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PubMed2003

Induction of plasminogen activator inhibitor-1 by urokinase in lung epithelial cells.

The plasminogen/plasmin system, urokinase-type plasminogen activator (uPA), its receptor (uPAR), and its inhibitor (PAI-1), influence extracellular proteolysis and cell migration in lung injury or neoplasia. In this study, we sought to determine whether tcuPA (two chain uPA) alters expression of its major inhibitor PAI-1 in lung epithelial cells. The expression of PAI-1 was evaluated at the protein and mRNA level by Western blot, immunoprecipitation, and Northern blot analyses. We found that tcuPA treatment enhanced PAI-1 protein and mRNA expression in Beas2B lung epithelial cells in a time- and concentration-dependent manner. The tcuPA-mediated induction of PAI-1 involves post-transcriptional control involving stabilization of PAI-1 mRNA. Inactivation of the catalytic activity of tcuPA had little effect on PAI-1 induction and the activity of the isolated amino-terminal fragment was comparable with full-length single- or two-chain uPA. In contrast, deletion of either the uPA receptor binding growth factor domain or kringle domain (kringle) from full-length single chain uPA markedly attenuated the induction of PAI-1. Induction of PAI-1 by exposure of lung epithelial cells to uPA is a newly recognized pathway by which PAI-1 could regulate local fibrinolysis and urokinase-dependent cellular responses in the setting of lung inflammation or neoplasia.

Blotting, Northern↗
PubMed2007

UVA induces granzyme B in human keratinocytes through MIF: implication in extracellular matrix remodeling.

In a previous study, we have described that UVB induces granzyme B (GrB) in human keratinocyte cells, and that confers potent cellular cytotoxicity against various cellular models, including immune cells (Hernandez-Pigeon, H., Jean, C., Charruyer, A., Haure, M. J., Titeux, M., Tonasso, L., Quillet-Mary, A., Baudouin, C., Charveron, M., and Laurent, G. (2006) J. Biol. Chem. 281, 13525-13532). Herein, we have found that, in contrast to UVB, UVA failed to enhance keratinocyte cellular cytotoxicity but was still able to trigger GrB production. We show that GrB is accumulated through a p38 MAPK-dependent transcriptional mechanism stimulated by redox-dependent migration inhibitory factor release. Moreover, GrB purified from UVA-treated cellular extracts was found to degrade fibronectin in vitro. Treatment with antisense oligonucleotide directed against GrB resulted in the inhibition of UVA-induced cell detachment and cell death and facilitated cell migration through fibronectin and vitronectin matrix upon UVA exposure. Altogether, these results suggest another function for GrB in the context of the UV response. Indeed, combined with our previous study, it appears that, whereas this enzyme mediates keratinocyte cellular cytotoxicity following UVB irradiation, GrB supports the capacity of keratinocyte to degrade extracellular matrix components following UVA irradiation. UV-mediated GrB production may thus have important consequences in photoaging and photocarcinogenesis.

Cell Movement↗
PubMed1980

Comparison of nerve cell and nerve cell plus Schwann cell cultures, with particular emphasis on basal lamina and collagen formation.

The availability of cultures of normal cells (NCs) and Schwann cells (SCs) with and without fibroblasts has allowed us to investigate the sources of endoneurial and perineurial constituents of peripheral nerve. NCs cultured alone, devoid of ensheathment but healthy in appearance, lack basal lamina and extracellular fibrils. In contrast, when SCs accompany NCs, basal lamina and extracellular fibrils are consistently visible around SCs in outgrowth areas formed de novo in culture. These fibrils average 18 nm in diameter, exhibit a repeating banding pattern, and are trypsin-resistant and collagenase-sensitive. Collagen synthesis is also indicated by the incorporation of [14C]proline into peptide-bound hydroxy-proline in NC + SC or SC cultures. That the [14C]hydroxyproline polypeptides formed in NC + SC cultures are collagenous was determined in part by pepsin digestion-ammonium sulfate precipitation-polyacrylamide gel electrophoresis techniques; the 14C-polypeptides migrate to the positions of alpha 1 (I), alpha 2, alpha 1 (III), and alpha B chains of type I, type III, and A-B collagens. Also formed are thin, ruthenium red-preserved strands interconnecting basal laminae. SC ensheathment of axons is similar to that found in the animal; one SC is related to a number of unmyelinated axons or a single myelinated axon. This proclivity to ensheathe and myelinate axons indicates that SC function is not lost during the preparative procedures or after lengthy isolation in culture and provides the most reliable means for SC identification. Perineurial ensheathment and macrophages are lacking in NC + SC culture preparations divested of fibroblasts. We conclude that SCs do not form perineurium or the larger diameter collagen fibrils typical of endoneurium but that in combination with neurons they generate biochemically detectable collagens and morphologically visible basal lamina and thin collagenous fibrils.

