Intracellular signal transduction mediated via 5-HT and NA receptors

The present brief review was discussed about the intracellular signal transduction mediated via 5-HT and NA receptors focussing on the mechanism of antidepressants. Recent studies demonstrated that long-term antidepressant treatments resulted in activation of cAMP pathway at several levels including CREB(cAMP response element-binding protein) and BDNF(brain-derived neurotrophic factor). These pathways are elevated via 5-HT and/or NA receptors which directly couple to the cAMP system(5-HT4,6,7 receptors or beta adrenoceptors), or via receptors that lead to activation of Ca(2+)-dependent protein kinase(5-HT2 receptors or alpha 1 adrenoceptors). Such factors could be common targets for many different type of antidepressants. Elucidation of the signal transduction mediated via 5-HT and/or NA receptors, therefore, provide significant information understanding the pathophysiology of depression.     

Terbinafine inhibits the mitogenic response to platelet-derived growth factor in vitro and neointimal proliferation in vivo

Terbinafine [(E)-N(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-1-naphthale nemethanamine], an antimycotic agent that inhibits fungal squalene epoxidase activity, was examined for its effects on platelet-derived growth factor (PDGF)-stimulated aortic smooth muscle cell DNA synthesis in vitro and neointimal proliferation in vivo. Exposure of bovine aortic smooth muscle cells to 0.25 to 25 microM terbinafine resulted in a concentration-dependent inhibition of PDGF-induced mitogenesis as determined by [3H]thymidine incorporation into DNA or cell number. The IC50 for inhibition of PDGF-stimulated smooth muscle cell DNA synthesis was approximately 5 microM. Micromolar concentrations of terbinafine also suppressed the mitogenic response to PDGF in fibroblasts. Neither the binding of [125I]PDGF to its plasma membrane receptors nor the uptake of [3H]thymidine or [3H]uridine was affected significantly by terbinafine. Oral administration of terbinafine (200 mg/kg/day) to rats for 2 days before and 14 days after balloon catheter injury to the carotid artery was associated with a 40% decrease in the area of the neointimal lesion. These observations indicate that terbinafine is both a potent in vitro antagonist of the smooth muscle cell mitogenic response to PDGF and an effective, well-tolerated p.o. active inhibitor of neointimal proliferation in vivo.     

Selective upregulation of platelet-derived growth factor alpha receptors by transforming growth factor beta in scleroderma fibroblasts

Transforming growth factor beta (TGF-beta), a multifunctional cytokine, is an indirect mitogen for human fibroblasts through platelet-derived growth factor (PDGF), particularly the A ligand-alpha receptor arm of that system. TGF-beta effects on PDGF alpha receptor expression were studied in vitro using ligand binding techniques in three human dermal fibroblast strains: newborn foreskin, adult skin, and scleroderma (systemic sclerosis, SSc). Each cell strain responded differently to TGF-beta. In newborn foreskin fibroblasts, PDGF alpha receptor number decreased in a dose-dependent manner after exposure to low concentrations of TGF-beta (0.1-1 ng/ml). Responses of normal skin fibroblasts were varied, and mean net receptor number was unchanged. Increases in PDGF alpha receptor number by TGF-beta occurred consistently with SSc fibroblasts and low concentrations of TGF-beta (0.1-1 ng/ml) were particularly stimulatory. Increased surface expression of alpha receptor subunit by TGF-beta in SSc fibroblasts correlated with increased new PDGF alpha receptor synthesis as demonstrated by radioimmunoprecipitation analysis of metabolically labeled cells and with increased steady-state levels of corresponding mRNAs. In normal adult skin fibroblasts, TGF-beta had no effect on either synthesis or mRNA expression of alpha receptor subunits. Proliferative responses to PDGF-AA after pretreatment with TGF-beta correlated positively with effects of TGF-beta on expression of alpha receptor subunit. Decreased mitogenic responses to PDGF-AA were observed in foreskin fibroblasts, small changes in responses in adult fibroblasts, and significant increases in SSc fibroblasts. Thus, costimulation with PDGF-AA and TGF-beta selectively enhanced proliferation of fibroblasts with the SSc phenotype. Immunohistochemical examination of SSc and control skin biopsies revealed the presence of PDGF-AA in SSc skin. Data obtained by ligand binding, immunoprecipitation, mRNA, and mitogenic techniques are consistent with the hypothesis that activation of the PDGF-AA ligand/alpha receptor pathway is a characteristic of the SSc fibroblast and may contribute to the expansion of fibroblasts in SSc.     

