T F Deuel

The Scripps Research Institute, لا هویا, California, United States

Are you T F Deuel?

Claim your profile

Publications (163)1178.95 Total impact

  • Thomas F Deuel
    [Show abstract] [Hide abstract]
    ABSTRACT: Anaplastic Lymphoma Kinase is essential in early development, differentiation, and maintenance of cell survival; nevertheless, the mechanism to activate ALK has remained elusive. ALK has remained an "orphan receptor." The studies cited below describe a unique mechanism termed "Ligand Independent Activation." It is shown activation of ALK results when the cytokine Pleiotrophin (PTN) interacts with its receptor, the Receptor Protein Tyrosine Phosphatase β/ζ (RPTPβ/ζ). Pleiotrophin inactivates the catalytic activity of RPTPβ/ζ, which, when not inactivated, dephosphorylates phosphotyrosine sites in the activation domain of ALK; as a consequence of the inactivation of RPTPβ/ζ by PTN, autophosphorylation and autoactivation of ALK rapidly follow. The PTN/RPTPβ/ζ Signaling Pathway thus regulates the catalytic activity of ALK and tyrosine phosphorylation levels of ALK downstream target proteins. Furthermore, since ALK is only one of the ALK several phosphoproteins targeted by the PTN/RPTPβ/ζ Signaling Pathway, the PTN/RPTPβ/ζ Signaling Pathway has the potential to coordinately regulate tyrosine phosphorylation of other different key proteins in multiple cellular compartments. This article is part of a Special Issue entitled: Emerging recognition and activation mechanisms of receptor tyrosine kinases.
    Biochimica et Biophysica Acta 06/2013; 1834(10). DOI:10.1016/j.bbapap.2013.06.004 · 4.66 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Pleiotrophin (PTN) is an extracellular matrix-associated growth factor and chemokine expressed in mesodermal and ectodermal cells. It plays an important role in osteoblast recruitment and differentiation. There is limited information currently available about PTN expression during odontoblast differentiation and tooth formation, and thus the authors aimed to establish the spatiotemporal expression pattern of PTN during mouse odontogenesis. Immortalized mouse dental pulp (MD10-D3, MD10-A11) and odontoblast-like (M06-G3) and ameloblast-like (EOE-3M) cell lines were grown and samples prepared for immunocytochemistry, Western blot, and conventional and quantitative PCR analysis. Effects of BMP2, BMP4, and BMP7 treatment on PTN expression in odontoblast-like M06-G3 cells were tested by quantitative PCR. Finally, immunohistochemistry of sectioned mice mandibles and maxillaries at developmental stages E16, E18, P1, P6, P10, and P28 was performed. The experiments showed that PTN, at both the mRNA and protein level, was expressed in all tested epithelial and mesenchymal dental cell lines and that the level of PTN mRNA was influenced differentially by the bone morphogenetic proteins. The authors observed initial expression of PTN in the inner enamel epithelium with prolonged expression in the ameloblasts and odontoblasts throughout their stages of maturation and strong expression in the terminally differentiated and enamel matrix-secreting ameloblasts and odontoblasts of the adult mouse incisors and molars.
