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Proceedings of the National Academy of... May 1985Hepatic alpha 2u-globulin protein and RNA levels are under developmental and complex multihormonal control. The present studies directly evaluate the degree to which...
Hepatic alpha 2u-globulin protein and RNA levels are under developmental and complex multihormonal control. The present studies directly evaluate the degree to which this regulation is transcriptional. alpha 2u-Globulin transcription was determined by measuring nuclear runoff RNA in vitro, and tissue alpha 2u-globulin mRNA levels were measured by dot blot hybridization. These studies reveal that (i) in male rats the transcriptional rate of the alpha 2u-globulin genes increases during postnatal development; (ii) no alpha 2u-globulin transcription is detectable in hepatic nuclei derived from hypophysectomized rats; (iii) growth hormone and glucocorticoid are both absolutely required, and glucocorticoid can replace androgen for alpha 2u-globulin gene transcription in the livers of hypophysectomized male rats; and (iv) chronic treatment of mature male rats with estrogen results in a progressive decrease in the hepatic transcription of alpha 2u-globulin genes. In all instances changes in the transcriptional rate of alpha 2u-globulin genes paralleled the tissue level of alpha 2u-globulin RNA. Thus transcriptional control predominates in regulating hepatic alpha 2u-globulin RNA levels.
Topics: Age Factors; Alpha-Globulins; Animals; Estrogens; Female; Gene Expression Regulation; Hormones; Hypophysectomy; In Vitro Techniques; Liver; Male; Nucleic Acid Hybridization; RNA Polymerase II; RNA, Messenger; Rats; Rats, Inbred Strains; Sex Factors; Transcription, Genetic
PubMed: 2581250
DOI: 10.1073/pnas.82.9.2579 -
The Journal of Histochemistry and... Dec 2020Inter-α-trypsin inhibitor (IαI) family members are ancient and unique molecules that have evolved over several hundred million years of vertebrate evolution. IαI is a... (Review)
Review
Inter-α-trypsin inhibitor (IαI) family members are ancient and unique molecules that have evolved over several hundred million years of vertebrate evolution. IαI is a complex containing the proteoglycan bikunin to which heavy chain proteins are covalently attached to the chondroitin sulfate chain. Besides its matrix protective activity through protease inhibitory action, IαI family members interact with extracellular matrix molecules and most notably hyaluronan, inhibit complement, and provide cell regulatory functions. Recent evidence for the diverse roles of the IαI family in both biology and pathology is reviewed and gives insight into their pivotal roles in tissue homeostasis. In addition, the clinical uses of these molecules are explored, such as in the treatment of inflammatory conditions including sepsis and Kawasaki disease, which has recently been associated with severe acute respiratory syndrome coronavirus 2 infection in children.
Topics: Alpha-Globulins; Animals; Arthritis; Asthma; Extracellular Matrix; Fibrosis; Humans; Hyaluronic Acid; Inflammation; Sepsis
PubMed: 32639183
DOI: 10.1369/0022155420940067 -
Environmental Health Perspectives Mar 1993This review paper examines the relationship between chemicals inducing excessive accumulation of alpha 2u-globulin (alpha 2u-g) (CIGA) in hyaline droplets in male rat... (Review)
Review
This review paper examines the relationship between chemicals inducing excessive accumulation of alpha 2u-globulin (alpha 2u-g) (CIGA) in hyaline droplets in male rat kidneys and the subsequent development of nephrotoxicity and renal tubule neoplasia in the male rat. This dose-responsive hyaline droplet accumulation distinguishes CIGA carcinogens from classical renal carcinogens. CIGA carcinogens also do not appear to react with DNA and are generally negative in short-term tests for genotoxicity, CIGA or their metabolites bind specifically, but reversibly, to male rat alpha 2u-g. The resulting complex appears to be more resistant to hydrolytic degradation in the proximal tubule than native, unbound alpha 2u-g. Single cell necrosis of the tubule epithelium, with associated granular cast formation and papillary mineralization, is followed by sustained regenerative tubule cell proliferation, foci of tubule hyperplasia in the convoluted proximal tubules, and renal tubule tumors. Although structurally similar proteins have been detected in other species, including humans, renal lesions characteristic of alpha 2u-g nephropathy have not been observed. Epidemiologic investigation has not specifically examined the CIGA hypothesis for humans. Based on cancer bioassays, hormone manipulation studies, investigations in an alpha 2u-g-deficient strain of rat, and other laboratory data, an increased proliferative response caused by chemically induced cytotoxicity appears to play a role in the development of renal tubule tumors in male rats. Thus, it is reasonable to suggest that the renal effects induced in male rats by chemicals causing alpha 2u-g accumulation are unlikely to occur in humans.
Topics: Alpha-Globulins; Animals; Female; Hazardous Substances; Humans; Kidney; Kidney Diseases; Kidney Neoplasms; Kidney Tubules; Male; Proteins; Rats
PubMed: 7686485
DOI: 10.1289/ehp.9399313 -
Blood May 2012I have always been puzzled by the ability of normal erythroid cells to produce a stoichiometric amount of α- and β-globin chains in the absence of cross-talk...
