Disease relevance of SERPINB6

• In conclusion, SERPINB6 is abundantly expressed by normal mast cells and by mast cells in mastocytoma lesions [1].
• Identification of a novel complex between human kallikrein 2 and protease inhibitor-6 in prostate cancer tissue [2].
• To evaluate whether elevated arterial free fatty acids (FFA) increase myocardial oxygen demand and ischemia, 15 fasting patients with coronary artery disease underwent a standardized atrial pacing test before (PTI) and during (PT2) heparin infusion [3].
• This study was designed to measure the pharmacokinetic parameters of two different preparations of unconjugated soy isoflavones, PTI G-2535 and PTI G-4660 (which contain 43% and 90% genistein, respectively), in human subjects with cancer, to evaluate toxicity and obtain pilot data on in vivo effects on protein-tyrosine phosphorylation [4].
• Postnatal growth patterns of weight, length/height and head circumference in full-term (FTI), preterm (PTI) and small-for-dates (SFDI) infants, are described by using distance and velocity data together with the concept of growth per unit of body weight [5].

Psychiatry related information on SERPINB6

• Results showed modest support for the SCZI and PTI but not the MMPI indicators [6].
• Using a sample of child and adolescent inpatients, we examined the relation of Rorschach variables (PTI, SCZI, M-, and X- %) to thought disorder indexes on a behavior rating scale (Behavior Assessment System for Children; Reynolds & Kamphaus, 1992) and a self-report measure (Personality Inventory for Youth; Lachar & Gruber, 1995) [7].

High impact information on SERPINB6

• PTI also resembles these inhibitors in that it contains oxidation-sensitive residues adjacent to the reactive site [8].
• The ability of native PTI to bind thrombin was destroyed by incubation with iodoacetamide [8].
• The PTI cDNA was expressed in rabbit reticulocyte lysate and in COS-7 cells and a 42-kDa protein was produced [8].
• Analysis of human tissue mRNA indicated that PTI is expressed widely with the highest levels in cardiac and skeletal muscle and placenta [8].
• In all cases the lesional mast cells expressed SERPINB6, and, in diffuse cutaneous mastocytosis and mastocytoma, SERPINB6 was expressed by a substantially higher number of mast cells when compared with tryptase [1].

Biological context of SERPINB6

• A serpin gene cluster on human chromosome 6p25 contains PI6, PI9 and ELANH2 which have a common structure almost identical to the 18q21 ovalbumin serpin genes [9].
• Another Ov-serpin gene PI6 (placental thrombin inhibitor) was colocalized to the same region, thus defining an Ov-serpin locus on chromosome 6 in addition to the previously defined PLANH2-containing Ov-serpin locus on chromosome 18 [10].
• Thus, PI9 joins its close relatives PI6 and PI8 as having the ability to utilize multiple reactive site loop residues as the inhibitory P(1) residue to expand its inhibitory spectrum [11].
• The degree of amino acid sequence identity between the novel serpins and PI6 (63-68%) significantly exceeds that of any other combination of known intracellular serpins [12].
• A human placental lambda gt11 cDNA library was screened for sequences encoding proteins related to human proteinase inhibitor 6 (PI6), and two plaques were identified that displayed weak hybridization at high stringency [12].

Anatomical context of SERPINB6

• We suggest that in mast cells, SERPINB6 serves to regulate the activity of endogenous beta-tryptase in the cytoplasm [1].
• Previous studies showed that SERPINB6 is localized mainly in the cytoplasm of endothelial cells, some epithelial cells, monocytes, and neutrophils [1].
• Using a polymerase chain reaction strategy we identified a serine proteinase inhibitor (serpin) in human bone marrow that is related to the cellular serpin proteinase inhibitor 6 (PI-6) and the viral serpin cytokine response modifier A (CrmA) [13].
• In this study we examined PI-6 expression in human skin and its primary cell type, the keratinocyte [14].
• Proteinase inhibitor 6 (PI-6) is a 42-kDa intracellular protein present in epithelial cells and endothelial cells [14].

Associations of SERPINB6 with chemical compounds

• Gel filtration experiments revealed that the latter cells contain a high-molecular-weight form of SERPINB6, which consists of sodium dodecyl sulfate (SDS)-stable complexes of this inhibitor with monomeric beta-tryptase [1].
• This platelet component is functionally and immunologically indistinguishable from the cytoplasmic antiproteinase (CAP), also known as placental thrombin inhibitor, a recently cloned member of the ovalbumin family of intracellular serpins (serine proteinase inhibitors) [15].
• The PI-6 cDNA was modified to encode six histidine residues immediately after the initiation codon, and was placed under the control of the P. pastoris alcohol oxidase promoter in the vector pHIL-D2 [16].
• On the methanol induction, active recombinant PI-6 was produced within the yeast cells, and following cell lysis, was separated from yeast proteins by affinity chromatography using nickel nitrilo-tri-acetic acid (NTA) resin [16].
• In addition to plasminogen activator inhibitor 1, these included pigment epithelium-derived factor (confirmed by Western immunoblot), placental thrombin inhibitor, pregnancy zone protein, and protease C1 inhibitor [17].

Physical interactions of SERPINB6

• In the current study we have shown that PI-6 forms a rapid in vitro complex with hK2 but does not complex with PSA [18].
• This identification of a PI-6/proteinase complex is the first example of a serpin bound to a proteinase in keratinocytes [14].

Other interactions of SERPINB6

• PI6 and PI9 are almost identical in structure to the ovalbumin serpin genes at 18q21 [9].
• These results indicate that the hK2-PI-6 complex may be a naturally occurring marker of tissue damage and necrosis associated with neoplasia [18].
• PI-6 is an intracellular serine protease inhibitor with both antitrypsin and antichymotrypsin activity [18].
• Immunoblot analyses using rabbit anti-PI6 IgG indicated the presence of PI8 in the cytosolic fraction of stably transfected cells that formed an SDS-stable 67-kDa complex with human thrombin [12].
• It exhibits close to 50% homology with several recently cloned protease inhibitors such as the leukocyte elastase inhibitor, the placental thrombin inhibitor and the squamous cell carcinoma antigen [19].

Analytical, diagnostic and therapeutic context of SERPINB6

• Immunoblotting of cultured primary keratinocytes revealed that PI-6 production increases 24-fold on differentiation [14].
• Analysis of an immortalized keratinocyte cell line, HaCat, showed a 5-fold increase in PI-6 mRNA and a 7-fold increase in PI-6 protein upon differentiation, and indirect immunofluorescence revealed that this is due to an increase in the number of differentiated cells expressing high levels of PI-6 [14].
• Chromosomal mapping of the human proteinase inhibitor 6 (PI6) gene to 6p25 by fluorescence in situ hybridization [20].
• Using reverse transcriptase-polymerase chain reaction assays on RNA isolated from 15-day-old embryos and adult mice, we have shown that mouse PI-6 expression is developmentally regulated, and that, unlike human PI-6, it is absent from the placenta [21].
• To determine whether PI-6 is secreted, we have examined its cellular distribution by immunohistochemistry and have attempted to induce its release from platelets and from cultured cells [22].

References