    Journal of Histochemistry and Cytochemistry 02/2012; 60(5):366-75. DOI:10.1369/0022155412439316 · 2.40 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Pleiotrophin (PTN; HB-GAM, OSF-1) is a secreted heparin-binding protein that effects osteoblast differentiation and recruitment. PTN and its receptor (protein tyrosine phosphatase beta/zeta) were found to be required for postnatal bone development (Imai et al. (2009) Bone 44: 785-794 and Schinke et al. (2008) Bone 42: 524-34). PTN deficiency results in a late stage developmental change in bone growth (mostly weight-bearing long bones). This indicates the osteogenic effect of PTN may be linked to mechanical stress in bones and be involved in mediating usage-dependent bone formation. Objectives: Investigate the expression of PTN in mice teeth to determine whether PTN plays a role in tooth usage-dependent mechanical stress response. Methods: Wildtype and PTN null mice were analyzed for gross tooth morphological and mineralization defects by high-resolution radiography, micro-computed tomography, and histology. Mouse pulp (MD10D3, MD10A11), odontoblast (MO6-G3), and ameloblast (MEOE-3M) cell lines were grown and collected for RT-PCR analysis, immunohistochemistry, and Western blot analysis. Results: PTN (mRNA and protein) was expressed in both epithelial/mesenchymal dental cells at different levels. Immunohistochemistry revealed initial PTN expression in inner enamel epithelium (E-16) with prolonged expression in ameloblasts throughout their maturation (days 1-10 postnatal). PTN was expressed at lower levels in the dental pulp (E-16) with increased staining associated with odontoblast cytodifferentation. Staining was seen within sub-populations of the stellate reticulum, the dental follicle and the periodontal ligament (PDL). Extended staining was observed in the odontoblasts, ameloblasts, at the dentino-enamel junction, and the enamel in 1 month old incisors. Molars showed staining at the odontoblasts/predentin surface, in the PDL, and alveolar bone. Conclusions: These studies demonstrate PTN is expressed during tooth development. Localization of PTN within the PDL and odontoblasts (mechanio-sensing cells) may indicate that PTN is involved in the production of dentin and enamel upon mechanical stress associated with incisor wear. Support: NIDCR/(HE), NIDCR/T35-HL007473(MM).
    AADR Annual Meeting 2010; 03/2010
  • [Show abstract] [Hide abstract]
    ABSTRACT: Pleiotrophin (PTN), a neurotrophic factor with important roles in survival and differentiation of dopaminergic neurons, is up-regulated in the nucleus accumbens after amphetamine administration suggesting that PTN could modulate amphetamine-induced pharmacological or neuroadaptative effects. To test this hypothesis, we have studied the effects of amphetamine administration in PTN genetically deficient (PTN -/-) and wild type (WT, +/+) mice. In conditioning studies, we found that amphetamine induces conditioned place preference in both PTN -/- and WT (+/+) mice. When these mice were re-evaluated after a 5-day period without amphetamine administration, we found that WT (+/+) mice did not exhibit amphetamine-seeking behaviour, whereas, PTN -/- mice still showed a robust drug-seeking behaviour. In immunohystochemistry studies, we found that amphetamine (10 mg/kg, four times, every 2 hours) causes a significant increase of glial fibrillary acidic protein positive cells in the striatum of amphetamine-treated PTN -/- mice compared with WT mice 4 days after last administration of the drug, suggesting an enhanced amphetamine-induced astrocytosis in the absence of endogenous PTN. Interestingly, we found in concomitant in vitro studies that PTN (3 µM) limits amphetamine (1 mM)-induced loss of viability of PC12 cell cultures, effect that could be related to the ability of PTN to induce the phosphorylation of Akt and ERK1/2. To test this possibility, we used specific Akt and ERK1/2 inhibitors uncovering for the first time that PTN-induced protective effects against amphetamine-induced toxicity in PC12 cells are mediated by the ERK1/2 signalling pathway. The data suggest an important role of PTN to limit amphetamine-induced neurotoxic and rewarding effects.
    Addiction Biology 02/2010; 15(4):403-12. DOI:10.1111/j.1369-1600.2009.00202.x · 5.93 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In light of evidence that macrophages participate in the local regulation of bone remodeling, we have examined the production of peptide stimulators of bone cell growth and specialization by the J774A.1 macrophage cell line. Cultured J774A.1 cells secrete growth-promoting activities which have an affinity for heparin. The first partially purified material, termed HEP I, appears to contain platelet-derived growth factor (PDGF)-like activity. It has a molecular weight of about 30,000 daltons, inhibits the binding of labeled PDGF to its receptors, reacts with polyclonal anti-human PDGF antibody, and exhibits mitogenic activity for osteoblasts, which is partially blocked by anti-PDGF antisera. Like PDGF, HEP I is active in a wide variety of mesenchyme-derived cells, including osteoblasts, chondrocytes, smooth muscle cells, fibroblasts, 3T3 cells and NRK cells. The J774A.1 cells contain mRNA, which hybridizes to a v-sis DNA probe, suggesting that they express the c-sis gene, which contains the code for a PDGF-like protein. The second factor, HEP II, has an approximate molecular weight of 20,000 daltons and possesses substantial mitogenic activity for osteoblasts, chondrocytes, and smooth muscle cells, but is not mitogenic for fibroblasts, 3T3 cells, and NRK cells. HEP II appears to be a unique bone cell mitogen, which is distinct from the growth factors presently known. Neither HEP I nor HEP II contained interleukin 1, a macrophage product known to promote bone resorption and perhaps the growth and activity of osteoblasts.