Cholera toxin inhibits signal transduction by several mitogens and the in vitro growth of human small-cell lung cancer.

Cholera toxin (CT) inhibited the in vitro growth of three of four human small-cell lung carcinoma (SCLC) cell lines with a 50% inhibitory concentration of 27-242 ng/ml. Loss of surface membrane ruffling and the capacity of [Tyr4]-bombesin, vasopressin, and fetal calf serum to stimulate increases in intracellular free calcium clearly preceded effects on cellular metabolic activity and cell growth. 125I-[Tyr4]-bombesin binding was unaffected by CT treatment but [Tyr4]-bombesin stimulated phospholipase C activity was decreased in membranes from CT-treated SCLC cells. CT stimulated a rapid but transient increase in intracellular cyclic AMP ([cAMP]i) in SCLC. The effects of CT on susceptible SCLC were not reproduced by elevations of [cAMP]i induced by forskolin or cyclic AMP analogues. GM1 ganglioside, the cellular binding site for CT, was highly expressed in the CT-sensitive but not the CT-resistant SCLC cell lines. In contrast, expression of guanine nucleotide binding protein substrates for ADP-ribosylation by CT was similar. These data demonstrate the existence of a CT-sensitive growth inhibitory pathway in SCLC-bearing GM1 ganglioside. Addition of CT results in decreased responsiveness to several mitogenic stimuli. These results suggest novel therapeutic approaches to human SCLC.     

Tissue localization of beta receptors for platelet-derived growth factor and platelet-derived growth factor B chain during wound repair in humans.

The expression and localization of PDGF beta receptors and PDGF-AB/BB in human healing wounds was evaluated by immunohistochemical techniques and in situ hybridization. Expression of PDGF beta receptor protein and PDGF-AB/BB were analyzed in wound margin biopsies using the PDGFR-B2 and PDGF 007 antibodies. PDGF beta receptor expression was minor in normal skin. An increased expression of PDGF beta receptor protein was prominent in vessels in the proliferating tissue zone in wounds as early as 1 d after surgery and was apparent < or = 4 wk after surgery. There was also a concordant increase in PDGF beta receptor mRNA detected by in situ hybridization. PDGF-AB/BB was present in healing wounds as well as in normal skin. In normal skin, expression of PDGF-AB/BB was confined to peripheral nerve fibers and to solitary cells of the epidermis and of the superficial dermis. In wounds, infiltrating mononuclear cells also stained for PDGF-AB/BB. To identify cell types expressing PDGF AB/BB and PDGF beta receptors, respectively, we performed double immunofluorescence stainings. PDGF beta receptors were expressed by vascular smooth muscle cells and cells in capillary walls; the receptor protein could not be detected in neurofilament containing structures, T lymphocytes, or CD68 expressing macrophages. PDGF-AB/BB colocalized with neurofilaments, it was present in Langerhans cells of the epidermis and in HLA-DR positive cells located in the epidermal/dermal junction area. Of the macrophages infiltrating the wound, 43 +/- 18% stained positively for PDGF AB/BB. Since PDGF-AB/BB and PDGF beta receptors are expressed in the healing wound, two essential prerequisites for a role of PDGF in wound healing are fulfilled.     

Naftidrofuryl inhibits the release of 5-hydroxytryptamine and platelet-derived growth factor from human platelets

Angioplasty and bypass-grafting are associated with restenosis which limits their efficacy. Platelet-rich thrombus formation is the predominant cause of acute occlusion whereas platelet release products with proliferating properties, e.g. 5-hydroxytryptamine (5-HT) and platelet-derived growth factor (PDGF), may contribute to late restenosis. Naftidrofuryl (NAF), a drug for the treatment of peripheral vascular disease, was shown previously to inhibit platelet shape change and aggregation. This study establishes whether NAF inhibits the release of 5-HT and PDGF from platelets obtained from healthy subjects. Platelets stimulated with agonists aggregated less and released less 5-HT/PDGF when pre-incubated with NAF. Indomethacin (INDO), a cyclooxygenase inhibitor, alone inhibited aggregation and PDGF/5-HT release; NAF enhanced the inhibitory effects of INDO. The effect of NAF, on its own or in combination with a cyclooxygenase inhibitor, may therefore confer protection against graft occlusion.     

