title: The amplified mouse squamous cell carcinoma antigen gene locus contains a serpin (Serpinb3b) that inhibits both papain-like cysteine and trypsin-like serine proteinases.
abstract: The clade B serpins occupy a unique niche among a larger superfamily by predominantly regulating intracellular proteolysis. In humans, there are 13 family members that map to serpin gene clusters at either 6p25 or 18q21. While most of these serpins display a unique inhibitory profile and appear to be well conserved in mammals, the clade B loci of several species show evidence of relatively recent genomic amplification events. However, it is not clear whether these serpin gene amplification events yield paralogs with functional redundancy or, through selective pressure, inhibitors with more diverse biochemical activities. A recent comparative genomic analysis of the mouse clade B cluster at 1D found nearly complete conservation of gene number, order, and orientation relative to those of 18q21 in humans. The only exception was the squamous cell carcinoma antigen (SCCA) locus. The human SCCA locus contains two genes, SERPINB3 (SCCA1) and SERPINB4 (SCCA2), whereas the mouse locus contains four serpins and three pseudogenes. At least two of these genes encoded functional, dual cross-class proteinase inhibitors. Mouse Serpinb3a was shown previously to inhibit both chymotrypsin-like serine and papain-like cysteine proteinases. We now report that mouse Serpinb3b extends the inhibitory repertoire of the mouse SCCA locus to include a second cross-class inhibitor with activity against both papain-like cysteine and trypsin-like serine proteinases. These findings confirmed that the genomic expansion of the clade B serpins in the mouse was associated with a functional diversification of inhibitory activity.
authors.affiliation: Department of Pediatrics and the Division of Newborn Medicine, Harvard Medical School, Children's Hospital, 300 Longwood Avenue, Enders 9, Boston, MA 02115, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Askew
authors.forename: Yuko S
authors.initials: YS
authors.lastname: Askew
authors.forename: Yukari
authors.initials: Y
authors.lastname: Kato
authors.forename: Cliff J
authors.initials: CJ
authors.lastname: Luke
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Pak
authors.forename: Dieter
authors.initials: D
authors.lastname: Brömme
authors.forename: Gary A
authors.initials: GA
authors.lastname: Silverman
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000951:Antigens, Neoplasm / Q000737:chemistry* / Q000235:genetics*; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D003546:Cysteine Endopeptidases / Q000737:chemistry*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D011480:Protease Inhibitors / Q000737:chemistry; D011544:Pseudogenes / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics*; D012697:Serine Endopeptidases / Q000737:chemistry*; D015843:Serpins / Q000737:chemistry* / Q000235:genetics*; D013379:Substrate Specificity / Q000235:genetics / Q000502:physiology
chemical_list: D000951:Antigens, Neoplasm; D011480:Protease Inhibitors; D015843:Serpins; C051072:squamous cell carcinoma-related antigen; C114880:trypsin-like serine protease; D012697:Serine Endopeptidases; D003546:Cysteine Endopeptidases