Disease relevance of PAPPA

• Differential display (DD)-PCR analysis comparing normal ovarian epithelial cultures and ovarian cancer cell lines identified pregnancy-associated plasma protein-A (PAPPA) because of its frequent loss of expression (LOE) in ovarian cancer cell lines [1].
• Furthermore, the complete absence of PAPPA in pregnancies associated with Cornelia de Lange syndrome (CL) has suggested a causal connection between PAPPA and the development of CL [2].
• In summary, phorbol ester tumor promoters and simian virus 40 transformation regulate IGFBP-4 proteolysis in human fibroblasts through induction of a novel inhibitor of PAPP-A, pro-MBP [3].
• Our finding that PAPP-A gene expression in hCASMC is stimulated by TNF-alpha and IL-1beta suggests a mechanism for the regulation of PAPP-A in response to vascular injury that may contribute to the enhanced IGF-I bioactivity in intimal hyperplasia and atherosclerotic plaque development [4].
• Genetic downregulation of pregnancy-associated plasma protein-A (PAPP-A) by bikunin reduces IGF-I-dependent Akt and ERK1/2 activation and subsequently reduces ovarian cancer cell growth, invasion and metastasis [5].

High impact information on PAPPA

• The first-trimester screening consisted of measurement of serum pregnancy-associated plasma protein A in 77 pregnancies affected by Down's syndrome and 383 unaffected pregnancies and measurements of nuchal translucency obtained by ultrasonography in 326 affected and 95,476 unaffected pregnancies [6].
• Frozen sections of human placenta were examined for the presence of four human pregnancy proteins, pregnancy-associated plasma proteins A and C (PAPP-A and PAPP-C), human chorionic somatomammotropin (hCS), and pregnancy zone protein (PZP), by the indirect immunofluorescence technique [7].
• The insulin receptor content in breast cancer tissues was also higher than in any normal tissue investigated including liver (Pezzino, V., V. Papa, V. Trischitta, A. Brunetti, P.A. Goodman, M.K. Treutelaar, J.A. Williams, B.A. Maddux, R. Vigneri, and I.D. Goldfine, 1989. Am. J. Physiol. 257:E451-457) [8].
• The insulin-like growth factor (IGF)-dependent IGF binding protein-4 protease secreted by human fibroblasts is pregnancy-associated plasma protein-A [9].
• Unlike PAPP-A, a homotetramer of 200-kDa polypeptides, the immunoreactive protein consists of a light (alpha) chain (16.5 kDa) and a heavy (beta) chain (40 kDa); protein microsequencing of the beta chain showed it to be a member of the haptoglobin family [10].

Chemical compound and disease context of PAPPA

• Endometria in the proliferative phase (n = 27) or early secretory phase (days 1-3 postovulation; n = 12), cystic glandular hyperplasia (n = 12), and postmenopausal endometria of untreated (n = 7) or estrogen-treated (n = 5) women were all PAPP-A negative [11].
• Levels of alpha-fetoprotein, alpha 2-pregnancy-associated glycoprotein, and pregnancy-associated plasma protein A, all immunosuppressive proteins associated with pregnancy, were not significantly different in pregnant patients with multiple sclerosis and pregnant controls without multiple sclerosis [12].
• Increased levels of pregnancy-associated plasma protein-A in patients with hypercholesterolemia: the effect of atorvastatin treatment [13].
• The immunoperoxidase technique was used to study the occurrence of placenta-associated plasma protein A (PAPP-A, SP4) in formalin-fixed paraffin-embedded tissue specimens from 15 hydatidiform moles, 6 invasive moles and 7 choriocarcinomas [14].

Biological context of PAPPA

• PAPPA is localized to human chromosome 9q32-33.1, a region associated with significant loss of heterozygosity (LOH) in ovarian tumors (>50%) and in close proximity to the FRA9E CFS [1].
• We have assigned the locus for PAPPA to chromosome region 9q33.1 on mitotic and meiotic chromosomes by fluorescence in situ hybridization, using a 3.7-kb partial PAPPA cDNA probe [2].
• Pregnancy-associated plasma protein-A gene expression in human ovaries is restricted to healthy follicles and corpora lutea [15].
• During wound healing, PAPP-A expression was induced in dermal granulation tissue within and adjacent to the injury [16].
• In conclusion, PAPP-A expression is regulated by inflammatory cytokines in adult human fibroblasts, with functional consequences on IGFBP-4 protease activity and IGF-I bioavailability [17].

Anatomical context of PAPPA

• Low levels of pregnancy-associated plasma protein A (PAPPA) during the first trimester has been suggested as a biochemical indicator of pregnancies with aneuploid fetuses [2].
• Complex of pregnancy-associated plasma protein-A and the proform of eosinophil major basic protein. Disulfide structure and carbohydrate attachment [18].
• Pregnancy-associated plasma protein A proteolytic activity is associated with the human placental trophoblast cell membrane [19].
• An intense signal for PAPP-A mRNA was also present in healthy corpora lutea (CL), being localized to a subset of large luteal cells [15].
• PAPP-A mRNA was low or undetectable in preantral follicles, small (1-2 mm) healthy and atretic antral follicles, larger atretic antral follicles, surface epithelium, tunica albuginea and connective tissue cells [15].

