Synthesis and secretion of α<sub>2</sub>‐macroglobulin by human hepatocytes in culture

Petersen, Claus Munck; Christiansen, Buris; Heickendorff, Lene; Ingerslev, Jørgen

doi:10.1111/j.1365-2362.1988.tb01054.x

Cited by 21 publications

(6 citation statements)

References 30 publications

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“…Expression of A2M mRNA is unique to the chicken oviduct. In humans, A2M is synthesized primarily in the liver [43,44] and as a major plasma protein, it makes up roughly 8-10% of the total protein in human blood [45,46]. However, in chickens, A2M (also known as ovomacroglobulin or ovostatin) is synthesized in the oviduct and found in egg whites [14,47,48].…”

Section: Discussionmentioning

confidence: 99%

Differential expression of alpha 2 macroglobulin in response to dietylstilbestrol and in ovarian carcinomas in chickens

Lim

Jeong

Kim

et al. 2011

Reprod Biol Endocrinol

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BackgroundAlpha 2 macroglobulin (A2M; also known as ovostatin), a homotetrameric protein with four disulfide-linked subunits, has the unique feature of inactivating/inhibiting most known proteases including serine-, threonine-, cysteine-, aspartic- and metalloproteases. In chickens, A2M has been identified and characterized biochemically, but little is known of its functional role(s) in the oviduct, hormonal regulation of expression or its expression in ovarian carcinomas in chickens. Therefore, we investigated estrogen regulation of A2M gene expression during development of the chicken oviduct, and its expression in normal and cancerous ovaries from chickens.MethodsTo determine tissue-specific expression of A2M in chickens, we collected various organs from male and female chickens and performed RT-PCR analyses. To examine A2M gene expression in the oviduct of 1-week-old female chicks that received a subcutaneous implant of 15 mg DES in the abdominal region for 20 days, we performed RT-PCR, qPCR and in situ hybridization analyses using cDNAs from control- (n = 5) and DES-treated oviducts (n = 5), and then each segment of the oviduct from DES-treated chicks. To determine if A2M is a biomarker of ovarian cancer in hens, we collected cancerous (n = 10) ovaries from a total of 136 chickens which had completely stopped egg-laying and performed RT-PCR and in situ hybridization analyses.ResultsWe found that A2M is most abundant in the chicken oviduct, specifically luminal (LE) and glandular epithelia (GE), but it was not detected in any other tissues of either sex. We then determined that DES (dietylstilbestrol, a synthetic nonsteroidal estrogen) increased A2M mRNA only in LE and GE of the oviduct of chicks. Further, expression of A2M was most abundant in GE of endometrioid adenocarcinoma of cancerous, but not normal ovaries of hens.ConclusionsCollectively, results of the present study indicate that A2M is novel estrogen-stimulated gene expressed in LE and GE of the chicken oviduct and may be used for monitoring effects of therapies for ovarian cancer in laying hens.

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Section: Discussionmentioning

confidence: 99%

Differential expression of alpha 2 macroglobulin in response to dietylstilbestrol and in ovarian carcinomas in chickens

Lim

Jeong

Kim

et al. 2011

Reprod Biol Endocrinol

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“…The (~2M serum levels are, therefore, not representative of intrapulmonary a2M concentration, as is the case with alAT. It has been shown, however, that a2M is not only synthesized and secreted by hepatocytes (Munck Petersen et al 1988a), but also by adult and fetal lung fibroblasts (Brissenden and Cox 1982;Mosher and Wing 1976) and by alveolar macrophages (White et al 1980). Localized intrapulmonary a2M synthesis under the control of cell-specific promotors could very efficiently regulate the activity of potentially damaging proteinases according to local requirements.…”

Section: Introductionmentioning

confidence: 98%

Cloning of the human ?2-macroglobulin gene and detection of mutations in two functional domains: the bait region and the thiolester site

