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At least 19 recordsLinked to original sources
PubMed1976

Extent of mitogen receptor occupancy and modulation of mitogen receptor exposure: possible mechanisms for the regulation of cell growth.

125I-Insulin was used as a model mitogen to examine the relationships of mitogen receptor occupancy and exposure in controlling cell replication. Labeled hormone was bound to substratum-attached, confluent fibroblasts with two affinities, K1 approximately equal to 2 X 108 M-1 and K2 approximately equal to 0.8 X 107 M-1. Approximately 9,000 receptors per cell were calculated from a scatchboard plot analysis with 80% of them of the affinity type. Treatment of confluent fibroblasts with 1.0 to 10 microng/ml of trypsin for 10 min increasd the number of exposed K2 sites by a factor of 2 to 3. Culturing the fibroblasts in the absence of serum for 12 to 24 hr also increased the quantity of exposed K2 sites to 60,000 per cell. The addition of unlabeled insulin to untreated, trypsin-treated, or serum-starved fibroblasts resulted in a stimulation of 2-deoxyglucose transport and thymidine incorporation activity that was proportional to the observed level of 125I-insulin binding. The quantity of exposed insulin receptors on uninfected fibroblasts decreases as the cell culture density increases. Hormone binding to B77 virus-transformed fibroblasts also decreases with culture density but plateaus at a density of 6 X 105 cells/plate. This resulted in a 2- to 3-fold difference in the level of exposed receptors between the uninfected and virus-transformed cells in confluent cultures, and proportionally higher rates of sugar transport and thymidine incorporation activity. Trypsin treatment and 12 hr of growth in the absence of serum did not result in an increase in the level of recepto exposure in the virus-transformed cells. The results of this study suggest that the pleotypic events associated with the stimulation of cell replication as represented by sugar transport and DNA synthesis are dependent upon and proportional to mitogen receptor occupancy. The control of cell replication, however, appears to be linked by a presently unknown mechanism with the degree of exposure of mitogen recipotrs. Receptor concentration is high and is similar in rapidly growing uninfected and virus-transformed cells, but the subsequent decrease observed with an increase in culture density reaches an early plateau for the transformed cells. This difference in exposed receptors could provide the growth advantage that is the hallmark of transformed cells.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1990

Relationship between mitogen receptors in peripheral blood lymphocytes and blastogenic responses to mitogen.

The relationship between the optimum concentration of mitogen which induces lymphocyte blastogenic response and the receptor occupancy by mitogen was investigated. The receptor occupancies which induced maximal blastogenic activity in equine, bovine and canine peripheral blood lymphocytes (PBL) were 31.1 per cent, 26.5 per cent and 38.4 per cent with phytohaemagglutinin-P, and 48.2 per cent, 17.9 per cent and 24.5 per cent with concanavalin A, respectively. The data clearly show that each animal species had its own optimum concentration of mitogen for stimulation of PBL. Optimum concentration for blastogenesis and number of binding sites of each mitogen had a good correlation with each other for all three species.

Animals↗
PubMed2004

The low-density lipoprotein receptor-related protein 1 is a mitogenic receptor for lactoferrin in osteoblastic cells.

Lactoferrin induces osteoblast proliferation and survival in vitro and is anabolic to bone in vivo. The molecular mechanisms by which lactoferrin exerts these biological actions are not known, but lactoferrin is known to bind to two members of the low-density lipoprotein receptor family, low- density lipoprotein receptor-related proteins 1 (LRP1) and 2 (LRP2). We have examined the role(s) of these receptors in the actions of lactoferrin on osteoblasts. We show that lactoferrin binds to cultured osteoblastic cells, and that LRP1 and LRP2 are expressed in several osteoblastic cell types. In primary rat osteoblastic cells, the LRP1/2 inhibitor receptor associated protein blocks endocytosis of lactoferrin and abrogates lactoferrin-induced p42/44 MAPK signaling and mitogenesis. Lactoferrin-induced mitogenesis is also inhibited by an antibody to LRP1. Lactoferrin also induces receptor associated protein-sensitive activation of p42/44 MAPK signaling and proliferation in osteoblastic human SaOS-2 cells, which express LRP1 but not LRP2. The mitogenic response of LRP1-null fibroblastic cells to lactoferrin is substantially reduced compared with that of cells expressing wild-type LRP1. The endocytic and signaling functions of LRP1 are independent of each other, because lactoferrin can activate mitogenic signaling in conditions in which endocytosis is inhibited. Taken together, these results 1) suggest that mitogenic signaling through LRP1 to p42/44 MAPKs contributes to the anabolic skeletal actions of lactoferrin; 2) demonstrate growth-promoting actions of a third LRP family member in osteoblasts; and 3) provide further evidence that LRP1 functions as a signaling receptor in addition to its recognized role in ligand endocytosis.

