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Gene Review

AMBP  -  alpha-1-microglobulin/bikunin precursor

Homo sapiens

Synonyms: A1M, EDC1, HCP, HI30, IATIL, ...
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Disease relevance of AMBP

  • To investigate a potential role of the ITI family chains in cancer and metastasis spreading, we engineered human H460M cell lines expressing both the green fluorescent protein (GFP) and one of these chains [1].
  • In HepG2 hepatoma cells cultured in conditions of hypotonic stress or a high extracellular glutamine availability, a specifically decreased expression of two human mRNAs, namely those of alphal-microglobulin/bikunin precursor (AMBP) and alpha2-HS-glycoprotein, that are also down-regulated in liver by AP, could be seen [2].
  • CONCLUSIONS: In patients with hypertension, age and the level of diurnal and nocturnal systolic blood pressures measured by 24-hour AMBP are important independent predictors for the onset of AF [3].
  • Lack of ITI causes severe infertility [4].
  • Activation of the transient inward current (ITI) by a rise in intracellular calcium concentration ([Ca2+]i) is believed to be responsible for generating triggered cardiac arrhythmias [5].

Psychiatry related information on AMBP

  • Higher childhood scores in adults and adolescents with nocturnal enuresis correlated significantly with current adult symptoms of urge, urge leakage, stress incontinence, hesitancy, incomplete emptying and UTI within the last year [6].
  • These findings suggest that ITI may be related to the pathogenesis of Alzheimer type dementia [7].
  • Two ITI implants were inserted into the anterior mandibular region of a patient with Huntington's chorea, because a complete denture could not be retained on the alveolar ridge, despite adequate vestibule depth, due to tongue dyskinesia [8].

High impact information on AMBP

  • In this study, the cellular basis of the rise in [Ca2+]i that activates ITI and aftercontractions in single rat ventricular myocytes was examined [5].
  • Stable overexpression in U251 glioma cells validated ITI H2's strong inhibition of human glioma cell invasion together with significant inhibition of cell proliferation and promotion of cell-cell adhesion [9].
  • These findings suggest that reduction of ITI H2 expression correlates with brain tumor progression and that targeting factors responsible for its loss or restoring the ITI supply exogenously may serve as potential therapeutic strategies for a variety of CNS tumors [9].
  • ITIH3 shares highly conserved exon size and intron-exon borders with other ITI heavy chain genes [10].
  • A model for the evolution of the ITI heavy chain gene family is presented that involves multiple rounds of gene duplication plus inversion events [10].

Chemical compound and disease context of AMBP

  • Indications for ceftazidime encompassed a broad spectrum of diseases: 10 complicated UTI, 13 skeletal and soft tissue infections, 4 bronchopulmonary infections, 6 intra-abdominal infections, 3 septicaemias, 1 brain abscess with meningitis [11].
  • Evaluation of the Coral UTI Screen system for rapid automated screening of significant bacteriuria in a regional centralized laboratory [12].
  • This article presents a clinical case where an ITI hollow-cylinder titanium implant type F (red mark, 16 mm) had to be removed simultaneously with the resection of a squamous cell carcinoma of the lower jaw [13].
  • The increase in resistance rates to TMP/SMX among E. coli causing community-acquired UTI has resulted in consideration of alternative agents as first line therapy for these infections [14].
  • The incidence of Candida vaginitis in women with acute symptomatic uncomplicated UTI given 3 days treatment with pivmecillinam 400 mg bid is similar to that seen with placebo and is significantly less than the incidence with norfloxacin 400 mg bid for 3 days [15].

Biological context of AMBP

  • The AMBP gene maintains a tight control over its expression by a unique enhancer, which is controlled by several hepatocyte-enriched nuclear factors; however, the mechanisms of regulation of the intracellular levels of the AMBP protein are currently unknown [16].
  • The relevance of AMBP dimerization and its possible biological significance are postulated [16].
  • The amino-acid sequence deduced from partial nucleotide sequencing of the corresponding cDNA insert perfectly matched a known ITI sequence, apart from an as yet unreported C-terminal dipeptide [17].
  • A synthetic Inter-alpha-Trypsin-Inhibitor (ITI) -specific oligonucleotide probe was used to isolate a clone from a human liver cDNA library [17].
  • The human inter-alpha-trypsin inhibitor (ITI) light-chain gene, which codes for the two proteins alpha 1-microglobulin (protein HC) and ITI-derived human inhibitor of 30 kDa (HI-30), was isolated from a human genomic library [18].