    Journal of Bone and Mineral Research 10/2009; 2(5):467-74. DOI:10.1002/jbmr.5650020515 · 6.59 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Pleiotrophin (PTN) is a growth factor that has been shown to be involved in hippocampal synaptic plasticity and learning. To further understand the involvement of PTN in memory processes, we performed in vitro electrophysiological studies in PTN-stimulated CA1 from rat hippocampal slices combined with the behavioural testing of PTN deficient (PTN - / - ) mice. We found that PTN inhibited hippocampal long-term potentiation (LTP) induced by high-frequency stimulation (HFS) consisted in three trains of 100 Hz separated by 20 s. To test the possibility that PTN might be involved in behavioural memory processes, we tested the learning behaviour of PTN - / - mice using the Y-maze test. We did not observe significant differences in recognition memory between PTN - / - and Wild Type (WT) mice when a 30 min-interval intertrial (ITI) was used in the Y-maze test. However, whereas WT mice showed disruption of recognition memory using a 60 min-ITI, PTN - / - mice maintained the recognition memory. The data demonstrate that PTN inhibits hippocampal LTP in vitro and might play a role in memory processes in vivo.
    Growth factors (Chur, Switzerland) 05/2009; 27(3):189-94. DOI:10.1080/08977190902906859 · 2.47 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Pleiotrophin (PTN) is an 18kDa heparin-binding protein expressed in mesodermal and ectodermal cells. It plays an important role in osteoblast differentiation and recruitment. Notably, when PTN is upregulated there is an increase in bone thickness. PTN binds to receptor protein tyrosine phosphatase beta/zeta, dimerizing and leading to increased tyrosine phosphorylation of beta-catenin, in addition to other proteins. Despite known effects of PTN on osteoblasts, there is limited information available about PTN involvement during tooth formation. Objectives: 1) to determine the expression of PTN in teeth; 2) determine the spatiotemporal expression pattern of PTN by immunohistochemistry; and 3) determine if PTN knock-out (KO) mice have a dental phenotype. Methods: Immortalized mouse dental pulp (MD10D3, MD10A11), odontoblast (MO6-G3) and ameloblast (3M-EOE) cell lines were grown and samples prepared for RT-PCR analysis, immunohistochemistry and Western blot analysis. PTN KO mice were analyzed for gross tooth morphological and mineralization defects by high resolution radiography, micro-computed tomography and histology as compared to age- and sex- matched wildtype animals. Results: PTN, at the mRNA and protein level, was expressed in both the epithelial and mesenchymal dental cell lines tested although at different levels. Immunohistochemistry reveal initial expression of PTN in the inner enamel epithelium (E-16) with prolonged expression in the ameloblasts throughout their stages of maturation (days 1-10 postnatal). PTN was also expressed at lower levels in the dental pulp mesenchyme (E-16) with increased staining associated with odontoblast cytodifferentation. Staining was also seen within sub-populations of the stellate reticulum, the dental follicle and the periodontal ligament. PTN KO mice showed a dramatic dentin phenotype with enlargement of the pulp chambers and decreased dentin mineralization. Conclusions: These studies demonstrate PTN is expressed during tooth development in both the ameloblasts and odontoblasts and plays a critical role in dentinogenesis. Support: NIDCR T35-HL007473 and UAB-SOD Faculty Development Grants (HE).