I have always been puzzled by the ability of normal erythroid cells to produce a stoichiometric amount of α- and β-globin chains in the absence of cross-talk mechanisms that would control and normalize the relative rate of expression of the genes encoding these proteins.
Topics: Alpha-Globulins; Animals; Antineoplastic Agents; Boronic Acids; Bortezomib; Erythroid Precursor Cells; Female; Humans; Male; Proteasome Inhibitors; Proteolysis; Pyrazines; Ubiquitination; beta-Thalassemia
PubMed: 22653953
DOI: 10.1182/blood-2012-04-418590 -
Environmental Health Perspectives Dec 1993Enhanced cell proliferation occurs at several stages of renal tumorigenesis. Initiation by genotoxic nephrocarcinogens such as dimethylnitrosamine (DMN) is likely a... (Review)
Review
Enhanced cell proliferation occurs at several stages of renal tumorigenesis. Initiation by genotoxic nephrocarcinogens such as dimethylnitrosamine (DMN) is likely a result of DNA damage coupled with an initial burst of DNA synthesis associated with the cytotoxic effects of the compound. The level of initiation by DMN can be further enhanced by unilateral nephrectomy or hydronephrosis, which induces a brief burst of cell proliferation followed by tumorigenesis in the contralateral kidney. The role of sustained cell proliferation in renal tumor development is less well understood. The most compelling evidence comes from studies with nongenotoxic renal carcinogens such as unleaded gasoline and d-limonene, which induce alpha 2u-globulin (alpha G) nephropathy and renal epithelial tumors exclusively in male rats. Sustained increases in cell proliferation in these studies depend on the presence of a chemical-alpha G complex in phagolysosomes of P2 proximal tubule cells, which results in cytotoxicity and compensatory hyperplasia only in male F344 rats, but not female F344 rats or alpha G deficient male NBR rats. Furthermore, initiation-promotion experiments demonstrated a strong correlation between the dose-response of cell proliferation and the incidence of preneoplastic and neoplastic lesions. Clearly, similar correlative studies with a number of other renal carcinogens and non-carcinogens are warranted before general conclusions can be made. Cell proliferation is excessively elevated in tubules affected by chronic progressive nephropathy, but the significance of the lesion to renal carcinogenesis is unclear. Elucidating mechanisms of renal cell proliferation are necessary for our understanding of cause and effect relationships. An exciting recent finding is altered expression of transforming growth factor-alpha in hereditary rat renal cell carcinoma.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Alpha-Globulins; Animals; Barbital; Cell Division; DNA Damage; Dimethylnitrosamine; Female; Humans; Kidney Neoplasms; Male; Models, Biological; Rats; Rats, Inbred F344
PubMed: 7516872
DOI: 10.1289/ehp.93101s5115 -
Journal of Experimental Botany Jul 2013Rice seed storage proteins glutelin and α-globulin are synthesized in the endoplasmic reticulum (ER) and deposited in protein storage vacuoles (PSVs). Sar1, a small...
Rice seed storage proteins glutelin and α-globulin are synthesized in the endoplasmic reticulum (ER) and deposited in protein storage vacuoles (PSVs). Sar1, a small GTPase, acts as a molecular switch to regulate the assembly of coat protein complex II, which exports secretory protein from the ER to the Golgi apparatus. To reveal the route by which glutelin and α-globulin exit the ER, four putative Sar1 genes (OsSar1a/b/c/d) were cloned from rice, and transgenic rice were generated with Sar1 overexpressed or suppressed by RNA interference (RNAi) specifically in the endosperm under the control of the rice glutelin promoter. Overexpression or suppression of any OsSar1 did not alter the phenotype. However, simultaneous knockdown of OsSar1a/b/c resulted in floury and shrunken seeds, with an increased level of glutelin precursor and decreased level of the mature α- and β-subunit. OsSar1abc RNAi endosperm generated numerous, spherical, novel protein bodies with highly electron-dense matrixes containing both glutelin and α-globulin. Notably, the novel protein bodies were surrounded by ribosomes, showing that they were derived from the ER. Some of the ER-derived dense protein bodies were attached to a blebbing structure containing prolamin. These results indicated that OsSar1a/b/c play a crucial role in storage proteins exiting from the ER, with functional redundancy in rice endosperm, and glutelin and α-globulin transported together from the ER to the Golgi apparatus by a pathway mediated by coat protein complex II.
