0.8% agarose gel and transferred to a nylon membrane (Micron Separations, Inc.) by diffusion using 10 × SSC. The blotted filter was probed with a [32P]dATP random primed 1400-bp GP1 cDNA (5Hagstrom J.E. Harvey S. Madden B. McCormick D. Wieben E.D. Mol. Endocrinol. 1989; 3: 1797-1806Crossref PubMed Scopus (14) Google Scholar) at 42°C overnight in 8% dextran sulfate, 46% formamide, 4.5 × SSC, 9 m sodium phosphate, pH 7.2, 0.5% SDS, 4.6 × Denhardt's solution, and 0.15 µg/ml salmon testis DNA. Following hybridization overnight at 42°C, the filter was washed in 0.1 × SSC and 0.25% SDS at 50°C for 2 h. The blot was exposed to film for 18 h at −70°C with an intensifying screen. Total RNA was isolated by the method of Cathala et al. (16Cathala G.G. Savouret J. Mendez B. West B.L. Karin M. Martial J.A. Baxter J.D. DNA (N. Y.). 1983; 2: 329-335Crossref PubMed Scopus (1223) Google Scholar), separated on a 1.0% agarose,2.2 formaldehyde gel, and transferred to MSI nylon by diffusion using 10 × SSC. The blotted filter was probed with a [32P]dATP random primed 1400-bp GP1 cDNA, washed, and exposed to film as described for the genomic Southern blot. The software package of the Genetics Computer Group was used to analyze and align nucleotide sequences (17Genetics Computer Group, Inc., 1994, Program Manual for the Wisconsin Package, Version 8, Madison, WI.Google Scholar). To estimate the number of copies of SVP-1/-3/-4-related sequences in the guinea pig genome, genomic DNA samples were hybridized with a 1400-bp cDNA probe coding for SVP-1/-3/-4 cDNA (GP1, see Ref. 5Hagstrom J.E. Harvey S. Madden B. McCormick D. Wieben E.D. Mol. Endocrinol. 1989; 3: 1797-1806Crossref PubMed Scopus (14) Google Scholar). A single band hybridizing with this probe was obtained in each case (Fig. 1). These data suggest that the guinea pig genome contains either a single copy of the gene for these secretory proteins or several copies of the gene in a similar genomic environment. To isolate genomic clones, we screened a guinea pig testis genomic library with GP1. Sequencing of one of five clones isolated from this library (1321) revealed that the SVP-1/-3/-4 gene spans approximately 6.3 kb and is organized into three exons that correspond to functional domains. The first exon is 93 nt in length and includes sequences for the 5′-UTR, the hydrophobic signal peptide, and the first 4 amino acids of mature SVP-3/-4 (Fig. 2). The second exon is 1127 nt long and encodes the vast majority of the protein coding region including the remainder of SVP-3/-4 and all of SVP-1. Exon three is 185 nts long and codes exclusively for the 3′-UTR. The primary structures of SVSPs from several mammalian species have been deduced from cloned cDNA sequences (6Lilja H. Abrahamsson P.-A. Lundwall AC AC AC Ao AC J. Biol. Chem. 1989; 264: 1894-1900Abstract Full Text PDF PubMed Google Scholar, 7Lilja H. Lundwall AC AC AC Ao AC Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 4559-4563Crossref PubMed Scopus (87) Google Scholar, 10McDonald C.J. Eliopoulos E. Higgins S.J. EMBO J. 1984; 3: 2517-2521Crossref PubMed Scopus (20) Google Scholar, 11Harris S.E. Harris M.A. Johnson C.M. Bean M.F. Dodd J.G. Matusik R.J. Carr S.A. Crabb J.W. J. Biol. Chem. 1990; 265: 9896-9903Abstract Full Text PDF PubMed Google Scholar, 12Williams L. McDonald C. Higgins S. Nucleic Acids Res. 1985; 13: 659-672Crossref PubMed Scopus (25) Google Scholar, 18Chen Y.H. Pentecost B.T. McLachian J.A. Teng C.T. Mol. Endocrinol. 1987; 1: 707-716Crossref PubMed Scopus (49) Google Scholar). Although many of the proteins contain repeated sequences with invariant glutamine, lysine, serine, and glycine residues, there is no specific primary sequence common to all. However, in each case, evolution has maintained a three-exon, two-intron structure with significant conservation of 5′-flanking and first exon sequences. The region of similarity includes both the TATA box and a 13-nt sequence found approximately 90 nt upstream of the transcription start site of all seminal vesicle secretory protein genes (the −90 sequence, Fig. 2). The SVP-1/-3/-4 gene has a perfect 13/13 nucleotide match to the consensus −90 sequence, which was first noted by Williams et al. (12Williams