Animals↗
PubMed2006

Gene targeting of Cdc42 and Cdc42GAP affirms the critical involvement of Cdc42 in filopodia induction, directed migration, and proliferation in primary mouse embryonic fibroblasts.

Recent studies in Cdc42 knockout mouse embryonic stem (ES) cells and ES-derived fibroblastoid cell lines raise concern on a body of literature derived by dominant mutant expression approach in a variety of cell lines implicating mammalian Cdc42 as a key regulator of filopodia induction, directional migration and cell cycle progression. To resolve the physiological function of mammalian Cdc42, we have characterized the Cdc42(-/-) and Cdc42GAP(-/-) primary mouse embryonic fibroblasts (MEFs) produced by gene targeting as the Cdc42 loss- or gain-of-activity cell model. The Cdc42(-/-) cells were defective in filopodia formation stimulated by bradykinin and in dorsal membrane ruffling stimulated by PDGF, whereas the Cdc42GAP(-/-) cells displayed spontaneous filopodia. The Cdc42 loss- or gain-of-activity cells were defective in adhesion to fibronectin, wound-healing, polarity establishment, and migration toward a serum gradient. These defects were associated with deficiencies of PAK1, GSK3beta, myosin light chain, and FAK phosphorylation. Furthermore, Cdc42(-/-) cells were defective in G1/S-phase transition and survival, correlating with deficient NF-kappaB transcription and defective JNK, p70 S6K, and ERK1/2 activation. These results demonstrate a different requirement of Cdc42 activity in primary MEFs from ES or ES-derived clonal fibroblastoid cells and suggest that Cdc42 plays cell-type-specific signaling roles.

Actins↗
PubMed1997

Arthralgia as an early extraintestinal symptom of Whipple's disease. Report of five cases.

Five patients with Whipple's disease all suffered from arthralgia for a long time (15 years in one case) before developing gastrointestinal or other symptoms. In all patients, arthralgia was seronegative, and there was no evidence of joint destruction. Arthralgias were symmetric and migrating. Whipple's disease is part of the differential diagnosis of enteropathic arthralgia. Thereby, the polymerase chain reaction can be a helpful tool to prove Whipple's disease in difficult differential diagnosis.

Arthralgia↗
PubMed1993

Anchorage and lymphocyte function: extracellular matrix substrata control morphogenesis and interleukin production but have minor effects on DNA synthesis.

Contact with collagen and fibronectin substrata triggers disruption of aggregates of activated lymphocytes, pseudopodia formation and migration of these lymphocytes onto the substrata. Monoclonal antibodies to the alpha 4 and alpha 5 chains of beta 1-integrins inhibit cell substrate adhesion and aggregate disruption on fibronectin substrata. A rat monoclonal antibody to the beta 1-integrin chain inhibits lymphocyte adhesion to collagen. Two-dimensional (2D) and three-dimensional (3D) collagen substrata have virtually the same capacity to abrogate lymphocyte aggregation. Fibronectin substrata trigger the initial phase(s) of aggregate disruption as effectively as collagen but the later part of the disruption process is relatively incomplete. Serum-coated plastic does not cause aggregate disruption. These results indicate that disruption of lymphocyte aggregates is a specific event induced via cell surface receptors for extracellular matrix (ECM) components. A major difference between lymphocytes on 2D and 3D extracellular matrix substrata seems to be that the cells detach from the former whereas on the latter infiltration dominates over detachment. Collagen and fibronectin substrata are non-mitogenic for lymphocytes but they can modulate lymphocyte activation induced by allogeneic cells and Con A. Thus, 3D collagen substrata augment and prolong such induced DNA synthesis, although they slightly delay entry into the S-phase and decrease IL-2 production. Collagen substrata, particularly in 3D form, also augment the DNA synthesis of preactivated lymphocytes above the magnitude on serum-coated plastic. The nature of the substratum determines IL-1 production. Accordingly, the spontaneous IL-1 production by mononuclear cells is substantially lower on collagen substrata than on plastic surfaces coated with serum or BSA. However, factors which induce IL-1 production (e.g. Con A or LPS) are more effective on collagen than on serum-coated plastic. Abrogation of cell aggregation, induction of morphogenesis and motile behaviour as well as control of IL-1 synthesis thus constitute major effects of ECM substrata on cells of the immune system. An additional but relatively minor influence of ECM substrata on these cells, as suggested by the present results, is exerted via modulation of DNA synthesis.