The insulin-like growth factor-I (IGF-I) receptor kinase inhibitor NVP-ADW742, in combination with STI571, delineates a spectrum of dependence of small cell lung cancer on IGF-I and stem cell factor signaling

Stem cell factor (SCF)/Kit and insulin-like growth factor-I (IGF-I)/IGF-I receptor (IGF-IR) autocrine loops play a prominent role in the growth of small cell lung cancer (SCLC). Previous data suggested that IGF-I protects cells from apoptosis induced by STI571, an efficient inhibitor of Kit signal transduction, by activating the critical phosphatidylinositol 3-kinase-Akt pathway. To determine if inhibition of IGF-IR signaling would be therapeutically relevant in SCLC, the activity of a novel kinase inhibitor of IGF-IR, NVP-ADW742 (Novartis Pharma AG, Basel, Switzerland), was characterized. Pretreatment of the H526 cell line with NVP-ADW742 inhibited IGF-IR signaling and growth with IC(50) values between 0.1 and 0.4 micro M. SCF-mediated Kit phosphorylation and Akt activation were inhibited with IC(50) values in the 1-5 micro M range. However, NVP-ADW742 affected neither hepatocyte growth factor-mediated Akt activation nor activity of constitutively active Akt. The therapeutic potential of NVP-ADW742 was assessed by determining its effect on growth of several SCLC cell lines in serum. These studies clearly delineated two populations of cell lines as determined by differential sensitivity to NVP-ADW742. One population, which lacks active SCF/Kit autocrine loops, was inhibited with IC(50) values between 0.1 and 0.5 micro M. A second population, which has active SCF/Kit autocrine loops, was inhibited with IC(50) values in the 4-7 micro M range. When these cell lines were treated with a combination of STI571 and NVP-ADW742, no advantage was seen in the former group, whereas, in the latter group, a clearly synergistic response to the combination was seen when growth, apoptosis, or Akt activation was assessed. These data demonstrate that NVP-ADW742 is a potent and selective IGF-IR kinase inhibitor that can efficiently inhibit the growth of cells that are highly dependent on IGF-I signaling. However, for optimal growth inhibition of SCLC cells with an active SCF/Kit autocrine loop, a combination of a Kit inhibitor (STI571) and an IGF-IR inhibitor (NVP-ADW742) appears to be necessary. These observations suggest that, in tumors in which critical signal transduction pathways can be activated by alternative receptors, optimal therapy may require inhibition of multiple receptors.     

ZD6474, a vascular endothelial growth factor receptor tyrosine kinase inhibitor with additional activity against epidermal growth factor receptor tyrosine kinase, inhibits orthotopic growth and angiogenesis of gastric cancer

Vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) have been strongly implicated in the growth and metastasis of gastric cancer. The purpose of this study was to examine the effects of ZD6474, an inhibitor of inhibitor of VEGF receptor (VEGFR) tyrosine kinase with additional activity against EGF receptor (EGFR), on tumor growth and angiogenesis in an orthotopic model of gastric cancer. In vitro, ZD6474 inhibited human umbilical vascular endothelial cell and TMK-1 human gastric tumor cell proliferation in a dose-dependent fashion. EGF-mediated activation of EGFR and Erk-1/2 was decreased in tumor cells after ZD6474 treatment. In addition, VEGF-mediated activation of VEGFR2 and Erk-1/2 was decreased in human umbilical vascular endothelial cells. TMK-1 human gastric adenocarcinoma cells were injected into the gastric wall of nude mice. ZD6474 therapy was initiated on day 10. Mice (n = 14 per group) were treated p.o. with (a) 1% Tween 80 (control), (b) 50 mg/kg/d ZD6474, or (c) 100 mg/kg/d ZD6474. Mice were sacrificed on day 33. Tumors from each group were stained for markers of blood vessels, pericytes, proliferation, and apoptosis. ZD6474 at both 50 and 100 mg/kg/d led to marked inhibition of tumor growth (P < 0.05). ZD6474 reduced tumor cell proliferation by 48% in the 50 mg/kg/d group and 65% in the 100 mg/kg/d group (P < 0.03) and increased tumor cell apoptosis (P < 0.001) in vivo. ZD6474 led to a 69% decrease in microvessel density in the 50 mg/kg/d group (P < 0.001) and a 62% decrease in the 100 mg/kg/d group (P < 0.001). Although microvessel density was decreased by ZD6474, the remaining vessels showed a relatively higher percentage of pericyte coverage (3-fold increase; P < 0.001), perhaps reflecting selective loss of uncovered vessels in the ZD6474 group. In conclusion, therapies such as ZD6474 that target two distinct aspects of tumor growth, angiogenesis and tumor cell proliferation, warrant further investigation.     