Animals↗
PubMed1994

Carcinogenesis and initiation of cell cycling by charge-induced membrane clusters may be due to mitogen receptors and Na+/H+ antiports.

The membrane cluster hypothesis of mitogenesis and carcinogenesis is extended by proposing that much of the Na+ ingress across a cell's plasma membrane at surface charge-induced (SCI) aggregates is due to mitogen-induced activation of Na+/H+ antiports. Intrinsic proteins (including mitogen receptors and antiports) are electrostatically attracted to and become part of the aggregate. In this location, close proximity facilitates antiport activation. Resulting Na+ ingress may cause sustained partial depolarization, cytoplasmic alkalinization, and initiation of cell cycling. Chronic phosphorylation-dephosphorylation at SCI aggregates too weak to induce cycling, may slowly form polyionic bonds between adjacent proteins at the inner lipid layer. These bonds convert the SCI aggregates to 'permanent' clusters that pass to a daughter cell with parental plasma membrane at mitosis, and are associated with malignancy. EGF and PDGF growth factors are used to develop the hypothesis, which is also applied to steroid and dioxin receptors and to oncogene products.

Animals↗
PubMed1976

Mitogen receptors in chick embryo fibroblasts. Kinetics, specificity, unmasking, and synthesis of 125I-insulin binding sites.

Insulin, a mitogen for cultured chick embryo fibroblasts (Temin, H.M. (1968) Cancer 3, 771-787), has been employed to characterize the effects of mitogen/cell membrane interactions as it relates to growth. The specific binding of 125I-insulin to substratum-attached cells is time- and temperature dependent and is optimum at a pH of 7.0. Fetal calf and chicken sera, somatomedin "A/C mixed," and desalanine or native porcine insulin compete with 125I-insulin for membrane-binding sites. Proinsulin, although competing less effectively than native insulin for binding, is more effective than desoctapeptide insulin. Unrelated polypeptide hormones do not compete for 125I-insulin binding. The lowest concentration of insulin at which specific binding is detected is 0.1 nM. Scatchard plot analysis of the binding data indicates that there are two types of binding sites in confluent cultures of fibroblasts: one of high affinity (K1 = 2 to 6 X 10(8) M-1) and low capacity, the other of low affinity (K2 = 0.8 to 3.0 X 10(7) M-1) and high capacity. Approximately 1.9 and 7.1 X 10(3) molecules of insulin are bound at each site, respectively. A 10-min incubation at 24 degrees of the fibroblasts with 10 mug/ml of trypsin causes a 2-fold stimulation of specific 125I-insulin binding and a similar 2-fold increase in insulin-stimulated 2-deoxy-D-glucose uptake and thymidine incorporation. Neuraminidase treatment also produces a 37% increase in specific 125I-insulin binding but treatment with alpha-chymotrypsin or phospholipase C are without significant effect. The results of this and additional experiments support the hypothesis that trypsin treatment of chick embryo fibroblasts leads to an unmasking of 125I-insulin binding sites. Serum starvation of fibroblasts for 12 or 24 h produces a 2.5- to 5-fold increase in specific 125I-insulin binding. This increase is the result of an increase in the number of hormone-binding sites from 9 X 10(3) to 6 X 10(4) per cell which are predominantly of the low affinity type. There is no change in the affinity constants. The presence of camptothecin, or cordycepin, or cycloheximide in the incubation medium completely blocks the increase in number of 125I-insulin-binding sites resulting from serum starvation. The addition of native insulin to the medium of serum-starved cultures also blocks this increase. The magnitude of insulin-stimulated 2-deoxy-D-glucose uptake and thymidine incorporation correlates with the levels of occupancy of the low affinity 125I-insulin-binding sites in untreated fibroblasts. In fibroblasts cultured in the absence of serum, the marked increase in insulin-stimulated 2-deoxy-D-glucose uptake and thymidine incorporation parallels the increase in number of mitogen receptors. The concentration of insulin that produces a half-maximum stimulation of thymidine incorporation is calculated to be 5 X 10(-8) M. At this concentration of insulin, 42% of the receptor sites are occupied.