Antigens, CD↗
PubMed2006

Gastric epithelial expression of macrophage migration inhibitory factor is not altered by Helicobacter pylori infection in humans.

BACKGROUND: Recent reports have shown an upregulation of macrophage migration inhibitory factor (MIF) during gastric ulcer development in a rat model and elevated counts of MIF-positive cells in biopsies from Helicobacter pylori-infected patients. H. pylori infection is a proven cofactor in humans causing gastritis and gastric ulcers. The aim of this study was to characterize MIF expression in human gastric epithelial cells in response to H. pylori. METHODS: MIF mRNA and MIF protein expression was detected in human gastric epithelial cell lines after stimulation with proinflammatory cytokines or infection with H. pylori (cagA+/vacA+) using real-time reverse transcriptase-polymerase and enzyme-linked immunosorbent assay. Interleukin-8 secretion was measured as positive control. MIF mRNA and MIF protein expression was assessed in H. pylori-positive and -negative human gastric biopsy samples. RESULTS: While interleukin-8 mRNA expression and interleukin-8 secretion were upregulated in gastric epithelial cells in vitro after H. pylori infection, no changes in MIF mRNA expression and MIF secretion could be detected. We found no significant differences in MIF expression in total RNA extracted from gastric biopsy tissue when comparing H. pylori-positive to control patients. Likewise, MIF protein expression in gastric epithelium was unaffected by H. pylori infection as compared to uninfected tissue. CONCLUSIONS: While an increased MIF expression and positive effects of MIF blockade in ulcer healing have been shown in a rodent model and elevated numbers of MIF-positive cells have been found in H. pylori-infected human tissue, we herein could not confirm any differences in human gastric epithelial MIF expression and secretion after H. pylori infection in vitro and in vivo.

Biopsy↗
PubMed2005

Correlation between laminin-5 gamma2 chain and epidermal growth factor receptor expression in esophageal squamous cell carcinomas.

OBJECTIVES: Laminin-5 gamma2 chain (LN-5 gamma2) is an extracellular matrix protein that plays an important role in cell migration and tumor invasion. We evaluated the association of LN-5 gamma2 and epidermal growth factor receptor (EGFR) expression in esophageal squamous cell carcinoma (SCC). METHODS: LN-5 gamma2 and EGFR expression was evaluated in 110 esophageal SCC patients by immunohistochemistry, and was confirmed using esophageal SCC cell lines by Western blot analysis. RESULTS: LN-5 gamma2 expression in the invasive front of the tumor was correlated with the depth of invasion (p = 0.0001), lymph node metastasis (p = 0.0011) and pathological stage (p = 0.0001). The strong expression of EGFR was also correlated with lymph node metastasis (p = 0.0456) and the pathological stage (p = 0.0055). In patient survival, LN-5 gamma2 positivity and/or strong EGFR expression showed a significantly low survival rate as compared with those with lesser expression of LN-5 gamma2 and EGFR. Immunohistochemically, LN-5 gamma2 expression was significantly correlated with EGFR expression (p < 0.0001). Western blot analysis also confirmed the correlated expression of LN-5 gamma2 and EGFR in SCC cell lines except 2 of the 5 cell lines. CONCLUSIONS: This study suggests that coexpression of LN-5 gamma2 and EGFR is closely related to the progression and poor prognosis of esophageal SCC.

Aged↗
PubMed1998

A truncated species of apolipoprotein B (B-38.7) in a patient with homozygous hypobetalipoproteinemia associated with diabetes mellitus.