Topics: Alpha-Globulins; Amino Acid Sequence; Endoplasmic Reticulum; Endosperm; Glutens; Molecular Sequence Data; Monomeric GTP-Binding Proteins; Oryza; Phylogeny; Plant Proteins; Protein Precursors; Protein Transport; Seeds; Sequence Alignment
PubMed: 23682119
DOI: 10.1093/jxb/ert128 -
The Biochemical Journal Apr 1996Inter-alpha-inhibitor (IalphaI) and related molecules, collectively referred to as the IalphaI family, are a group of plasma protease inhibitors. They display attractive... (Review)
Review
Inter-alpha-inhibitor (IalphaI) and related molecules, collectively referred to as the IalphaI family, are a group of plasma protease inhibitors. They display attractive features such as precursor polypeptides that give rise to mature chains with quite distinct fates and functions, and inter-chain glycosaminoglycan bonds within the various molecules. The discovery of an ever growing number of such molecules has raised pertinent questions about their pathophysiological functions. The knowledge of this family has long been structure-oriented, whereas the structure/function and structure/regulation relationships of the family members and their genes have been largely ignored. These relationships are now being elucidated in events such as gene transcription, precursor processing, changes in plasma protein levels in health and disease and binding capacities that involve hyaluronan as well as other plasma proteins as ligands. This review presents some recent progress made in these fields that paves the way for an understanding of the functions of IalphaI family members in vivo. Finally, given the wealth of heterogeneous, complicated and sometimes contradictory nomenclatures and acronyms currently in use for this family, a new, uniform, nomenclature is proposed for IalphaI family genes, precursor polypeptides and assembled proteins.
Topics: Alpha-Globulins; Amino Acid Sequence; Animals; Carbohydrate Sequence; Chymotrypsin; Gene Expression Regulation; Humans; Molecular Sequence Data; Structure-Activity Relationship; Trypsin Inhibitors
PubMed: 8670091
DOI: 10.1042/bj3150001 -
Cancer Genomics & Proteomics 2018In this review we summarize the principles of anti-metastatic therapy with selected serpin family proteins, such as pigment epithelial-derived factor (PEDF) and maspin,... (Review)
Review
In this review we summarize the principles of anti-metastatic therapy with selected serpin family proteins, such as pigment epithelial-derived factor (PEDF) and maspin, as well as inter α-trypsin inhibitor (IαIs) light chains (bikunin) and heavy chains (ITIHs). Case-by-case, antimetastatic activity may be dependent or independent of the protease-inhibitory activity of the corresponding proteins. We discuss the incidence of target deregulation in different tumor entities, mechanisms of deregulation, context-dependent functional issues as well as in vitro and in vivo target validation studies with transfected tumor cells or recombinant protein as anti-metastatic agents. Finally, we comment on possible clinical evaluation of these proteins in adjuvant therapy.
Topics: Alpha-Globulins; Humans; Neoplasm Metastasis; Neoplasms; Prognosis; Serpins; Trypsin Inhibitors
PubMed: 29976628
DOI: 10.21873/cgp.20081 -
Blood Purification 2013β2-Microglobulin (β2-MG) is the substance that causes dialysis amyloidosis, and its predialysis value is useful for evaluating the quality of dialysis therapy itself.... (Review)
Review
β2-Microglobulin (β2-MG) is the substance that causes dialysis amyloidosis, and its predialysis value is useful for evaluating the quality of dialysis therapy itself. In addition, β2-MG is also an important biomarker for evaluating the removal performance of hemodialysis and hemodiafiltration (HDF). However, since β2-MG has a molecular weight of 11.8 kDa and can be efficiently removed by diffusion with existing high-performance dialyzers, a higher molecular weight substance should be used for evaluating removal performance of HDF, in which diffusion and convection are performed simultaneously. α1-Microglobulin (α1-MG) has a molecular weight of 33 kDa, and it is removed by convection during dialysis. When we used α1-MG to evaluate the removal performance of HDF in a study based on our own cases, we were able to describe the distinctive features and benefits of HDF with precision. α1-MG removal rate exactly paralleled the changes in symptoms. Kt/V and the β2-MG removal rate, however, did not undergo significant changes as the symptoms fluctuated. α1-MG should be used as a biomarker for evaluation of clinical outcomes of HDF.
Topics: Alpha-Globulins; Biomarkers; Convection; Hemodiafiltration; Humans; Prolactin; Serum Albumin; Treatment Outcome; beta 2-Microglobulin
PubMed: 23466382
DOI: 10.1159/000346364 -
Genes Oct 2021Proteoglycans consist of proteins linked to sulfated glycosaminoglycan chains. They constitute a family of macromolecules mainly involved in the architecture of organs... (Review)
Review
Proteoglycans consist of proteins linked to sulfated glycosaminoglycan chains. They constitute a family of macromolecules mainly involved in the architecture of organs and tissues as major components of extracellular matrices. Some proteoglycans also act as signaling molecules involved in inflammatory response as well as cell proliferation, adhesion, and differentiation. Inborn errors of proteoglycan metabolism are a group of orphan diseases with severe and irreversible skeletal abnormalities associated with multiorgan impairments. Identifying the gene variants that cause these pathologies proves to be difficult because of unspecific clinical symptoms, hardly accessible functional laboratory tests, and a lack of convenient blood biomarkers. In this review, we summarize the molecular pathways of proteoglycan biosynthesis, the associated inherited syndromes, and the related biochemical screening techniques, and we focus especially on a circulating proteoglycan called bikunin and on its potential as a new biomarker of these diseases.
Topics: Alpha-Globulins; Biomarkers; Carbohydrate Metabolism, Inborn Errors; Clinical Laboratory Techniques; Diagnostic Tests, Routine; Humans; Laboratories; Mass Screening; Metabolic Networks and Pathways; Proteoglycans
PubMed: 34828260
DOI: 10.3390/genes12111654