Animals↗
PubMed2007

PSM/SH2-B distributes selected mitogenic receptor signals to distinct components in the PI3-kinase and MAP kinase signaling pathways.

The Pro-rich, PH, and SH2 domain containing mitogenic signaling adapter PSM/SH2-B has been implicated as a cellular partner of various mitogenic receptor tyrosine kinases and related signaling mechanisms. Here, we report in a direct comparison of three peptide hormones, that PSM participates in the assembly of distinct mitogenic signaling complexes in response to insulin or IGF-I when compared to PDGF in cultured normal fibroblasts. The complex formed in response to insulin or IGF-I involves the respective peptide hormone receptor and presumably the established components leading to MAP kinase activation. However, our data suggest an alternative link from the PDGF receptor via PSM directly to MEK1/2 and consequently also to p44/42 activation, possibly through a scaffold protein. At least two PSM domains participate, the SH2 domain anticipated to link PSM to the respective receptor and the Pro-rich region in an association with an unidentified downstream component resulting in direct MEK1/2 and p44/42 regulation. The PDGF receptor signaling complex formed in response to PDGF involves PI 3-kinase in addition to the same components and interactions as described for insulin or IGF-I. PSM associates with PI 3-kinase via p85 and in addition the PSM PH domain participates in the regulation of PI 3-kinase activity, presumably through membrane interaction. In contrast, the PSM Pro-rich region appears to participate only in the MAP kinase signal. Both pathways contribute to the mitogenic response as shown by cell proliferation, survival, and focus formation. PSM regulates p38 MAP kinase activity in a pathway unrelated to the mitogenic response.

Animals↗
PubMed1999

Timing-dependence of insulin-receptor mitogenic versus metabolic signalling: a plausible model based on coincidence of hormone and effector binding.

Mitogenic signalling through the insulin receptor is enhanced compared with metabolic signalling for insulin analogues having slower dissociation kinetics than insulin itself. A plausible explanation in molecular terms of this timing-dependent specificity is lacking. We show here that if signalling is transmitted through a single effector, binding coincidentally with hormone to the insulin receptor and whose association and dissociation kinetics are slow relative to the hormone dissociation rate, the resulting biological effect is predicted to be dependent on hormone-binding kinetics. However, known primary effector molecules associating with the insulin receptor bind and interact rapidly with the receptor, contrary to the assumptions of the single-effector model. A model with two effectors which must bind coincidentally with hormone for signalling to occur also gives the required dependence of signalling on hormone-binding kinetics, provided that at least one of the effectors has slow binding kinetics relative to hormone binding. In this case, the other effector can have rapid kinetics, which is consistent with the properties of the major known substrates of the insulin receptor, such as the insulin receptor substrate (IRS) molecules.

Binding Sites↗
PubMed1984

Platelet-derived growth factor labeled to colloidal gold for use as a mitogenic receptor probe.