Anatomical context of AMBP


Associations of AMBP with chemical compounds

  • Inter-alpha-trypsin inhibitor (ITI) is a 180 kd serine proteinase inhibitor found in human serum [23].
  • Tight blood glucose control is not associated with deleterious effects on 24-h AMBP in normoalbuminuric IDDM patients [24].
  • Transfection of HepG2 and Chinese hamster ovary cells with chloramphenicol acetyltransferase constructs harbouring the core or extended AMBP enhancer with wild-type or mutated boxes and co-transfection with expression plasmids for a wild-type or defective HNF-4 identified box 7 as an essential element for the basal activity of this enhancer [25].
  • AMBP kinase was not activated by ABA in guard cells isolated by enzyme treatment [26].
  • Quantitative differences were detected for alpha-1-microglobulin (AMBP; P02760), collagen alpha 1 (I) chain (CO1A1; P02452), collagen alpha 1 (III) chain (CO3A1; P02461), collagen alpha 1 (V) chain d (CO5A1; P20908), and basement membrane-specific heparin sulfate proteoglycan core protein (PGBM; P98160) [27].

Physical interactions of AMBP

  • The strict liver-specific expression of the AMBP gene is controlled by a potent enhancer made of six clustered boxes numbered 1-6 that have been reported to be proven or potential binding sites for the hepatocyte-enriched nuclear factors HNF-1, -4, -3, -1, -3, -4, respectively [28].

Regulatory relationships of AMBP

  • In the present study, an electrophoretic technique by which hyaluronan-bound ITI is immobilized was used to demonstrate that tumour necrosis factor stimulated gene 6 (TSG-6) is necessary for the coupling reaction [4].

Other interactions of AMBP

  • Despite their lack of any structural or functional relationship, both A1M and bikunin originate from AMBP cleavage by a furin-like protease that releases the two mature molecules [16].
  • The significant linkage disequilibrium observed in this genetic study indicates that the ITI locus, with the alleles ITI*1 and ITI*2, must be close to, or reside within, the ITIH1 gene [29].
  • The genes for aldolase-B (ALDOB), the alpha 1-microglobulin/bikunin precursor (AMBP), the paired box gene PAX5, and the anonymous DNA marker D9S3 map to human chromosome 9 (HSA9) [30].
  • Binding of the plasma proteinase inhibitor inter-alpha-trypsin inhibitor (ITI) to hyaluronan is necessary for normal expansion of the cumulus-oocyte complex [4].

Analytical, diagnostic and therapeutic context of AMBP

  • Hybridization on Northern blots evidenced that this cDNA insert originated from an ITI light chain-encoding mRNA whose size was estimated to be 1 300 bases [17].
  • RESULTS: Mean urine MIF amounts +/- SEM determined by enzyme-linked immunosorbent assay were significantly greater in 14 patients with UTI compared to that in 16 controls (1.96 +/- 0.40 vs 0.59 +/- 0.09 ng/mg creatinine, p <0.01) [31].
  • Western blotting under denaturing conditions showed several high molecular weight complexes (100 to 165 kDa) that increased in UTI urine as well as typical, monomeric MIF (12 kDa) [31].
  • This population-based cohort study followed neonates in Ontario, Canada, prospectively to study the relation between circumcision and subsequent UTI risk [32].
  • Binding of the H-chains of ITI to immobilized HA was detected and quantified using colorimetric immunoassays [33].