    IADR General Session 2009; 04/2009
  • [Show abstract] [Hide abstract]
    ABSTRACT: Enhanced angiogenesis is a hallmark of cancer. Pleiotrophin (PTN) is an angiogenic factor that is produced by many different human cancers and stimulates tumor blood vessel formation when it is expressed in malignant cancer cells. Recent studies show that monocytes may give rise to vascular endothelium. In these studies, we show that PTN combined with macrophage colony-stimulating factor (M-CSF) induces expression of vascular endothelial cell (VEC) genes and proteins in human monocyte cell lines and monocytes from human peripheral blood (PB). Monocytes induce VEC gene expression and develop tube-like structures when they are exposed to serum or cultured with bone marrow (BM) from patients with multiple myeloma (MM) that express PTN, effects specifically blocked with antiPTN antibodies. When coinjected with human MM cells into severe combined immunodeficient (SCID) mice, green fluorescent protein (GFP)-marked human monocytes were found incorporated into tumor blood vessels and expressed human VEC protein markers and genes that were blocked by anti-PTN antibody. Our results suggest that vasculogenesis in human MM may develop from tumoral production of PTN, which orchestrates the transdifferentiation of monocytes into VECs.
    Blood 01/2009; 113(9):1992-2002. DOI:10.1182/blood-2008-02-133751 · 9.78 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: This study seeks to integrate recent studies that identify new critical mechanisms through which the 136 amino acid secreted heparin-binding cytokine pleiotrophin (PTN, Ptn) stimulates both normal and pathological angiogenesis. Pleiotrophin is directly angiogenic; it initiates an angiogenic switch in different cancer models in vivo. It acts as an angiogenic factor through multiple mechanisms that include a unique signaling pathway that activates newly identified downstream tyrosine kinases through a unique mechanism, an interaction with endothelial cells to initiate proliferation, migration, and tube formation, the regulation of basic fibroblast growth factor and vascular endothelial growth factor signaling, the remodeling of the stromal microenvironment, and induction of transdifferentiation of monocytes into endothelial cells. Recently also, domains of PTN that stimulate angiogenesis and peptides that function to inhibit PTN signaling have been identified. Recent studies have identified new mechanisms dependent on activation of the PTN signaling pathway that regulate angiogenesis and new targets to use PTN to both stimulate angiogenesis and block its activity to control pathological angiogenesis.
    Current Opinion in Hematology 06/2008; 15(3):210-4. DOI:10.1097/MOH.0b013e3282fdc69e · 4.05 Impact Factor
  • Thomas F Deuel
    Current Opinion in Hematology 06/2008; 15(3):196. DOI:10.1097/MOH.0b013e3282fdc6b0 · 4.05 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Pleiotrophin (PTN) and midkine (MK) are two growth factors highly redundant in function that exhibit neurotrophic actions and are upregulated at sites of nerve injury, both properties being compatible with a potential involvement in the pathophysiological events that follow nerve damage (i.e. neuropathic pain). We have tested this hypothesis by comparatively studying PTN and MK gene expression in the spinal cord and dorsal root ganglia (DRG) of three rat strains known to differ in their behavioural responses to chronic constriction injury (CCI) of the sciatic nerve: Lewis, Fischer 344 (F344) and Sprague-Dawley (SD). Real time RT-PCR revealed minimal changes in PTN/MK gene expression in the spinal cord after CCI despite the strain considered, but marked changes were detected in DRG. A significant upregulation of PTN gene expression occurred in injured DRG of the F344 strain, the only strain that recovers from CCI-induced mechanical allodynia 28 days after surgery. In contrast, PTN was found to be downregulated in injured DRG of SD rats, the most sensitive strain in behavioural studies. These changes in PTN were not paralleled by concomitant modifications of MK gene expression. The results demonstrate previously unidentified differences between PTN and MK patterns of expression. Furthermore, the data suggest that upregulation of PTN, but not MK, could play an important role in the recovery from CCI.