Studies by others utilizing 125I-PDGF have indicated that target cells express a high affinity surface receptor for PDGF. We have bound purified platelet-derived growth factor (PDGF) to gold colloid particles to explore the interaction of PDGF with mouse 3T3 cells. The gold-PDGF complex consists of approximately 26 PDGF molecules electrostatically absorbed to gold colloid (approximately 14.1 nm). The gold-PDGF complex induced mitogenic stimulation similar to unbound PDGF, although a 5 to 6 fold greater amount of complexed PDGF was required for the same effect. Incubation of the gold-PDGF complex with 3T3 cells for 4 h at 4 degrees C revealed that 98% of the membrane binding was randomly distributed on the cell surface with respect to coated pits, with each cell binding 7000 to 11000 complexes. Addition of a 20-fold excess of unlabeled PDGF reduced surface binding of the gold-PDGF complex by 87% (1230 probes/cell). Warming to 37 degrees C followed by time-interval fixation permitted visualization of endocytosis of the complexes in coated vesicles (1-3 min), internalization (3-15 min) and lysosomal accumulation (15-60 min). Pretreatment of cultures with monensin (2 h, 10 microM) abolished receptor binding, internalization and subsequent mitogenesis of the gold-PDGF complex. These studies support the suggestion that PDGF requires a surface receptor to elicit mitogenesis.

Animals↗
PubMed1997

Divergence in the G-protein-coupled receptor mitogenic signalling pathway at the level of Raf kinase.

While activation of tyrosine kinase growth factor receptors is accompanied by hyperphosphorylation of Raf-1, stimulation of receptors coupled to G-proteins has in some cases been shown to result in activation of a non-Raf MEKK rather than of Raf itself. Our finding (Weiss, R. H., and Nuccitelli, R. (1992) J. Biol. Chem. 267, 5608-5613) that the thrombin receptor requires tyrosine phosphorylation for its mitogenic effect in vascular smooth muscle cells led us to search for the molecules which are being tyrosine phosphorylated by this receptor. To determine whether mitogenic signalling of G-protein-coupled growth factor receptors results in tyrosine phosphorylation of Raf, we examined activation of Raf by two such receptors. Both thrombin and angiotensin II are mitogenic in NIH3T3 cells, but only thrombin causes hyperphosphorylation of Raf-1. Activation of Raf by thrombin is associated with phosphorylation of Raf-1 on tyrosine residues, whereas activation of Raf by angiotensin II does not involve significant tyrosine phosphorylation. However, Shc is tyrosine phosphorylated by both thrombin and angiotensin II. Thus, there exists a divergence in the mitogenic signalling pathways of the G-protein-coupled receptors relative to the Raf signalling cascade. While both thrombin and angiotensin II phosphorylate Shc and activate Raf catalytic activity, only thrombin phosphorylated Raf-1 on tyrosine. This signalling through disparate Raf-coupled pathways suggests one means by which the G-protein-coupled receptors may confer specificity in their signalling properties.

3T3 Cells↗
PubMed2004

[Increased expression of endothelin-1 and its mitogen receptor ET(A) in thyroid papillary cancer in humans].

Since its discovery in 1988, endothelin has initiated intense research activities, showing that it was not only a vasoconstrictor and mitogenic peptide produced by the vascular endothelium but also a ubiquitous molecule with various functions. A production of ET-1 has been evidenced in the thyroid and ET-1 receptors have been detected on thyroid cells. Produced by the vessels and the thyrocytes, ET-1 could exert paracrine and/or autocrine effects on vascular tone in the thyroid and on some functions of thyrocytes. Because of proliferative effects, its role in thyroid diseases could involve goitrogenesis and carcinogenesis. Using thyroid samples obtained at the time of surgery, we demonstrated increased expressions of ET-1 and its mitogenic receptor ET(A) in papillary carcinoma of the thyroid. Immunohistochemical studies and real-time quantitative polymerase chain reaction (RTQ-PCR) were used for this purpose. As demonstrated in other cancers, activation of endothelin axis, particularly through ET(A) receptor could contribute to cell proliferation, cell survival, angiogenesis and the development of bone metastases. ET-1 is also a proinflammatory mediator and we demonstrated an overexpression of ET-1 and of its receptor ET(A) in Hashimoto's thyroiditis. This suggests a role of ET-1 as a cytokine. In nodular goitre, ET-1 is also overexpressed but to a lesser extent than in papillary thyroid carcinoma and in Hashimoto's thyroiditis. Finally, antagonists of ET-1 receptors are currently under development and could be used in man. They could open new therapeutic perspectives in the treatment of metastatic thyroid carcinoma.

