Growth factor receptor inhibitor

About: Growth factor receptor inhibitor is a research topic. Over the lifetime, 4730 publications have been published within this topic receiving 297500 citations.

Editorial: Growth Inhibition by Insulin-Like Growth Factor (IGF) Binding Protein-3—What’s IGF Got To Do with It?

Abstract: Life has suddenly become more interesting for the insulinlike growth factor binding proteins (IGFBPs). For years the IGFBPs were relegated to preventing IGF-I or IGF-II from binding to IGF-I receptors and activating the signaling pathways that stimulated cell proliferation or survival (1, 2). They did this job well because they bound IGFs with higher affinity than did the receptors, forming inactive complexes that could not bind to the IGF-I receptor. First came the suggestion that they could potentiate IGF action, albeit only under precisely defined in vitro conditions (2). Now, recent studies with IGFBP-3, the most abundant IGFBP in the circulation, have opened new vistas for the proteins. Recent papers from several laboratories have reported that IGFBP-3 can: 1) inhibit growth without binding IGF-I and blocking its access to the IGF-I receptor; 2) travel to the cell nucleus instead of remaining outside the cell like a pariah; 3) induce apoptosis; and 4) mediate the potent growth inhibitory actions of transforming growth factor(TGF-) b and possibly the induction of apoptosis by the tumor suppressor, p53. And if this were not enough, new cousins (IGFBPs 7–10) have been discovered. These are heady times, indeed. There were earlier premonitions that IGFBP-3 might have a secret life as an inhibitor of cell proliferation independent of IGFs and IGF-I receptors by a mechanism that did not involve sequestering IGF-I. Liu et al. (3) reported that rat IGFBP-3 inhibited the stimulation of chick embryo fibroblast (CEF) DNA synthesis by a serum fraction from which IGFs had been removed by acid gel-filtration. But the skeptics countered that other growth factors in serum might have stimulated the synthesis of endogenous IGFs, so that sequestration remained a possibility. Support came from Oh et al. (4), who showed that exogenous IGFBP-3 inhibited constitutively activated DNA synthesis in a human breast cancer cell line, and from Cohen et al. (5), who demonstrated that stable transfection of Balb c/3T3 mouse fibroblasts with human IGFBP-3 complementary DNA (cDNA) decreased the rate of cell proliferation. The key to the latter experiment was that addition of insulin, which has mitogenic activity in these cells but does not bind to and therefore can not be inhibited by IGFBP-3, could not overcome the decrease in cell proliferation. Still another blow to the skeptics came when Lalou et al. (6) showed that a 16-kDa fragment of IGFBP-3, generated by limited proteolysis of human recombinant IGFBP-3 with plasmin, inhibited IGF-Iand insulin-stimulated DNA synthesis in CEFs. Although both peptides act through the IGF-I receptor, the critical point is that the 16-kDa IGFBP-3 fragment has negligible binding affinity for IGF-I and presumably does not bind insulin, so that sequestration of the growth peptides was unlikely to explain the inhibition of cell proliferation. The best was yet to come. Studies using a fibroblast cell line developed from mice with a targeted disruption of the IGF-I receptor (R cells) (7) established that the growth inhibitory effects of IGFBP-3 did not involve IGF binding to the IGF-I receptor. First, Valentinis et al. (8) reported that stable transfection of human IGFBP-3 cDNA slowed the proliferation of R cells, as it had in Balb c/3T3 fibroblasts. And in the present issue, Zadeh and Binoux (9) demonstrate that the 16-kDa IGFBP-3 fragment inhibited the stimulation of DNA synthesis in R cells by basic fibroblast growth factor (bFGF). Even if bFGF induced IGF-I synthesis in these experiments, the IGF-I could not have stimulated DNA synthesis through the IGF-I receptor. (Only a diehard skeptic would suggest that IGF-I still might act through another receptor pathway, such as the insulin receptor). If IGFBP-3 is not acting by simply preventing IGF-I from binding to the IGF-I receptor, how does it inhibit growth? The final answer is not in, but some important clues are available. First, it has been appreciated for several years that IGFBP-3 associates with different cells and that this binding was decreased by incubation with heparin (10, 11). Although these experiments were initially interpreted as indicating that heparin competitively inhibited the binding of IGFBP-3 to a cell-associated heparan sulfate proteoglycan, this does not appear to be the case because complete enzymatic removal of heparan sulfate and other glycosaminoglycans from the cell surface did not affect IGFBP-3 binding (12). An alternative explanation, that the binding of heparin to IGFBP-3 induced a conformational change in the protein that decreased its ability to bind to putative IGFBP-3 receptors on the cell surface, was proposed. A heparin binding domain (XBBBXXBX, where B is a basic amino acid and X is a nonbasic amino acid) is present in a highly basic region (residues 214–232) in the COOH-terminal portion of IGFBP-3. Identification of the putative IGFBP-3 receptors remains elusive. Although several cell-associated proteins that bind IGFBP-3 have been described (13–15), the specificity of the binding and whether these IGFBP-3-binding proteins have a functional role in growth inhibition by IGFBP-3 must be established before they can be considered signaling IGFBP-3 receptors. Nonetheless, the ability of IGFBP-3 to bind to cells is strongly correlated with its ability to cause growth inhibition, suggesting that IGFBP-3 must interact with specific cell receptors before growth inhibition can occur. The strongest evidence for this hypothesis comes from the concomiReceived May 8, 1997. Address all correspondence and requests for reprints to: Dr. Matthew M. Rechler, National Institutes of Health, Building 10, Room 8D-14, 10 Center Drive, MSC 1758, Bethesda, Maryland 20892-1758. E-mail: mrechler@helix.nih.gov. 0013-7227/97/$03.00/0 Vol. 138, No. 7 Endocrinology Printed in U.S.A. Copyright © 1997 by The Endocrine Society