Familial hypobetalipoproteinemia is caused by mutations in the apolipoprotein (apo) B gene. We identified a 57-year-old woman whose plasma total cholesterol and apoB levels were 2.17 mmol/L and 0.03 g/L, respectively. Separation of plasma lipoproteins by sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed the absence of apoB-100 and the presence of a faster-migrating form of apoB with an apparent Mr of 195 kDa. Direct sequencing of a polymerase chain reaction-amplified fragment of the patient's apoB gene DNA revealed a single C-->T transition at nucleotide 5472 that converts glutamine 1755 (CAA) to a stop codon (TAA). We predict this novel nonsense mutation of the apoB gene to produce a truncated protein that contains 1754 amino-terminal amino acid residues of apoB-100. We designated this mutant form of apoB apoB-38.7 by following the centile nomenclature of the apoB species. The same mutation was found in both of her children. The proband revealed clinical findings of retinitis pigmentosa, acanthocytosis, and loss of deep tendon reflexes that are characteristic of severe hypobetalipoproteinemia. In addition, the proband had type II diabetes mellitus with nephropathy, anemia, cholelithiasis, hepatic hemangioma, bronchiectasis, and extensive calcification of major arteries including, the celiac, splenic, and renal. In summary, we have found a novel truncated apoB, apoB-38.7, in a patient with an unusual presentation of hypobetalipoproteinemia that includes diabetes mellitus and extensive arterial calcification.

Apolipoproteins B↗
PubMed2000

Determination of temporal expression patterns for multiple genes in the rat carotid artery injury model.

Vascular injury induces extensive alteration to the extracellular matrix (ECM). These changes contribute to lesion formation and promote cell migration and proliferation. To elucidate ECM response to arterial injury, we used real-time polymerase chain reaction monitoring to quantitate the expression levels of 81 genes involved in the synthesis and breakdown of ECM as well as receptors and signaling proteins that communicate and respond to ECM molecules. The temporal regulation of gene expression in the carotid was measured at 1, 3, 5, 7, 9, 14, and 28 days postinjury. Among the 68 genes that showed detectable expression by our method, 47 (69%) were significantly induced or repressed over time, confirming the extensive ECM gene response in this model. More ECM-related genes (31) were regulated at day 1 than at any other time point, and the number of regulated genes decreased over time. However, 14 of the genes were still induced or repressed at day 28, indicating that return to preinjury expression patterns did not occur and no new steady state was achieved over 28 days. In spite of the large number of changes in gene expression, only a small number of expression patterns was observed, suggesting that ECM-related genes could potentially be coregulated.

Animals↗
PubMed2002

Macrophage migration inhibitory factor is markedly expressed in active and early-stage endometriotic lesions.

The establishment of a new vascular supply is essential for the survival of endometrial tissue and its development in ectopic locations. We have previously shown that ectopic endometrial cells release an important mitogenic activity for human endothelial cells and identified macrophage migration inhibitory factor (MIF) as one of the principal bioactive molecules involved in endothelial cell proliferation. In the present study, immunohistochemical and dual immunofluorescence analyses showed that MIF is effectively expressed by endometriotic tissue, particularly in the glands, and identified endothelial cells, macrophages, and T lymphocytes as cells markedly expressing MIF in the stroma. Western blot analysis showed a single 12.5-kDa band corresponding to the known mol wt of the molecule. The highest concentrations of MIF protein in endometriotic tissue, as measured by ELISA, were found in flame-like red endometriotic lesions, compared with typical black-bluish (P < 0.01) or with white lesions (P < 0.01). Interestingly, MIF displayed a marked expression in lesions from the initial stage of endometriosis (stage I). Semiquantitative RT-PCR analysis of MIF mRNA levels in the same endometriotic tissues showed a pattern of expression comparable with that of the protein. In view of its potent proinflammatory and angiogenic properties, local production of MIF within endometrial implants, particularly in those that are highly vascularized and representing the earliest and most active forms of the disease, make plausible the involvement of this factor in the local immunoinflammatory process observed in endometriosis and the initial steps of endometriotic tissue growth and development.

Adult↗
PubMed2005

Balinese Y-chromosome perspective on the peopling of Indonesia: genetic contributions from pre-neolithic hunter-gatherers, Austronesian farmers, and Indian traders.