Growth inhibition and induction of apoptosis in acute myeloid leukemia cells by new indolinone derivatives targeting fibroblast growth factor, platelet-derived growth factor, and vascular endothelial growth factor receptors

In acute myeloid leukemia (AML), receptor tyrosine kinase ligands promote growth and survival and contribute to AML-associated marrow neoangiogenesis. We have tested simultaneous inhibition of vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor receptor signaling by novel indolinone derivatives using 14 myeloid, including 11 human leukemic, cell lines. Compounds inhibited colony formation of all cell lines in a dose-dependent fashion. Inhibitory concentrations for 50% of the colony formation/survival (IC50) for BIBF1000 were <100 nmol/L for 3 of 11, 相似文献   

心肌肥大的机制:丝裂素活化蛋白激酶抑制剂对血管紧张素Ⅱ诱导心肌细胞血小板衍生生长因子受体表达的影响

背景血管紧张素Ⅱ(angiotensinⅡ,AngⅡ)是诱导心肌肥大的强刺激因子,血小板衍生生长因子(platelet-derived growthfactor,PDGF)也是致心肌肥大因素之一,AngⅡ是否可以通过诱导PDGF受体表达进一步促使心肌肥大?目的探讨丝裂素活化蛋白激酶在AngⅡ致心肌细胞肥大的作用,为心肌肥大的防治提供理论依据.设计以分离纯化培养的Wistar乳鼠心肌细胞为研究对象的对照性实验研究.单位一所大学的病理生理教研室.材料实验在北京大学医学院病理生理学实验室进行.实验动物为80只出生1～3 d的Wistar乳鼠(北京大学医学部动物中心提供),雌雄不限.均在细胞培养室取出心脏做心肌细胞培养.干预分离纯化培养的乳鼠心肌细胞,分为3组,以1×10-7 mol/L AngⅡ刺激为AngⅡ组;以1×10-5 mol/L PD98059(一种丝裂素活化蛋白激酶抑制剂)预孵育30 min后再用AngⅡ刺激为PD98059组;以正常的乳鼠心肌细胞为对照组.培养24 h后采用免疫印迹法测定每组心肌细胞PDGF-β受体的含量.主要观察指标各组心肌细胞PDGF-β受体的含量.结果AngⅡ刺激培养24 h的乳鼠心肌细胞PDGF-β受体表达(432.41±54.08)和对照组(197.65±44.10)比较增强,差异有显著性意义(q=6.77,P<0.01),PD98059组PDGF-β受体表达(317.2±21.12)与AngⅡ组比较明显下降,差异有显著性意义(q=3.91,P<0.05),但并未完全恢复至对照组水平,两者比较差异有显著性意义(q=3.85,P<0.05).结论AngⅡ可以上调心肌细胞PDGF-β受体的表达,丝裂素活化蛋白激酶参与这一过程.这可能是AngⅡ促进心肌肥大的又一个重要机制.此研究结果可为心脏康复的一、二级预防提供实验学数据.     

Growth factor and signal transduction in lung cancer cell

Growth factors are molecules that participate in the control of cell proliferation. They require specific receptors on the target cell and intracellular signaling pathways to transmit the stimulus to the nucleus. Growth factors can stimulate or inhibit cell division. Most of the factors implicated in lung cancer growth are thought to act through positive feedback loops in which factors secreted by the cancer cells bind to receptors on their own surfaces(autocrine stimulation) or those of neighboring cells (paracrine stimulation). Abnormal expression of growth factors, their receptors, or components of their signaling pathways can result in the unrestrained growth of cancer. In this review, we described outlines of the growth factors, their receptors, signal transduction pathways, as well as their clinical applications.     