et al. 1992

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Overlapping genomic clones of the human alpha 2-macroglobulin (alpha 2M) gene were isolated from a cosmid library and were used to map 80 kb of the chromosomal region of this gene. Fragments carrying the two exons encoding the bait region and the exon encoding the thiolester site were partially sequenced and PCR primers were designed for the amplification of both functional domains. By direct genomic sequencing of these domains in 30 healthy individuals and in 30 patients with chronic lung disease three mutations were detected. The first was a sequence polymorphism occurring near the thiolester site of the gene, changing Val1000 (GTC) to Ile1000 (ATC), with allele frequencies of 0.30 (GTC) and 0.70 (ATC), respectively. No difference of alpha 2M serum levels was observed for these two alleles. The second mutation occurred within the thiolester site of one patient, changing Cys972(TGT) to Tyr972(TAT). Since activation of the internal thiolester formed between Cys972 and Gln975 in each of the subunits of the tetrameric alpha 2M is involved in the covalent cross-linking of the activating proteinase, this mutation is predicted to interfere with alpha 2M function. The alpha 2M serum level was within the normal range in this patient. In one healthy individual we detected an alteration of the bait region sequence, which is usually encoded by two different exons separated by an intron of size 1.6 kb. In this individual, PCR amplification of genomic DNA using the bait region primers produced the common fragment of size 1.8 kb and an additional variant fragment of size 0.23 kb. This finding, and the genomic sequencing data of this individual, indicate that he carries two different alleles of the alpha 2M gene: one with the regular structure (bait exon I-intron-bait exon II), the other with the two bait exons fused into one. Direct genomic sequencing of the two alpha 2M functional domains is a useful tool for the detection of the genetic, and possibly the functional, heterogeneity of alpha 2M. This, in turn, may provide some insight into the hitherto unknown physiological role(s) of alpha 2M, by studying in vivo effects of naturally occurring mutations of the gene.

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“…a 2 -macroglobulin (a 2 M), a binding protein and a protease inhibitor regulates the biologic activity of several growth factors and cytokines (94). Plasma a 2 M accounts for 3% to 5% of total proteins and is primarily synthesized in the liver (95), while small amounts of this protein are synthesized by microglia as well (96). They act as modulators of acute phase response (97) and bind to and moderate the function of cytokines (97,98), a variety of growth factors (99) and potent proteases (100).…”

Section: Pdgf Peptide and Their Receptorsmentioning

confidence: 99%

Growth factors in the fetal and neonatal lung

Kumar

Ryan²

2004

Front Biosci

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Formation and orderly development of the mammalian lung results from a complex set of cell to cell and cell to matrix interactions following transcriptional regulation during pulmonary organogenesis. Transcriptional control of differentiation genes early on and epithelial-mesenchymal interactions mediated by growth factors later on, resulting in the formation of conducting airways and an extensive alveolar capillary interface, is critical for normal lung development. HNF-3beta and TTF-1 are transcription factors that are involved in gene regulation and formation and differentiation of respiratory epithelium. Studies done in early mouse embryonic lung demonstrate that a variety of peptide growth factors and their receptors are expressed early on in lung development. Signalling through the FGFR2 is critical to normal development of the distal epithelium and mesenchyme. The inductive and permissive influences of growth factors on lung development has been demonstrated by gain or loss of function experiments in early embryonic mouse lung organ culture, in transgenic and in null mutant mice. VEGF present in airway epithelial cells is involved in the maturation as well as proliferation of capillary endothelial cells. Epithelial-endothelial interactions during lung development are important in establishing a functional blood gas interface. Epithelial-mesenchymal interactions mediated by growth factors are also important in the restoration of normal alveolar architecture after lung injury. Further understanding of the role of these growth factors and their cellular interactions in bronchopulmonary dysplasia and in tissue repair following lung injury, may lead to development of better therapeutic modalities in treating these disorders.

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Synthesis and secretion of α₂‐macroglobulin by human hepatocytes in culture

Cited by 21 publications

References 30 publications

Differential expression of alpha 2 macroglobulin in response to dietylstilbestrol and in ovarian carcinomas in chickens

Differential expression of alpha 2 macroglobulin in response to dietylstilbestrol and in ovarian carcinomas in chickens

Cloning of the human ?2-macroglobulin gene and detection of mutations in two functional domains: the bait region and the thiolester site

Growth factors in the fetal and neonatal lung

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Synthesis and secretion of α2‐macroglobulin by human hepatocytes in culture

Cited by 21 publications

References 30 publications

Differential expression of alpha 2 macroglobulin in response to dietylstilbestrol and in ovarian carcinomas in chickens

Differential expression of alpha 2 macroglobulin in response to dietylstilbestrol and in ovarian carcinomas in chickens

Cloning of the human ?2-macroglobulin gene and detection of mutations in two functional domains: the bait region and the thiolester site

Growth factors in the fetal and neonatal lung

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Synthesis and secretion of α₂‐macroglobulin by human hepatocytes in culture