L. McDonald C. Higgins S. Nucleic Acids Res. 1985; 13: 659-672Crossref PubMed Scopus (25) Google Scholar) as a conserved element with similarity to a CCAAT box. In this regard, it is notable that GP1G also has a perfect match to the consensus CCAAT box sequence upstream of the transcription start site (underlined in Fig. 2). Similarity between GP1G and the upstream regions of the rat SVS II, IV and V genes extends beyond these sequences, and each has about 60% identity to GP1G within the first 140 nt of 5′-flanking sequence (9Harris S.E. Mansson P.E. Tully D.B. Burkhart B. Proc. Natl. Acad. Sci. U. S. A. 1983; 80: 6460-6464Crossref PubMed Scopus (52) Google Scholar, 11Harris S.E. Harris M.A. Johnson C.M. Bean M.F. Dodd J.G. Matusik R.J. Carr S.A. Crabb J.W. J. Biol. Chem. 1990; 265: 9896-9903Abstract Full Text PDF PubMed Google Scholar, 12Williams L. McDonald C. Higgins S. Nucleic Acids Res. 1985; 13: 659-672Crossref PubMed Scopus (25) Google Scholar). The first exons of the rat and guinea pig genes are even more related, with the predicted signal peptides of SVS IV and V having 12/21 and 10/21 identity to the GP1G product (Fig. 3). The SVSP gene with the greatest similarity to GP1G is the human Sg II gene (8Ulvsbäck M. Lazure C. Lilja H. Spurr N.G. Rao V.V.N.G. Löffler C. Hansmann I. Lundwall AC AC AC Ao AC J. Biol. Chem. 1992; 267: 18080-18084PubMed Google Scholar) (Fig. 4, A and C). Comparison of the 5′-flanking 650 nucleotides of the GP1 gene to the corresponding region of the human Sg II gene revealed a 65% nucleotide conservation throughout this region. In addition to the 5′-flanking region, the first exons of the GP1 and Sg II genes are 78% identical at the nucleotide level and code for signal peptides with 15/21 identity at the amino acid level (Fig. 3). These findings suggest that the two genes may have diverged from a common ancestral gene. This interpretation is supported by the finding that the similarity between GP1G and the Sg II genes continues past the first exons. In contrast to the 4.5-kb first intron of the GP1G gene, the first intron of the Sg II gene is relatively short (0.25 kb). Homology between the two genes is not only maintained through the span of the human intron but continues with significant homology between the second exon of the Sg II gene and the 5′-end of the first intron of GP1G. The matrix comparison demonstrates that the GP1G intron contains a single copy of a sequence that is repeated 6 times in the human coding exon. This finding correlates well with the known structure of the Sg II coding sequence, which contains four copies of a 180-nt sequence (type I) and two copies of a related (type II) repeat (7Lilja H. Lundwall AC AC AC Ao AC Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 4559-4563Crossref PubMed Scopus (87) Google Scholar). Pairwise comparisons of the entire second exon of Sg II with the 5′-half of the GP1G exon reveal an overall similarity of 57% through this span. However, using the BESTFIT algorithm (17Genetics Computer Group, Inc., 1994, Program Manual for the Wisconsin Package, Version 8, Madison, WI.Google Scholar), a 139-nt stretch of a type II Sg II repeat is found to be 69% identical to the GP1G intron without the insertion of any gaps in either sequence. This level of similarity further supports the hypothesis that the guinea pig and human genes evolved from a common ancestral gene. However, DNA sequences used by the human gene to code for the seminal vesicle secretory protein were relegated to intron status in the guinea pig lineage. While there are definite evolutionary relationships between the GP1 gene and other SVSP genes, searches of the entire GenBank data base with GP1G sequence reveal that GP1G is most closely related to the human SKALP/elafin gene (14Sallenave J. Silva A. Am. J. Respir. Cell Mol. Biol. 1993; 8: 439-445Crossref PubMed Scopus (75) Google Scholar, 15Saheki T. Ito F. Hagiwara H. Saito Y. Kuroki J. Tachibana S. Hirose S. Biochem. Biophys. Res. Commun. 