Carcinoma, Papillary↗
PubMed1994

Autocrine stimulation of a human lung mesothelioma cell line is mediated through the transforming growth factor alpha/epidermal growth factor receptor mitogenic pathway.

Malignant cells frequently acquire a certain independency of exogenous growth factors via the coexpression of epidermal growth factor receptor (EGFR) and epidermal growth factor (EGF)-related molecules. In the present study we investigate a possible involvement of EGF-related molecules in the growth of human lung mesothelioma. Four well-characterised cell lines are analysed for their responsiveness to exogenous EGF and transforming growth factor alpha (TGF-alpha) as well as for coexpression of EGFR and EGF/TGF-alpha. Both growth factors are able to stimulate DNA synthesis in three cell lines, although the degree of responsiveness is very variable, but neither EGF nor TGF-alpha has an effect on the cell line ZL34. In contrast, no heterogeneity is observed in the expression of EGFR, which is similarly high in all cell lines. Analysis of cell supernatants reveals that, whereas no EGF is detected, TGF-alpha is released by two cell lines. Furthermore, these two cell lines, ZL5 and ZL34, are shown to express the membrane anchored precursor pro-TGF-alpha. Thus, coexpression of EGFR and TGF-alpha is observed on two mesothelioma cell lines. The potential autocrine mitogenic role of TGF-alpha in these two cell lines was tested using neutralising antibodies against TGF-alpha and EGFR. In ZL5 cells DNA synthesis was not affected by the presence of neutralising antibodies, indicating that an external autocrine mitogenic pathway is not active in these cells. In ZL34 cells, however, the potential autocrine loop could be disrupted, as DNA synthesis was significantly reduced in the presence of neutralising antibodies. This result gives strong evidence for an autocrine role of TGF-alpha in the growth of the mesothelioma cell line ZL34.

Antibodies, Neoplasm↗
PubMed2003

Increased expression of endothelin-1 and its mitogenic receptor ETA in human papillary thyroid carcinoma.

OBJECTIVE: Since the isolation of endothelin-1 (ET-1) in 1988, there has been tremendous interest in the pathophysiological roles of ET-1 as a vasoconstrictive and mitogenic peptide. Whereas ET-1 is mainly released by vascular endothelial cells, it also proved to be produced by various tissues including the thyroid. Because of its mitogenic properties in malignancy and its role as an inflammatory modulator, ET-1 could be involved in thyroid carcinogenesis and thyroiditis. DESIGN AND PATIENTS: Studies were performed in human thyroid samples obtained at the time of surgery from 39 men and women aged 15-72 years. Thyroid samples were classified in four groups according to conventional histology: normal thyroid (n = 7) papillary thyroid carcinoma (n = 12), Hashimoto's thyroiditis (n = 9) and benign nontoxic nodular goitres (n = 11). Immunohistochemistry and real-time quantitative polymerase chain reaction were used to determine the expression of ET-1 and its receptors (ETAR and ETBR). RESULTS: ET-1 and ETAR mRNA levels were, respectively, 3.8 +/- 1.3 and 4.1 +/- 1.5 times greater (P < 0.001) in papillary thyroid carcinoma than in normal thyroid. Expression of ETBR was unaltered. In Hashimoto's thyroiditis, ET-1 and ETAR were also overexpressed (P < 0.005). Furthermore, immunohistochemistry demonstrated a greater percentage of ET-1-positive follicular cells in these conditions (P < 0.001). In nodular goitres, the expression was increased by 1.7 +/- 0.7 times (P < 0.05) but expression of receptors remained unchanged. CONCLUSIONS: ET-1 and ETAR overexpression observed in thyroid carcinoma suggest a mitogenic role of ET-1 that theoretically could be countered by ETAR antagonists. ET-1 and ETAR overexpression in thyroiditis supports a role of ET-1 in the inflammatory process.

Adolescent↗
PubMed1978

Shared antigenic determinants by mitogen receptors and antibody molecules to the same thymus-independent antigen.

