* 600518

SERPIN PEPTIDASE INHIBITOR, CLADE B (OVALBUMIN), MEMBER 4; SERPINB4


Alternative titles; symbols

SQUAMOUS CELL CARCINOMA ANTIGEN 2; SCCA2
LEUPIN


HGNC Approved Gene Symbol: SERPINB4

Cytogenetic location: 18q21.33     Genomic coordinates (GRCh38): 18:63,637,259-63,644,256 (from NCBI)


TEXT

Description

Squamous cell carcinoma antigen (SCCA) is a member of the ovalbumin family of serine proteinase inhibitors. The protein was isolated from a metastatic cervical squamous cell carcinoma by Kato and Torigoe (1977). SCCA is detected in the superficial and intermediate layers of normal squamous epithelium, whereas the mRNA is detected in the basal and subbasal levels. The clinical import of SCCA has been as a circulating tumor marker for squamous cell carcinoma, especially those of the cervix, head and neck, lung, and esophagus. Many clinical studies of cervical squamous cell carcinoma show that the percentage of patients with elevated circulating levels of SCCA increases from approximately 12% at stage 0 to more than 90% at stage IV. Levels fall after tumor resection and rise in approximately 90% of the patients with recurrent disease. Similar trends occur in the other types of squamous cell carcinoma, with a maximum sensitivity of approximately 60% for lung, 50% for esophageal, and 55% for head and neck tumors. The neutral form of SCCA (SCCA1, or SERPINB3; 600517) is detected in the cytoplasm of normal and some malignant squamous cells, whereas the acidic form (SCCA2, or SERPINB4) is expressed primarily in malignant cells and is the major form found in the plasma of cancer patients. Thus, the appearance of the acidic fraction of SCCA is correlated with more aggressive tumors (summary by Schneider et al., 1995).


Cloning and Expression

In an analysis of chromosomal aberrations involving human chromosome band 18q21, Silverman et al. (1991) identified a DNA fragment, A56R (D18S86), that contained a 56/57-bp match with the cDNA sequence of SCCA1. Schneider et al. (1995) showed that this fragment contained exon 3 of a new gene, SCCA2. SCCA2 shares 92% amino acid identity with SCCA1. Based on the predicted pI values and molecular masses of SCCA1 and SCCA2, Schneider et al. (1995) suggested that the neutral and acidic forms of SCCA are encoded by SCCA1 and SCCA2, respectively.

Barnes and Worrall (1995) described the cloning of a member of the serpin family of serine protease inhibitors by degenerate PCR and screening of a HeLa cell cDNA library. The isolated cDNA encodes a 390-amino acid protein, designated leupin by them, that is 91.8% identical to SCCA1. The authors stated that the reactive site of leupin differs from SCCA1 by the presence of a leucine residue rather than a serine at the P(1) position within the loop region that acts as a pseudosubstrate for the target protease. Barnes and Worrall (1995) speculated that leupin may be a cysteine protease inhibitor.


Gene Function

Schick et al. (1997) found that SCCA2 inhibited the chymotrypsin-like proteinases cathepsin G (116830) and mast cell chymase (118938) in vitro. SCCA2 was ineffective against papain-like cysteine proteinases, which have been shown to be inhibited by SCCA1.

Ray et al. (2005) stated that mouse Scca2, or Serpinb3a, exhibits the cysteine-like serine protease inhibitory function of human SCCA1 and the trypsin-like serine protease inhibitory function of human SCCA2. Thus, Scca2 is the mouse ortholog of both human SCCA1 and SCCA2. Ray et al. (2005) found that challenge of uteroglobin (UGB, or SCGB1A1; 192020)-knockout mice with the allergen chicken ovalbumin (OVA) resulted in elevated lung expression of Scca2, as well as elevated levels of the cytokines Il4 (147780) and Il13 (147683) in lung and exacerbated airway inflammation. These effects were countered by reintroduction of recombinant Ugb. Treatment of cultured human bronchial epithelial cells with IL4 or IL13 stimulated SCCA1 and SCCA2 expression via phosphorylation of the transcription factors STAT1 (600555) and STAT6 (601512). SCCA1 and SCCA2 expression was not upregulated by IL4 or IL13 in the presence of an inhibitor of tyrosine phosphorylation. Ray et al. (2005) proposed that UGB controls allergic asthma by downregulating signaling through IL4 and IL13 and inhibiting SCCA1 and SCCA2 expression.


Mapping

Schneider et al. (1995) found that SCCA1 and SCCA2 are tandemly arrayed on chromosome 18q21.3 and are flanked by 2 members of the ovalbumin family of serine proteinase inhibitors, plasminogen activator inhibitor type-2 (SERPINB2; 173390) and maspin (SERPINB5; 154790).