Associations of PAPPA with chemical compounds

• The PAPP-A subunit contains a total of 82 cysteine residues, of which 81 have been accounted for [18].
• Pregnancy-associated plasma protein-a is the insulin-like growth factor binding protein-4 protease secreted by human ovarian granulosa cells and is a marker of dominant follicle selection and the corpus luteum [20].
• Actinomycin D had no effect on PAPP-A mRNA levels in the absence or presence of beta-PDD [3].
• Heparin and heparan sulfate, but not dermatan or chondroitin sulfate, effectively compete for PAPP-A surface binding, and because incubation of cells with heparinase abrogated PAPP-A adhesion, binding is probably mediated by a cell surface heparan sulfate proteoglycan [21].
• Furthermore, PAPP-A levels in estrogen-dominant and androgen-dominant follicular fluids reflect their IGFBP-4 proteolytic activity [22].

Physical interactions of PAPPA

• Pregnancy-associated plasma protein-A accounts for the insulin-like growth factor (IGF)-binding protein-4 (IGFBP-4) proteolytic activity in human pregnancy serum and enhances the mitogenic activity of IGF by degrading IGFBP-4 in vitro [23].
• BACKGROUND: Pregnancy-associated plasma protein-A is a zinc-binding matrix metalloproteinase abundantly expressed in eroded and ruptured plaques and may serve as a marker of plaque destabilization [24].

Enzymatic interactions of PAPPA

• PAPP-A specifically cleaves IGF-binding protein (IGFBP)-4, one of six antagonists of IGF action, which results in release of IGF bound to IGFBP-4 [25].
• Herein, we first determined that PAPP-A cleaves IGFBP-4 at a single site (Met-135/Lys-136), and we analysed the influence of ionic strength, pH and zinc ion concentration on the cleavage reaction [26].

Co-localisations of PAPPA

• PAPP-A expression in cells of granulation tissue colocalized with alpha-smooth actin staining of myofibroblasts and new blood vessels as well as with CD68 staining of macrophages and was associated with the compact, newly synthesized collagen of the healing wound [16].

Regulatory relationships of PAPPA

• Proteolysis of radiolabeled IGFBP-4 in conditioned media from OSE(tsT) lines was IGF-dependent and blocked by anti-PAPP-A antisera [27].
• On the other hand, interferon-gamma (IFN gamma) treatment markedly inhibited PAPP-A expression [17].
• Purified PAPP-A protein directly up-regulated runt-related transcription factor 2 and Igf-I gene expression but not Osterix [28].
• Interestingly, pretreatment of hCASMC with resveratrol, a polyphenol found in the skin of grapes and in red wine purported to underlie the "French paradox," inhibited TNF-alpha- and IL-1beta-induced PAPP-A expression and, hence, its IGFBP-4 proteolytic activity [4].
• CONCLUSIONS: Elevated serum PAPP-A levels represent a potential marker of the degree of echogenicity of carotid atherosclerotic plaques in asymptomatic hyperlipidemic patients at high cardiovascular risk and equally of an enhanced local inflammatory state involving remodeling of subendothelial extracellular matrix [29].

Other interactions of PAPPA

• FISH analysis determined that PAPPA was contained within the distal end of FRA9E [1].
• IGF-I, IGF-II, IGFBP-4, and PAPP-A gene expression was determined in a panel of GCT and compared to the levels in normal ovary and in epithelial ovarian tumors [30].
• Insulin-like growth factor, insulin-like growth factor-binding protein-4, and pregnancy-associated plasma protein-A gene expression in human granulosa cell tumors [30].
• In 20 human normal tissues tested, DIPLA1 mRNA expression was placenta-specific, whereas DIPAS mRNA expression was higher in placenta, brain, kidney and testis [31].
• Furthermore, the proteolytic activity of PAPP-A is preserved while bound to cells, suggesting that adhesion functions to target its activity to the vicinity of the IGF receptor, decreasing the probability that released IGF is captured by another IGFBP molecule before receptor binding [21].

Analytical, diagnostic and therapeutic context of PAPPA

• Short-term ovarian tumor cell cultures expressed variable levels of PAPP-A and high levels of proMBP, and consequently secreted little or no IGFBP-4 protease activity [27].
• Coculture of fibroblasts with cells transfected with pro-MBP cDNA resulted in inhibition of IGFBP-4 proteolytic activity without having any effect on PAPP-A synthesis [3].
• Using flow cytometry, we first demonstrate that PAPP-A reversibly binds to the cell surface of several cell types analyzed [21].
• PAPP-A mRNA levels were the same in control and Dex-treated cultures as evaluated by RT-PCR [32].
• PAPP-A mRNA was quantified by real-time PCR, and PAPP-A protein expression was studied by immunocytochemistry and TRACE technology with specific monoclonal antibodies [33].

References