1992; 185: 240-245Crossref PubMed Scopus (68) Google Scholar). Homology between the elafin precursor and SVP-1 at the amino acid level has been noted previously and was used to predict the presence of a functional transglutaminase cross-linking domain in the amino terminus of the primary translation product of the elafin gene (19Molhuizen H.O.F. Alkemade H.A.C. Zeeuwen P.L.J.M. deJongh G.J. Wieringa B. Schalkwijk J. J. Biol. Chem. 1993; 268: 12028-12032Abstract Full Text PDF PubMed Google Scholar, 20Nara K. Ito S. Ito T. Suzuki Y. Ghoneim M.A. Tachibana S. Hirose S. J. Biochem. (Tokyo). 1994; 115: 441-448Crossref PubMed Scopus (110) Google Scholar). As noted for the SVSPs, the elafin precursor has a primary structure that is based on amino acid repeats containing invariant lysine, glutamine, and glycine residues. The human elafin gene also has the same three-exon structure as the SVSP genes but spans only 1.7 kb in its entirety. Dot matrix comparison of the human elafin gene with GP1G at high stringency (16/21, requiring 76% identity over 21 nucleotides to register a match) reveals extensive similarity throughout the entire length of the elafin gene (Fig. 4, B and C). The region of homology extends to both 5′- and 3′-flanking sequences of the elafin gene and is maximal between the second introns and third (non-coding) exons (Fig. 5), which are 70% identical with only 4 gaps. Within the coding sequences, the similarity is highest between the amino terminus of the elafin gene product and the SVP-1 coding sequence. The elafin gene does not contain a region homologous to SVP-3/-4, nor does the GP1G gene contain a region homologous to the carboxyl-terminal protease inhibitor domain of human elafin. Our understanding of the function of SVSPs has been that these proteins are involved in providing an appropriate environment for sperm transfer to the female and in the formation of the copulatory plug. However, the presence of an elafin gene homolog embedded within the guinea pig GP1 gene suggested the possibility that sequences from this genomic locus could also be expressed outside the seminal vesicle. Northern blot analysis of total RNA isolated from several guinea pig tissues revealed that GP1-related transcripts are, in fact, present outside the seminal vesicle (Fig. 6). The GP1-related transcripts identified in the lung, liver, and kidney appear to be the same size as those produced in the seminal vesicle. However, the testis RNA sample yielded three bands that hybridized to the GP1 probe. The smallest of these bands migrates just slower than the GP1 mRNA produced in the seminal vesicle, whereas the two larger species appear to be at least 500 nt larger than the major seminal vesicle GP1 mRNA. The SVSPs appear to belong to a growing list of genes that code for proteins involved in reproduction that exhibit unusual divergence within protein coding regions (10McDonald C.J. Eliopoulos E. Higgins S.J. EMBO J. 1984; 3: 2517-2521Crossref PubMed Scopus (20) Google Scholar, 21Whitfield L.S. Lovell-Badge R. Goodfellow P.N. Nature. 1993; 364: 713-715Crossref PubMed Scopus (321) Google Scholar, 22Tucker P.K. Lundrigan B.L. Nature. 1993; 364: 715-717Crossref PubMed Scopus (195) Google Scholar, 23Swanson W.J. Vacquier V.D. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 4957-4961Crossref PubMed Scopus (117) Google Scholar). While GP1G appears to share common regulatory sequences and signal peptides with the SVSPs from other mammals, the protein coding region has little similarity to the coding exons of those genes. The 5′-end of the guinea pig gene is most closely related to the Sg II gene, which codes for a functional homolog of SVP-1. The alignment of the 5′-flanking regions and first exons of these two genes is straightforward and reveals a high level of sequence identity over a span of 750 nt (Fig. 4). By itself, this extended similarity could be interpreted as either conservation of sequence from a common ancestor or convergent evolution based on a functional requirement for specific sequences necessary to effect high level expression of these proteins in the seminal vesicle. However, the finding that sequences related to the human Sg II exon are found in the first intron of the GP1G gene argues strongly in favor of a common ancestral secretory protein gene. This hypothesis suggests that a single ancestral sequence has been selected for function as a coding exon