REFERENCES

  1. Barnes, R. C., Worrall, D. M. Identification of a novel human serpin gene; cloning sequencing and expression of leupin. FEBS Lett. 373: 61-65, 1995. [PubMed: 7589435, related citations] [Full Text]

  2. Kato, H., Torigoe, T. Radioimmunoassay for tumor antigen of human cervical squamous cell carcinoma. Cancer 40: 1621-1628, 1977. [PubMed: 332328, related citations] [Full Text]

  3. Ray, R., Choi, M., Zhang, Z., Silverman, G. A., Askew, D., Mukherjee, A. B. Uteroglobin suppresses SCCA gene expression associated with allergic asthma. J. Biol. Chem. 280: 9761-9764, 2005. [PubMed: 15677460, related citations] [Full Text]

  4. Schick, C., Kamachi, Y., Bartuski, A. J., Cataltepe, S., Schechter, N. M., Pemberton, P. A., Silverman, G. A. Squamous cell carcinoma antigen 2 is a novel serpin that inhibits the chymotrypsin-like proteinases cathepsin G and mast cell chymase. J. Biol. Chem. 272: 1849-1855, 1997. [PubMed: 8999871, related citations] [Full Text]

  5. Schneider, S. S., Schick, C., Fish, K. E., Miller, E., Pena, J. C., Treter, S. D., Hui, S. M., Silverman, G. A. A serine proteinase inhibitor locus at 18q21.3 contains a tandem duplication of the human squamous cell carcinoma antigen gene. Proc. Nat. Acad. Sci. 92: 3147-3151, 1995. [PubMed: 7724531, related citations] [Full Text]

  6. Silverman, G. A., Jockel, J. I., Domer, P. H., Mohr, R. M., Taillon-Miller, P., Korsmeyer, S. J. Yeast artificial chromosome cloning of a two-megabase-siz e contig within chromosomal band 18q21 establishes physical linkage between BCL2 and plasminogen activator inhibitor type-2. Genomics 9: 219-228, 1991. [PubMed: 2004771, related citations] [Full Text]


Matthew B. Gross - updated : 4/8/2011
Patricia A. Hartz - updated : 2/25/2011
Rebekah S. Rasooly - updated : 4/7/1998
Alan F. Scott - updated : 4/23/1996
Creation Date:
Victor A. McKusick : 5/7/1995
mgross : 04/08/2011
mgross : 4/8/2011
mgross : 4/8/2011
terry : 2/25/2011
alopez : 8/11/1999
psherman : 4/7/1998
mark : 4/23/1996
mimadm : 11/3/1995
mark : 5/7/1995

* 600518

SERPIN PEPTIDASE INHIBITOR, CLADE B (OVALBUMIN), MEMBER 4; SERPINB4


Alternative titles; symbols

SQUAMOUS CELL CARCINOMA ANTIGEN 2; SCCA2
LEUPIN


HGNC Approved Gene Symbol: SERPINB4

Cytogenetic location: 18q21.33     Genomic coordinates (GRCh38): 18:63,637,259-63,644,256 (from NCBI)


TEXT

Description

Squamous cell carcinoma antigen (SCCA) is a member of the ovalbumin family of serine proteinase inhibitors. The protein was isolated from a metastatic cervical squamous cell carcinoma by Kato and Torigoe (1977). SCCA is detected in the superficial and intermediate layers of normal squamous epithelium, whereas the mRNA is detected in the basal and subbasal levels. The clinical import of SCCA has been as a circulating tumor marker for squamous cell carcinoma, especially those of the cervix, head and neck, lung, and esophagus. Many clinical studies of cervical squamous cell carcinoma show that the percentage of patients with elevated circulating levels of SCCA increases from approximately 12% at stage 0 to more than 90% at stage IV. Levels fall after tumor resection and rise in approximately 90% of the patients with recurrent disease. Similar trends occur in the other types of squamous cell carcinoma, with a maximum sensitivity of approximately 60% for lung, 50% for esophageal, and 55% for head and neck tumors. The neutral form of SCCA (SCCA1, or SERPINB3; 600517) is detected in the cytoplasm of normal and some malignant squamous cells, whereas the acidic form (SCCA2, or SERPINB4) is expressed primarily in malignant cells and is the major form found in the plasma of cancer patients. Thus, the appearance of the acidic fraction of SCCA is correlated with more aggressive tumors (summary by Schneider et al., 1995).


Cloning and Expression

In an analysis of chromosomal aberrations involving human chromosome band 18q21, Silverman et al. (1991) identified a DNA fragment, A56R (D18S86), that contained a 56/57-bp match with the cDNA sequence of SCCA1. Schneider et al. (1995) showed that this fragment contained exon 3 of a new gene, SCCA2. SCCA2 shares 92% amino acid identity with SCCA1. Based on the predicted pI values and molecular masses of SCCA1 and SCCA2, Schneider et al. (1995) suggested that the neutral and acidic forms of SCCA are encoded by SCCA1 and SCCA2, respectively.

Barnes and Worrall (1995) described the cloning of a member of the serpin family of serine protease inhibitors by degenerate PCR and screening of a HeLa cell cDNA library. The isolated cDNA encodes a 390-amino acid protein, designated leupin by them, that is 91.8% identical to SCCA1. The authors stated that the reactive site of leupin differs from SCCA1 by the presence of a leucine residue rather than a serine at the P(1) position within the loop region that acts as a pseudosubstrate for the target protease. Barnes and Worrall (1995) speculated that leupin may be a cysteine protease inhibitor.