Protein C inhibitor directly and potently inhibits activated hepatocyte growth factor activator

Background:  Hepatocyte growth factor (HGF) plays an important role in tissue repair and regeneration. HGF activator (HGFA), a factor XIIa-like serine protease, activates HGF precursor to HGF. The precursor of HGFA, proHGFA, is activated by thrombin generated at sites of tissue injury. It is known that protein C inhibitor (PCI), an inhibitor of activated protein C (APC), also inhibits thrombin–thrombomodulin (TM) complex. Objectives:  In the present study we evaluated the effect of PCI on thrombin-catalyzed proHGFA activation in the presence of TM, and on HGFA activity. Results:  PCI did not inhibit thrombin-TM-mediated proHGFA activation, but it directly inhibited activated HGFA by forming an enzyme inhibitor complex. The second-order rate constants ( m ⁻¹ min⁻¹) of the reaction between HGFA and PCI in the presence or absence of heparin (10 U mL⁻¹) were 4.3 × 10⁶ and 4.0 × 10⁶, respectively. The inhibition of HGFA by PCI resulted in a significant decrease of HGFA-catalyzed activation of HGF precursor. Exogenous HGFA added to normal human plasma formed a complex with plasma PCI, and this complex formation was competitively inhibited by APC in the presence of heparin, but very weakly in the absence of heparin. We also demonstrated using recombinant R362A-PCI that Arg362 residue of PCI is important for HGFA inhibition by PCI as judged from the three-dimensional structures constructed using docking models of PCI and HGFA or APC. Conclusion:  These observations indicate that PCI is a potent inhibitor of activated HGFA, suggesting a novel function for PCI in the regulation of tissue repair and regeneration.     

人血小板源性生长因子B基因的体外扩增以及克隆和鉴定

目的：自行构建人血小板源性生长因子B（PDGF-B）真核表达载体，为人血小板源性生长因子B基因转染真核细胞的实验研究及基因治疗奠定基础。方法：实验于2002-01／2005-01在青岛大学医学院附属医院中心实验室完成。①根据GeIlbank的人血小板源性生长因子B的全长基因序列，设计合成一对附加BamHⅠ，XhoⅠ两个限制性内切酶酶切位点的特异性引物。②采用反转录聚合酶链反应从人胎盘mRNA中扩增出人血小板源性生长因子B基因片段，将其插入真核表达载体PcDNA4构建成重组真核表达载体PcDNA4／PDGF-B。⑧经测序鉴定后，再用双酶切和聚合酶链反应对插入片段进行分析和验证。结果：反转录-聚合酶链反应产物经琼脂糖电泳结果显示在预期位置有相对分子质量为725bp的特异性扩增带。②序列分析、双酶切和聚合酶链反应结果证实插入片段序列正确。结论：成功扩增出完整的人血小板源性生长因子B基因，构建了基因重组真核表达载体PcDNA4／PDGF-B。为人及动物细胞的转基因研究，在基因水平改变其遗传性状打下基础。     

人血小板源性生长因子B基因的体外扩增以及克隆和鉴定

目的:自行构建人血小板源性生长因子B(PDGF-B)真核表达载体,为人血小板源性生长因子B基因转染真核细胞的实验研究及基因治疗奠定基础。方法:实验于2002-01/2005-01在青岛大学医学院附属医院中心实验室完成。①根据Genbank的人血小板源性生长因子B的全长基因序列,设计合成一对附加BamHⅠ,XhoⅠ两个限制性内切酶酶切位点的特异性引物。②采用反转录聚合酶链反应从人胎盘mRNA中扩增出人血小板源性生长因子B基因片段,将其插入真核表达载体PcDNA4构建成重组真核表达载体PcDNA4/PDGF-B。③经测序鉴定后,再用双酶切和聚合酶链反应对插入片段进行分析和验证。结果:反转录-聚合酶链反应产物经琼脂糖电泳结果显示在预期位置有相对分子质量为725bp的特异性扩增带。②序列分析、双酶切和聚合酶链反应结果证实插入片段序列正确。结论:成功扩增出完整的人血小板源性生长因子B基因,构建了基因重组真核表达载体PcDNA4/PDGF-B。为人及动物细胞的转基因研究,在基因水平改变其遗传性状打下基础。     