in the human and as intron in the guinea pig. Subsequent duplications of functional domains involved in cross-linking in each lineage would account for much of the difference between the present day coding sequences. This hypothetical pattern of evolution is reminiscent of the selective amplification of different repeat segments during the evolution of the involucrin gene, which also codes for a transglutaminase substrate (24Tseng H. Green H. Cell. 1988; 54: 491-496Abstract Full Text PDF PubMed Scopus (48) Google Scholar). Inspection of the nucleotide sequence of the GP1G intron in the region of homology to the 3′-splice site of the Sg II gene suggests a possible explanation for this unusual evolutionary pattern. While the overall sequence similarity near the Sg II splice junctions is quite good, the GP1G gene contains an additional AG dinucleotide seven bases upstream of the 3′-splice junction that is used in the Sg II gene (Fig. 7). If the upstream AG is actually used as a splice acceptor by the splicing apparatus, it would lead to the production of a spliced product that is out of frame with the Sg II product. Under these circumstances, the use of a splice acceptor site in a downstream ancestral elafin gene could have been favored (Fig. 4C). Thus, a single A → G transition creating this AG immediately upstream of the active splice junction could have been a pivotal event in the divergence of the coding sequences for these SVSPs. Whatever the cause, it is clear that the coding sequence in the second exon of the GP1G gene is not related to that of the Sg II gene except for the presence of repeated motifs coding for invariant Lys, Gln, Gly, and Ser residues. Neither the length of the repeats nor the actual sequence of the repeating units appears to have been critical during the divergence of these genes. The preferential conservation of UTRs over coding regions has been noted before in a comparison of the sequences of two rat seminal vesicle secretory protein mRNA sequences (10McDonald C.J. Eliopoulos E. Higgins S.J. EMBO J. 1984; 3: 2517-2521Crossref PubMed Scopus (20) Google Scholar). The current analysis extends this observation to other members of this gene family and demonstrates that the 5′-flanking regions and introns can also maintain a higher degree of conservation than coding regions for this family of genes. It is tempting to speculate that the rapid divergence of the coding sequences might promote increased resistance of the copulatory plug to proteolysis. Thus, there might be direct positive selection for diversity in these seminal vesicle proteins as there is in acrosomal proteins of the abalone (23Swanson W.J. Vacquier V.D. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 4957-4961Crossref PubMed Scopus (117) Google Scholar). Alternatively, as suggested by McDonald et al. (10McDonald C.J. Eliopoulos E. Higgins S.J. EMBO J. 1984; 3: 2517-2521Crossref PubMed Scopus (20) Google Scholar), this unusual pattern of sequence divergence might simply reflect the lack of selection for a particular protein sequence since any repetitive sequence capable of forming intermolecular cross-links could fulfill the known role for these proteins in reproduction. The evolutionary history of other genes that have experienced unusual patterns of divergence is often obscure. In the case of GP1G, a key factor in the divergence from the Sg II gene could have been the appropriation of coding sequences from an ancestral elafin gene. Whatever the origin, the presence of a nearly full-length elafin gene embedded in the GP1G gene is unexpected and suggests that the protein products of GP1G might have additional functional roles. The only known function of the SVSPs is to participate in the formation of the vaginal plug after copulation. In the guinea pig, biochemical studies suggest that SVP-1 is the major component of the vaginal plug (3Notides A.C. Williams-Ashman H.G. Proc. Natl. Acad. Sci. U. S. A. 1967; 58: 1991-1995Crossref PubMed Scopus (43) Google Scholar, 25Williams-Ashman H.G. Notides A.C. Pabalan S.S. Lorand L. Proc. Natl. Acad. Sci. U. S. A. 1972; 69: 2322-2325Crossref PubMed Scopus (92) Google Scholar). The transient clotting of human semen appears to be due primarily to the formation of disulfide bridges between molecules of semenogelin although a contribution from transglutaminase activity has not been excluded (6Lilja H. Abrahamsson P.