The antibody response to dextran B1355 is thymus independent, and in high responder mice, over 90% of the antibodies carry the idiotype of an alpha-1,3 binding myeloma protein (J558). The present experiments demonstrate: (a) dextran B1355 is a B-cell mitogen both in a strain which carries the J558 idiotype on antibodies and in a low-responder strain which does not express that idiotype on antibodies to dextran; (b) anti-idiotypic antibodies to J558 recognize a dextran-specific surface receptor on 10--15% of all splenic B cells in those two strains as well as in all strains so far tested; (c) as shown by inhibition experiments such surface receptors cross-react with J558, and (d) anti-idiotypic antibodies are mitogenic for spleen cells of both strains resulting in B-cell proliferation and maturation to polyclonal antibody secretion.

Antibodies↗
PubMed2005

beta1A integrin expression is required for type 1 insulin-like growth factor receptor mitogenic and transforming activities and localization to focal contacts.

The cells' ability to proliferate in response to growth factor stimulation is significantly altered during cancer progression. To investigate the mechanisms underlying these alterations in prostate cancer, the role and expression of beta1A integrin and type 1 insulin-like growth factor receptor (IGF-IR), known to contribute to cell proliferation and transformation, were analyzed. Using small interfering RNA oligonucleotides to down-regulate beta1A, we show that beta1A expression is required for IGF-IR-mediated prostate cancer cell proliferation and anchorage-independent growth. In vivo, using age-matched transgenic adenocarcinoma of mouse prostate (TRAMP) mice at different stages of prostate cancer [prostatic intraepithelial neoplasia, PIN; well-differentiated adenocarcinoma, WD; and poorly differentiated adenocarcinoma, PD], the expression of beta1A and of IGF-IR was studied. beta1A and IGF-IR expression levels were concurrently up-regulated in high PIN and WD, whereas their expression did not correlate in late-stage PD. In contrast to the up-regulated expression of beta1A, the levels of beta1C, a beta1 cytoplasmic variant that inhibits cell proliferation, were down-regulated in all stages of prostate cancer. A similar expression pattern was observed for a beta1C downstream effector, Grb2-associated binder-1 (Gab1) which is known to inhibit IGF-IR phosphorylation. To analyze in vitro the mechanistic implications of beta1A, beta1C, and Gab1 deregulation in prostate cancer, we investigated whether expression of either beta1 variant in beta1-null cells affected IGF-IR localization. We found that IGF-IR and beta1A were colocalized in highly specialized integrin signaling compartments, designated focal contacts. However, in the presence of beta1C, IGF-IR remained diffuse on the cell surface and did not localize to focal contacts. The findings that beta1 integrins and IGF-IR are concurrently deregulated and that expression of beta1 integrins is necessary to achieve appropriate IGF-IR intracellular distribution point to the important role that the cross-talk between these receptors may have during prostate cancer progression and will be helpful in formulating new therapeutic strategies.

Adaptor Proteins, Signal Transducing↗
PubMed1977

Mitogenic receptors on human peripheral blood lymphocytes: the interaction of Phaseolus vulgaris erythroagglutinating phytohemagglutinin and anti-thymocyte globulin on the human peripheral blood lymphocyte membrane.

A horse anti-human thymocyte antibody (ATG) obtained from the Upjohn Company was shown to stimulate DNA synthesis in human lymphocytes with a time course and magnitude of radioactive thymidine uptake comparable to that seen with phytohemagglutinin (E-PHA) and concanavalin A (Con A). Low mitogenic or nonmitogenic concentrations of intact ATG or its Fab fragments inhibited E-PHA-induced mitogenesis, whereas the response to Con A was unaffected. Competitive binding studies with ATG and E-PHA revealed mutual inhibition of binding to lymphocytes suggesting that E-PHA and the ATG share a common receptor site on the cell surface. ATG binding was unaffected by Con A. From the analysis of the binding data and the inhibition of mitogenesis, it appears that at least part of the E-PHA response in human lymphocytes involves receptors that are not acted on by Con A.

Antilymphocyte Serum↗