  1. Inhibition of tumor growth and metastatic spreading by overexpression of inter-alpha-trypsin inhibitor family chains. Paris, S., Sesboüé, R., Delpech, B., Chauzy, C., Thiberville, L., Martin, J.P., Frébourg, T., Diarra-Mehrpour, M. Int. J. Cancer (2002) [Pubmed]
  2. Down-regulation of negative acute-phase response genes by hypotonic stress in HepG2 hepatoma cells. Claeyssens, S., Banine, F., Rouet, P., Lavoinne, A., Salier, J.P. FEBS Lett. (1998) [Pubmed]
  3. Clinical study to investigate the predictive parameters for the onset of atrial fibrillation in patients with essential hypertension. Ciaroni, S., Cuenoud, L., Bloch, A. Am. Heart J. (2000) [Pubmed]
  4. Role of tumour necrosis factor stimulated gene 6 (TSG-6) in the coupling of inter-alpha-trypsin inhibitor to hyaluronan in human follicular fluid. Jessen, T.E., Ødum, L. Reproduction (2003) [Pubmed]
  5. Cellular origins of the transient inward current in cardiac myocytes. Role of fluctuations and waves of elevated intracellular calcium. Berlin, J.R., Cannell, M.B., Lederer, W.J. Circ. Res. (1989) [Pubmed]
  6. Nocturnal enuresis in adolescents and adults is associated with childhood elimination symptoms. Bower, W.F., Sit, F.K., Yeung, C.K. J. Urol. (2006) [Pubmed]
  7. Demonstration of an active component of inter-alpha-trypsin inhibitor in the brains of Alzheimer type dementia. Yoshida, E., Yoshimura, M., Ito, Y., Mihara, H. Biochem. Biophys. Res. Commun. (1991) [Pubmed]
  8. Implant-supported denture in a patient with Huntington's disease: interdisciplinary aspects. Jackowski, J., Andrich, J., Käppeler, H., Zöllner, A., Jöhren, P., Müller, T. Special care in dentistry : official publication of the American Association of Hospital Dentists, the Academy of Dentistry for the Handicapped, and the American Society for Geriatric Dentistry. (2001) [Pubmed]
  9. Isolation of a natural inhibitor of human malignant glial cell invasion: inter alpha-trypsin inhibitor heavy chain 2. Werbowetski-Ogilvie, T.E., Agar, N.Y., Waldkircher de Oliveira, R.M., Faury, D., Antel, J.P., Jabado, N., Del Maestro, R.F. Cancer Res. (2006) [Pubmed]
  10. Human inter-alpha-trypsin inhibitor heavy chain H3 gene. Genomic organization, promoter analysis, and gene linkage. Diarra-Mehrpour, M., Sarafan, N., Bourguignon, J., Bonnet, F., Bost, F., Martin, J.P. J. Biol. Chem. (1998) [Pubmed]
  11. Open study of ceftazidime in serious infections due to multiply-resistant bacteria. Pechère, J.C., Delisle, R. J. Antimicrob. Chemother. (1983) [Pubmed]
  12. Evaluation of the Coral UTI Screen system for rapid automated screening of significant bacteriuria in a regional centralized laboratory. Semeniuk, H., Noonan, J., Gill, H., Church, D. Diagn. Microbiol. Infect. Dis. (2002) [Pubmed]
  13. Histological evidence of osseointegration 4 years after implantation. A case report. Grätz, K.W., Zimmermann, A.P., Sailer, H.F. Clinical oral implants research. (1994) [Pubmed]
  14. Outcomes associated with trimethoprim/sulphamethoxazole (TMP/SMX) therapy in TMP/SMX resistant community-acquired UTI. Gupta, K., Stamm, W.E. Int. J. Antimicrob. Agents (2002) [Pubmed]
  15. Symptomatic vaginal candidiasis after pivmecillinam and norfloxacin treatment of acute uncomplicated lower urinary tract infection. Menday, A.P. Int. J. Antimicrob. Agents (2002) [Pubmed]
  16. The liver-specific human alpha(1)-microglobulin/bikunin precursor (AMBP) is capable of self-association. Tyagi, S., Salier, J.P., Lal, S.K. Arch. Biochem. Biophys. (2002) [Pubmed]
  17. Human inter-alpha-trypsin-inhibitor: characterization and partial nucleotide sequencing of a light chain-encoding cDNA. Bourguignon, J., Diarra-Mehrpour, M., Sesboüé, R., Frain, M., Sala-Trepat, J.M., Martin, J.P., Salier, J.P. Biochem. Biophys. Res. Commun. (1985) [Pubmed]