-A. Lundwall AC AC AC Ao AC J. Biol. Chem. 1989; 264: 1894-1900Abstract Full Text PDF PubMed Google Scholar, 26Lilja H. Oldbring J. Rannevik G. Laurell C. J. Clin. Invest. 1987; 80: 281-285Crossref PubMed Scopus (327) Google Scholar). Although SVP-1 contains no cysteine (and therefore cannot use disulfide linkages in clot formation), both of the semenogelins are rich in glutamines and lysines and could presumably function as transglutaminase substrates. Whatever cross-linking mechanism is operative, there is no reason for proteins involved solely in the formation of the vaginal plug to be expressed outside the reproductive system. However, our data suggest that GP1G mRNAs are easily detectable in total RNA samples from the kidney, liver, and lung. At least three novel mRNAs from the testis also hybridize to a GP1 cDNA probe. Expression of the SVSP genes outside the seminal vesicle is not limited to the guinea pig. Sg II mRNA is also produced in the epididymis (6Lilja H. Abrahamsson P.-A. Lundwall AC AC AC Ao AC J. Biol. Chem. 1989; 264: 1894-1900Abstract Full Text PDF PubMed Google Scholar), rat SVS II transcripts are found in the prostate (27Dodd J.G. Kreis C. Sheppard P.C. Hamel A. Matusik R.J. Mol. Cell. Endocrinol. 1986; 47: 191-200Crossref PubMed Scopus (27) Google Scholar), and rat SVS IV mRNA is abundant in skeletal muscle (28Yoo-Warren H. Willse A.G. Hull J. Brownell E. J. Exp. Zool. 1993; 265: 653-658Crossref Scopus (4) Google Scholar). Although rat SVS IV has been reported to have immunosuppressive, anti-inflammatory, and anti-thrombotic properties (1Aumuller G. Steitz J. Int. Rev. Cytol. 1990; 121: 127-231Crossref PubMed Scopus (123) Google Scholar, 29Di Micco B. Colonna G. Porta R. Metafora S. Biochem. Pharmacol. 1994; 48: 345-352Crossref Scopus (16) Google Scholar, 30Porta R. Esposito C. Metafora S. Malorni A. Pucci P. Siciliano R. Marino G. Biochemistry. 1991; 30: 3114-3120Crossref PubMed Scopus (47) Google Scholar), there are no data supporting a function for any of the SVSPs outside of the reproductive tract. The homology of SVP-1 to the “pro” segment of elafin (called “cementoin” by Nara et al. (20Nara K. Ito S. Ito T. Suzuki Y. Ghoneim M.A. Tachibana S. Hirose S. J. Biochem. (Tokyo). 1994; 115: 441-448Crossref PubMed Scopus (110) Google Scholar)) raises the possibility that SVP-1 might also have a role in the extracellular matrix. Whether this protein serves as an anchor segment for other extracellular proteins (SVP-3/-4?) as proposed for the cementoin product from the elafin gene or has some other role in cell physiology remains to be determined. The functions of the other products of the GP1G gene, SVP-3 and SVP-4, have not been established, and no obvious evolutionary homologs of these proteins have been identified. With reference to the data reported here, it is curious that the primary sequence of these proteins has no sequence similarity to either the protease inhibitor domain of elafin or any of the known SVSPs. Thus, it is difficult to speculate regarding possible functions of these GP1G gene products outside the reproductive system. Further studies will be needed to address this question and to determine the structure and function of the novel GP1G-related transcripts found in the guinea pig testis. We thank Dr. James Lee for preparing the guinea pig genomic DNA used for the Southern blot; Lisa Hendel, Scott Harvey, and the Mayo Molecular Biology Core Facility for efforts in sequencing the GP1G gene; and Debbie Pearson for assistance with the preparation of the manuscript." @default.
• W1986863816 created "2016-06-24" @default.
• W1986863816 creator A5019416515 @default.
• W1986863816 creator A5021574466 @default.
• W1986863816 creator A5038929700 @default.
• W1986863816 creator A5039177493 @default.
• W1986863816 creator A5067353454 @default.
• W1986863816 date "1996-08-01" @default.
• W1986863816 modified "2023-09-29" @default.
• W1986863816 title "Exons Lost and Found" @default.
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