The island of Bali lies near the center of the southern chain of islands in the Indonesian archipelago, which served as a stepping-stone for early migrations of hunter-gatherers to Melanesia and Australia and for more recent migrations of Austronesian farmers from mainland Southeast Asia to the Pacific. Bali is the only Indonesian island with a population that currently practices the Hindu religion and preserves various other Indian cultural, linguistic, and artistic traditions (Lansing 1983). Here, we examine genetic variation on the Y chromosomes of 551 Balinese men to investigate the relative contributions of Austronesian farmers and pre-Neolithic hunter-gatherers to the contemporary Balinese paternal gene pool and to test the hypothesis of recent paternal gene flow from the Indian subcontinent. Seventy-one Y-chromosome binary polymorphisms (single nucleotide polymorphisms, SNPs) and 10 Y-chromosome-linked short tandem repeats (STRs) were genotyped on a sample of 1,989 Y chromosomes from 20 populations representing Indonesia (including Bali), southern China, Southeast Asia, South Asia, the Near East, and Oceania. SNP genotyping revealed 22 Balinese lineages, 3 of which (O-M95, O-M119, and O-M122) account for nearly 83.7% of Balinese Y chromosomes. Phylogeographic analyses suggest that all three major Y-chromosome haplogroups migrated to Bali with the arrival of Austronesian speakers; however, STR diversity patterns associated with these haplogroups are complex and may be explained by multiple waves of Austronesian expansion to Indonesia by different routes. Approximately 2.2% of contemporary Balinese Y chromosomes (i.e., K-M9*, K-M230, and M lineages) may represent the pre-Neolithic component of the Indonesian paternal gene pool. In contrast, eight other haplogroups (e.g., within H, J, L, and R), making up approximately 12% of the Balinese paternal gene pool, appear to have migrated to Bali from India. These results indicate that the Austronesian expansion had a profound effect on the composition of the Balinese paternal gene pool and that cultural transmission from India to Bali was accompanied by substantial levels of gene flow.

Asia, Southeastern↗
PubMedDate not supplied

Immunobarriers of the mucosa of the upper respiratory and digestive pathways.

The mucosa that lines the upper respiratory and digestive pathways is protected by a secretory immune system which is under complex and only partly understood immunoregulatory control. B cells of relatively immature memory clones with a potential for J-chain expression, are initially stimulated in mucosa-associated lymphoid tissue (probably including the tonsils) and migrate thereafter through lymph and blood to glandular sites where they are subjected to terminal differentiation and become immunoglobulin (Ig)-producing immunocytes. Most locally produced Ig is normally dimeric IgA which is selectively transported through the serous type of glandular cells by means of an epithelial receptor protein called the secretory component (SC). IgM is also subjected to SC-mediated transport. In patients with selective IgA deficiency, secretory IgA is lacking, but may be satisfactorily replaced by protective secretory IgM. In other IgA-deficient patients, however, immunoregulatory compensation gives rise to a large number of IgD-producing cells in respiratory mucosa. IgD cannot act as a secretory antibody and these patients are prone to have recurrent infections. These observations show that there are large individual variations in the secretory immune system.

Antibody-Producing Cells↗
PubMed1996

In vivo migration of tonsil lymphocytes in rheumatoid synovial tissue engrafted in SCID mice: involvement of LFA-1.

Integrin-adressin binding is a critical step in lymphocte attachment to target tissues. The mucosal recognition systems (alpha E beta 7, alpha 4 beta 7, MADcam-1) have been implicated in the autoimmune process in rheumatoid arthritis. We developed a model for in vivo study of radio-labelled lymphocyte circulation and their attachment to human rheumatoid synovium. We studied the homing of tonsil lymphocytes, considered as mucosal lymphocytes, and the involvement of alpha E beta 7 integrin and LFA1 in the homing of tonsil lymphocytes. We engrafted human rheumatoid synovium subcutaneously in 6 week old SCID CB17 mice. Three weeks later, we injected intraperitoneally 20 IO6 human peripheral blood or tonsil mononuclear cells, previously labelled with 3 mCFi HMPAO-99mTc. A mouse total body scintigram was obtained 20 h postinjection. The same protocol was performed after treatment of the MNC and mAb against LFA-1 (CD11a) or alpha E beta 7 (CD103). Tonsil MNC retention in the rheumatoid synovial graft 20 h post-injection was enhanced compared to blood MNC (12731 +/- 8297cpm/200 pixel) versus 5982 +/- 4713cpm/200 pixel, p < 0.05). A monoclonal antibody against LFA 1 decreased the activity in the graft (4152 +/- 1287 cpm/200 pixel), p < 0.05. No significant difference in tonsil MNC attachment to rheumatoid synovial tissue was observed with a mAb against alpha E beta 7 (8057 +/- 5009 cpm/200 pixel). Our results showed an increase in radiolabelled mucosal MNC migration in synovial tissue engrafted in SCID mice compared with blood MNC. Moreover, the date suggest that LFA-1 but not the alpha E beta 7 integrin is involved in tonsil MNC binding to synovial tissue in RA.