    Growth Factors 03/2008; 26(1):44-8. DOI:10.1080/08977190801987711 · 3.09 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Increasing evidence suggests mutations in human breast cancer cells that induce inappropriate expression of the 18-kDa cytokine pleiotrophin (PTN, Ptn) initiate progression of breast cancers to a more malignant phenotype. Pleiotrophin signals through inactivating its receptor, the receptor protein tyrosine phosphatase (RPTP)beta/zeta, leading to increased tyrosine phosphorylation of different substrate proteins of RPTPbeta/zeta, including beta-catenin, beta-adducin, Fyn, GIT1/Cat-1, and P190RhoGAP. PTN signaling thus has wide impact on different important cellular systems. Recently, PTN was found to activate anaplastic lymphoma kinase (ALK) through the PTN/RPTPbeta/zeta signaling pathway; this discovery potentially is very important, since constitutive ALK activity of nucleophosmin (NPM)-ALK fusion protein is causative of anaplastic large cell lymphomas, and, activated ALK is found in other malignant cancers. Recently ALK was identified in each of 63 human breast cancers from 22 subjects. We now demonstrate that RPTPbeta/zeta is expressed in each of these same 63 human breast cancers that previously were found to express ALK and in 10 additional samples of human breast cancer. RPTPbeta/zeta furthermore was localized not only in its normal association with the cell membrane but also scattered in cytoplasm and in nuclei in different breast cancer cells and, in the case of infiltrating ductal carcinomas, the distribution of RPTPbeta/zeta changes as the breast cancer become more malignant. The data suggest that the PTN/RPTPbeta/zeta signaling pathway may be constitutively activated and potentially function to constitutively activate ALK in human breast cancer.
    Biochemical and Biophysical Research Communications 11/2007; 362(1):5-10. DOI:10.1016/j.bbrc.2007.06.050 · 2.28 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Pleiotrophin (PTN, Ptn) is a widely expressed, developmentally regulated 136 amino acid secreted heparin-binding cytokine. It signals through a unique signaling pathway; the PTN receptor is the transmembrane receptor protein tyrosine phosphatase (RPTP)beta/zeta. RPTPbeta/zeta is inactivated by PTN, which leads to increased tyrosine phosphorylation of the downstream targets of the PTN/RPTPbeta/zeta signaling pathway. Pleiotrophin gene expression is found in cells in early differentiation during different developmental periods. It is upregulated in cells with an early differentiation phenotype in wound repair. The Ptn gene also is a proto-oncogene; PTN is expressed in human tumor cells, and, in cell lines derived from human tumors that express Ptn, Ptn expression is constitutive and thus "inappropriate". Importantly, properties of different cells induced by PTN in PTN-stimulated cells are strikingly similar to properties of highly malignant cells. Furthermore, transformed cells into which Ptn is introduced undergo "switches" to malignant cells of higher malignancy with properties that are strikingly similar to properties of PTN-stimulated cells. These unique features of PTN support the conclusion that constitutive PTN signaling in malignant cells that inappropriately express Ptn functions as a potent tumor promoter. Recently, in confirmation, Ptn targeted by the mouse mammary tumor virus (MMTV) promoter in a transgenic mouse model was found to promote breast cancers to a more aggressive breast cancer cell phenotype that morphologically closely resembles scirrhous carcinoma in human; in addition, it promoted a striking increase in tumor angiogenesis and a remarkable degree of remodeling of the micro-environment. Pleiotrophin thus regulates both different normal and pathological functions; collectively, the different studies have uncovered the unique ability of a single cytokine PTN, which signals through the unique PTN/RPTPbeta/zeta signaling pathway, to induce the many properties associated with tumor promotion in the malignant cells that constitutively express Ptn and in their microenvironment.
    Cell cycle (Georgetown, Tex.) 10/2007; 6(23):2877-83. DOI:10.4161/cc.6.23.5090 · 5.24 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) first discovered as the constitutively active nucleophosmin-ALK oncoprotein in anaplastic large cell lymphomas (ALCL). Full-length ALK has a critical role in normal development and differentiation. Activated full-length ALK also is found in different malignant cancers. Nevertheless, the ligand to activate ALK remained unknown until recently, when ALK was proposed to be the physiological receptor of the cytokine pleiotrophin (PTN, Ptn). However, earlier studies had demonstrated that receptor protein tyrosine phosphatase (RPTP) beta/zeta is a physiological PTN receptor. We now demonstrate that phosphorylation of ALK in PTN-stimulated cells is mediated through the PTN/RPTPbeta/zeta signaling pathway. ALK is phosphorylated independently of a direct interaction of PTN with ALK. The data thus support a unique model of ALK activation. In cells not stimulated by PTN, RPTPbeta/zeta dephosphorylates ALK at the site(s) in ALK that is undergoing autophosphorylation through autoactivation. In contrast, when RPTPbeta/zeta is inactivated in PTN-stimulated cells, the sites that are autophosphorylated in ALK no longer can be dephosphorylated by RPTPbeta/zeta; thus, autoactivation and tyrosine phosphorylation of ALK rapidly increase. The data indicate that the PTN/RPTPbeta/zeta signaling pathway is a critical regulator of the steady state levels of tyrosine phosphorylation and activation of ALK; the data support the conclusion that ALK phosphorylation and activation in PTN-stimulated cells are increased through a unique "alternative mechanism of RTK activation."