Gene Function

Schick et al. (1997) found that SCCA2 inhibited the chymotrypsin-like proteinases cathepsin G (116830) and mast cell chymase (118938) in vitro. SCCA2 was ineffective against papain-like cysteine proteinases, which have been shown to be inhibited by SCCA1.

Ray et al. (2005) stated that mouse Scca2, or Serpinb3a, exhibits the cysteine-like serine protease inhibitory function of human SCCA1 and the trypsin-like serine protease inhibitory function of human SCCA2. Thus, Scca2 is the mouse ortholog of both human SCCA1 and SCCA2. Ray et al. (2005) found that challenge of uteroglobin (UGB, or SCGB1A1; 192020)-knockout mice with the allergen chicken ovalbumin (OVA) resulted in elevated lung expression of Scca2, as well as elevated levels of the cytokines Il4 (147780) and Il13 (147683) in lung and exacerbated airway inflammation. These effects were countered by reintroduction of recombinant Ugb. Treatment of cultured human bronchial epithelial cells with IL4 or IL13 stimulated SCCA1 and SCCA2 expression via phosphorylation of the transcription factors STAT1 (600555) and STAT6 (601512). SCCA1 and SCCA2 expression was not upregulated by IL4 or IL13 in the presence of an inhibitor of tyrosine phosphorylation. Ray et al. (2005) proposed that UGB controls allergic asthma by downregulating signaling through IL4 and IL13 and inhibiting SCCA1 and SCCA2 expression.


Mapping

Schneider et al. (1995) found that SCCA1 and SCCA2 are tandemly arrayed on chromosome 18q21.3 and are flanked by 2 members of the ovalbumin family of serine proteinase inhibitors, plasminogen activator inhibitor type-2 (SERPINB2; 173390) and maspin (SERPINB5; 154790).


REFERENCES

  1. Barnes, R. C., Worrall, D. M. Identification of a novel human serpin gene; cloning sequencing and expression of leupin. FEBS Lett. 373: 61-65, 1995. [PubMed: 7589435] [Full Text: https://doi.org/10.1016/0014-5793(95)01015-7]

  2. Kato, H., Torigoe, T. Radioimmunoassay for tumor antigen of human cervical squamous cell carcinoma. Cancer 40: 1621-1628, 1977. [PubMed: 332328] [Full Text: https://doi.org/10.1002/1097-0142(197710)40:4<1621::aid-cncr2820400435>3.0.co;2-i]

  3. Ray, R., Choi, M., Zhang, Z., Silverman, G. A., Askew, D., Mukherjee, A. B. Uteroglobin suppresses SCCA gene expression associated with allergic asthma. J. Biol. Chem. 280: 9761-9764, 2005. [PubMed: 15677460] [Full Text: https://doi.org/10.1074/jbc.C400581200]

  4. Schick, C., Kamachi, Y., Bartuski, A. J., Cataltepe, S., Schechter, N. M., Pemberton, P. A., Silverman, G. A. Squamous cell carcinoma antigen 2 is a novel serpin that inhibits the chymotrypsin-like proteinases cathepsin G and mast cell chymase. J. Biol. Chem. 272: 1849-1855, 1997. [PubMed: 8999871] [Full Text: https://doi.org/10.1074/jbc.272.3.1849]

  5. Schneider, S. S., Schick, C., Fish, K. E., Miller, E., Pena, J. C., Treter, S. D., Hui, S. M., Silverman, G. A. A serine proteinase inhibitor locus at 18q21.3 contains a tandem duplication of the human squamous cell carcinoma antigen gene. Proc. Nat. Acad. Sci. 92: 3147-3151, 1995. [PubMed: 7724531] [Full Text: https://doi.org/10.1073/pnas.92.8.3147]

  6. Silverman, G. A., Jockel, J. I., Domer, P. H., Mohr, R. M., Taillon-Miller, P., Korsmeyer, S. J. Yeast artificial chromosome cloning of a two-megabase-siz e contig within chromosomal band 18q21 establishes physical linkage between BCL2 and plasminogen activator inhibitor type-2. Genomics 9: 219-228, 1991. [PubMed: 2004771] [Full Text: https://doi.org/10.1016/0888-7543(91)90245-a]


Contributors:
Matthew B. Gross - updated : 4/8/2011
Patricia A. Hartz - updated : 2/25/2011
Rebekah S. Rasooly - updated : 4/7/1998
Alan F. Scott - updated : 4/23/1996

Creation Date:
Victor A. McKusick : 5/7/1995

Edit History:
mgross : 04/08/2011
mgross : 4/8/2011
mgross : 4/8/2011
terry : 2/25/2011
alopez : 8/11/1999
psherman : 4/7/1998
mark : 4/23/1996
mimadm : 11/3/1995
mark : 5/7/1995