  18. Structural analysis of the human inter-alpha-trypsin inhibitor light-chain gene. Diarra-Mehrpour, M., Bourguignon, J., Sesboüé, R., Salier, J.P., Léveillard, T., Martin, J.P. Eur. J. Biochem. (1990) [Pubmed]
  19. Structural aspects of the effectiveness of bisphosphonates as competitive inhibitors of the plant vacuolar proton-pumping pyrophosphatase. Gordon-Weeks, R., Parmar, S., Davies, T.G., Leigh, R.A. Biochem. J. (1999) [Pubmed]
  20. TSG-6 and calcium ions are essential for the coupling of inter-alpha-trypsin inhibitor to hyaluronan in human synovial fluid. Jessen, T.E., Ødum, L. Osteoarthr. Cartil. (2004) [Pubmed]
  21. Cleavage of the alpha 1-microglobulin-bikunin precursor is localized to the Golgi apparatus of rat liver cells. Bratt, T., Olsson, H., Sjöberg, E.M., Jergil, B., Akerström, B. Biochim. Biophys. Acta (1993) [Pubmed]
  22. Management strategies for urinary and vaginal infections. Komaroff, A.L., Pass, T.M., McCue, J.D., Cohen, A.B., Hendricks, T.M., Friedland, G. Arch. Intern. Med. (1978) [Pubmed]
  23. The mRNA for a proteinase inhibitor related to the HI-30 domain of inter-alpha-trypsin inhibitor also encodes alpha-1-microglobulin (protein HC). Kaumeyer, J.F., Polazzi, J.O., Kotick, M.P. Nucleic Acids Res. (1986) [Pubmed]
  24. No deleterious effects of tight blood glucose control on 24-hour ambulatory blood pressure in normoalbuminuric insulin-dependent diabetes mellitus patients. Poulsen, P.L., Hansen, K.W., Ebbehøj, E., Knudsen, S.T., Mogensen, C.E. J. Clin. Endocrinol. Metab. (2000) [Pubmed]
  25. An array of binding sites for hepatocyte nuclear factor 4 of high and low affinities modulates the liver-specific enhancer for the human alpha1-microglobulin/bikunin precursor. Rouet, P., Raguenez, G., Ruminy, P., Salier, J.P. Biochem. J. (1998) [Pubmed]
  26. ABA activation of an MBP kinase in Pisum sativum epidermal peels correlates with stomatal responses to ABA. Burnett, E.C., Desikan, R., Moser, R.C., Neill, S.J. J. Exp. Bot. (2000) [Pubmed]
  27. Proteomic analysis of amniotic fluid in pregnancies with Down syndrome. Tsangaris, G.T., Karamessinis, P., Kolialexi, A., Garbis, S.D., Antsaklis, A., Mavrou, A., Fountoulakis, M. Proteomics (2006) [Pubmed]
  28. Hierarchy and positive/negative interplays of the hepatocyte nuclear factors HNF-1, -3 and -4 in the liver-specific enhancer for the human alpha-1-microglobulin/bikunin precursor. Rouet, P., Raguenez, G., Tronche, F., Mfou'ou, V., Salier, J.P. Nucleic Acids Res. (1995) [Pubmed]
  29. The polymorphism of the plasma inter-alpha-trypsin inhibitor (ITI) and its relationship to the heavy chain H1 subunit gene (ITIH1) at 3p211-212. Vogt, U., Sesboüé, R., Bourguignon, J., Diarra-Mehrpour, M., Martin, J.P., Cleve, H. Hum. Genet. (1994) [Pubmed]
  30. Linkage mapping of the Aldo-2, Pax-5, Ambp, and D4h9S3E loci on mouse chromosome 4 in the region of homology with human chromosome 9. Pilz, A., Fountain, J., Peters, J., Abbott, C. Genomics (1993) [Pubmed]
  31. Macrophage migration inhibitory factor is increased in the urine of patients with urinary tract infection: macrophage migration inhibitory factor-protein complexes in human urine. Meyer-Siegler, K.L., Iczkowski, K.A., Vera, P.L. J. Urol. (2006) [Pubmed]
  32. Cohort study on circumcision of newborn boys and subsequent risk of urinary-tract infection. To, T., Agha, M., Dick, P.T., Feldman, W. Lancet (1998) [Pubmed]
  33. Inter-alpha-trypsin inhibitor bound to tumor cells is cleaved into the heavy chains and the light chain on the cell surface. Kobayashi, H., Gotoh, J., Hirashima, Y., Terao, T. J. Biol. Chem. (1996) [Pubmed]
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