A rapid decrease in epidermal growth factor-binding capacity accompanies the terminal differentiation of mouse myoblasts in vitro.

Abstract: Specific mitogens stimulate the proliferation and repress the differentiation of mouse myoblasts (MM14). When mitogens are depleted, MM14 cells cease proliferation, commit to terminal differentiation, and become refractory to growth stimulation. The behavior of mitogen receptors during the transition from a proliferative to a permanently postmitotic state was examined using the epidermal growth factor receptor (EGFR) as a model system. Whereas proliferating myoblasts bound substantial amounts of EGF, their binding capacity declined rapidly upon exposure to low-mitogen medium. The decline became irreversible when a cell differentiated. Within 24 h, less than 5% of the original EGF binding capacity remained. Since the ability to internalize and degrade bound EGF was unaffected, the change presumably reflected a decrease in EGFR availability. Several observations indicated that loss of EGFR following mitogen removal is related to differentiation rather than the result of starvation or cell-cycle arrest. First, the decline is correlated with the absence of a single mitogen (fibroblast growth factor) and is independent of serum concentrations. Second, myoblasts that are either cycling through G1 or arrested at G0, but prevented from differentiating, all bind large amounts of EGF. These findings suggest that specific reduction in mitogen receptors could be part of a mechanism whereby terminally differentiating cells become refractory to mitogenic stimulation.

Hypoxia-induced interleukin-6 and interleukin-8 Production Is Mediated by Platelet-Activating Factor and Platelet-Derived Growth Factor in Primary Human Lung Cells

Abstract: Hypoxia has been shown to induce the expression of different growth factors, cytokines, and proinflammatory mediators, including platelet-derived growth factor (PDGF), interleukin-6 (IL-6), interleukin-8 (IL-8), and platelet-activating factor (PAF) in animal models. PAF and PDGF are thought to play important roles in vascular remodeling and have been shown to induce expression of IL-6 and IL-8 genes under normoxic conditions. We hypothesize that de novo synthesis of IL-6, IL-8, and cell proliferation is enhanced in human pulmonary cells under hypoxic cell culture conditions. We further assumed an important role of PAF and/or PDGF in hypoxia-induced cell activation. Using cultures of primary human pulmonary fibroblasts and pulmonary vascular smooth muscle cells (VSMC) we show that hypoxia (3% O2) induced transcription and translation of IL-6 (4- to 5-fold) and IL-8 (5- to 6-fold) in both cell types. Hypoxia-induced expression of IL-6 was suppressed by 50% to 60% in the presence of the PAF antagonist WEB217...

Molecular aspects of pancreatic cancer and future perspectives.

Abstract: SummaryPancreatic cancer has one of the worst prognoses of all human malignancies and the molecular mechanisms underlying this aggressive disease have been extensively investigated in the