Animals↗
PubMed2004

Function of oval cells in hepatocellular carcinoma in rats.

AIM: To study oval cells' pathological characteristics and relationship with the occurrence of hepatocellular carcinoma (HCC); to observe the form and structural characteristics of oval cells; to explore the expression characteristics of C-kit, PCNA mRNA and c-myc gene during the occurrence and development of HCC and the effect of ulinastatin (UTI) on C-kit and PCNA expression. METHODS: One hundred and twenty-five SD rats fed on 3,3'-diaminobenzidine (DAB) to construct HCC models were divided into control group, cancer-inducing group and UTI intervention group. In each group, rat liver samples were collected at weeks 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 and 24 respectively to study pathological distribution characteristics of oval cells in the process of carcinogenesis under optical microscope. Oval cells were separated by the methods of improved density gradient centrifugation and their structural characteristics were observed under optical microscope and electronic microscope respectively; the oval cells expressing C-kit and PCNA in the collected samples were observed by the methods of immunohistochemistry and image analysis and the expression of c-myc mRNA was also detected by reverse transcription polymerase chain reaction (RT-PCR). RESULTS: Oval cells proliferated firstly in the portal area then gradually migrated into hepatic parenchyma in the inducing group and intervention group. The oval cells distributed inside and outside the carcinoma nodes. The oval cells presented the characteristics of undifferentiated cells: a high ratio of nucleolus and cellular plasm and obvious nucleoli, rare organelle in plasm. Only a few mitochondria and endoplasmic reticulum and some villus-like apophysis on surface of cells could be seen. Cells stained with C-kit and PCNA antibody were mainly oval cells distributed in the portal area. The expression of c-myc mRNA increased with the progression of HCC. However, in the intervention group, UTI could retard its increase. CONCLUSION: Oval cells work throughout the development of HCC, and might play important roles in this process. c-myc gene may be a kind of promoter gene of HCC, and play a key role in hepatic injury and development of HCC. UTI could retard the occurrence of HCC.

Animals↗
PubMed2000

Purification and characterization of two mannan-binding lectins from mouse serum.

Mannan-binding lectin (MBL) is a serum protein that activates the complement system after binding to glycoconjugates found on the surface of microorganisms. By molecular cloning two forms of MBL have been identified in the mouse (mMBL-A and mMBL-C), but only mMBL-A has been purified and characterized at the protein level. MBL-C has been termed the liver form of MBL. The present report describes the purification and characterization of mMBL-A and mMBL-C from serum. The two forms of mMBL could be separated both by ion-exchange and carbohydrate-affinity chromatography. The initial identification by immunochemical technique was confirmed by N-terminal amino-acid sequencing. Both proteins give bands corresponding to polypeptide chains of 28 kDa on SDS-PAGE in the reduced state, but mMBL-A migrated more rapidly than mMBL-C in acid/urea-PAGE, in accordance with the calculated pIs. Both forms mediated activation of complement component C4 in mannan-coated microtiter wells. MBL-A showed a higher affinity for d -glucose and alpha-methyl-d -glucose then did MBL-C. Serum concentrations of mMBL-A in laboratory strains and wild mice were found to vary from 5 to 80 microg/ml, with wild mice tending to show higher levels than laboratory strains.

Amino Acid Sequence↗
PubMed1992

Assignment of interchain disulfide bonds in platelet-derived growth factor (PDGF) and evidence for agonist activity of monomeric PDGF.

Platelet-derived growth factor (PDGF) is a dimeric factor stabilized by disulfide bonds. Using an approach involving partial reduction of PDGF, we have identified the 2nd and 4th cysteine residues in the PDGF chains as the cysteine residues forming interchain disulfide bonds. Analysis of PDGF mutants in which the 2nd and 4th cysteine residues were mutated to serine residues revealed that the disulfide bonds are arranged in a cross-wise manner, with the 2nd cysteine residue in one chain being linked to the 4th cysteine residue in the other. A PDGF B-chain mutant, in which both the 2nd and 4th cysteine residues were substituted with serine residues, migrated as a monomer in sodium dodecyl sulfate gel electrophoresis and retained receptor binding activity. When analyzed in receptor dimerization and autophosphorylation assays, this mutant showed agonistic activity. Thus, structural information has been obtained that will allow the large scale production of properly folded monomeric PDGF, as well as design of specific PDGF heterodimers.

Amino Acid Sequence↗