Smads介导转化生长因子β1信号转导通路与病理性瘢痕

背景：有研究表明转化生长因子β1既能促进创伤愈合又是刺激瘢痕增生的主要生长因子,而转化生长因子β1及其胞内转化生长因子β1/Smads信号转导途径与瘢痕形成存在重要关系。目的：通过研究瘢痕形成过程中转化生长因子β1/Smads信号转导途径进一步探讨瘢痕发生的分子机制。方法：以＂瘢痕、转化生长因子β1、Smad蛋白＂为关键词通过计算机检索分别检索CNKI数据库（http：//epub.cnki.net/grid2008/index/ZKCALD.htm）;维普数据库（http：//www.cqvip.com/）;Pubmed数据库（http：//www.ncbi.nlm.nih.gov/pubmed/）,选择1995年10月至2011年10月相关文献,筛选出主要论述瘢痕形成及转化生长因子β1/Smads信号转导通路并于近期发表在国内外权威期刊的相关文章。结果与结论：共纳入相关文献27篇,经整理分析后认为转化生长因子β1/Smads信号转导通路参与瘢痕形成,通过干预该途径的各环节可导致病理性瘢痕的发生。信号转导是转化生长因子β1发挥生物学功能的基本途径,所以更加深入研究转化生长因子β1信号转导及其调节可进一步补充瘢痕发生机制,以此为理论基础有利于应用生物工程等先进手段从分子水平干预瘢痕形成过程,使细胞能适时适度增殖、分化、凋亡及发挥功能,使创伤愈合更加理想。     

Biology of platelet-derived growth factor and its involvement in disease

Platelet-derived growth factor (PDGF) is mainly believed to be an important mitogen for connective tissue, especially for fibroblasts that serve in wound healing. However, PDGF also has important roles during embryonal development, and its overexpression has been linked to different types of fibrotic disorders and malignancies. Platelet-derived growth factor is synthesized by many different cell types, and its expression is broad. Its synthesis is in response to external stimuli, such as exposure to low oxygen tension, thrombin, or stimulation by other cytokines and growth factors. In addition, PDGF may function in autocrine stimulation of tumor cells, regulation of interstitial fluid pressure, and angiogenesis. Recently, several drugs were developed that are potent inhibitors of the tyrosine kinase activity of PDGF receptors. Thus, it is important to understand the physiology of PDGF and its receptors and the role of PDGF in different diseases. This review summarizes the physiologic activity of PDGF, the expression of PDGF during embryonal development, and the roles of PDGF expression in nonmalignant disease and in different tumors.     

Modulation of platelet-derived growth factor receptor expression in microvascular endothelial cells during in vitro angiogenesis.

Microvascular endothelial cells in vivo exhibit a plastic phenotype, forming a nonproliferative, differentiated capillary network, while retaining their ability to respond to injury by proliferation, migration and neovascularization. The presence of PDGF receptors and PDGF responsiveness in microvascular endothelial cells and the significance of PDGF isoforms in the control of endothelial cell growth and differentiation remain controversial. Since culture of microvascular endothelial cells in a three-dimensional (3D) system induced cell differentiation and angiogenesis and inhibited proliferation, the present study investigates the role of different extracellular matrix environments in inducing different microvascular endothelial cell phenotypes on microvascular endothelial cell PDGF receptor expression and PDGF responsiveness. In conventional two-dimensional (2D) culture, microvascular endothelial cells expressed both PDGF receptor alpha and beta chains. Suramin treatment demonstrated continuous downregulation of the alpha receptor surface expression. PDGF BB and, to a lesser extent, PDGF AB were mitogenic in 2D-culture, PDGF AA failed to induce any proliferative response despite inducing receptor autophosphorylation. During in vitro angiogenesis induced by 3D-culture, both PDGF receptors were rapidly downregulated. Assessment of cell proliferation showed quiescent cells and PDGF unresponsiveness. We conclude that the induction of a differentiated phenotype during in vitro angiogenesis (tube formation) driven in part by the spatial organization of the surrounding matrix is associated with a downregulation of PDGF receptors. Identification of the molecular cell-matrix interactions involved in this receptor regulation may allow for targeted manipulation of cell growth in vivo and lead to novel therapeutic applications for PDGF.