    Journal of Biological Chemistry 10/2007; 282(39):28683-90. DOI:10.1074/jbc.M704505200 · 4.60 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Pleiotrophin (PTN) is an important developmental cytokine that is highly expressed during embryogenesis but shows very limited expression in adult tissues, where it is largely restricted to the brain. High PTN serum levels are associated with a variety of solid tumors. We recently showed that patients with multiple myeloma (MM) also have elevated serum levels of this protein and the amount of PTN correlated with the patients' disease status and response to treatment. In this study, we demonstrate that MM cell lines and the malignant cells from MM patients' bone marrow produced PTN and secreted PTN protein into the supernatants during short-term culture. Moreover, Ptn gene expression correlated with the patients' disease status. Inhibition of PTN with a polyclonal anti-PTN antibody reduced growth and enhanced apoptosis of MM cell lines and freshly isolated bone marrow tumor cells from MM patients in vitro. Importantly, this antibody also markedly suppressed the growth of MM in vivo using a severe combined immunodeficiency (SCID)-hu murine model. This represents the first study showing the importance of PTN in the growth of any hematological disorder. Because the expression of this protein is very limited in normal adult tissues, PTN may represent a new target for the treatment of MM.
    Blood 08/2007; 110(1):287-95. DOI:10.1182/blood-2006-08-042374 · 9.78 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Pleiotrophin (PTN, Ptn) is an 18kDa cytokine expressed in human breast cancers. Since inappropriate expression of Ptn stimulates progression of breast cancer in transgenic mice and a dominant negative PTN reverses the transformed phenotype of human breast cancer cells that inappropriately express Ptn, it is suggested that constitutive PTN signaling in breast cancer cells that inappropriately express Ptn activates pathways that promote a more aggressive breast cancer phenotype. Pleiotrophin signals by inactivating its receptor, the receptor protein tyrosine phosphatase (RPTP)beta/zeta, and, recently, PTN was found to activate anaplastic lymphoma kinase (ALK) through the PTN/RPTPbeta/zeta signaling pathway in PTN-stimulated cells, not through a direct interaction of PTN with ALK and thus not through the PTN-enforced dimerization of ALK. Since full-length ALK is activated in different malignant cancers and activated ALK is a potent oncogenic protein, we examined human breast cancers to test the possibility that ALK may be expressed in breast cancers and potentially activated through the PTN/RPTPbeta/zeta signaling pathway; we now demonstrate that ALK is strongly expressed in different histological subtypes of human breast cancer; furthermore, ALK is expressed in both nuclei and cytoplasm and, in the ;;dotted" pattern characteristic of ALK fusion proteins in anaplastic large cell lymphoma. This study thus supports the possibility that activated ALK may be important in human breast cancers and potentially activated either through the PTN/RPTPbeta/zeta signaling pathway, or, alternatively, as an activated fusion protein to stimulate progression of breast cancer in humans.
    Biochemical and Biophysical Research Communications 07/2007; 358(2):399-403. DOI:10.1016/j.bbrc.2007.04.137 · 2.28 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Pleiotrophin (PTN, Ptn) is an 18-kDa secretory cytokine expressed in many breast cancers; however, the significance of Ptn expression in breast cancer has not been established. We have now tested three models to determine the role of inappropriate expression of Ptn in breast cancer. Mouse mammary tumor virus (MMTV) promoter-driven Ptn expressed in MMTV-polyoma virus middle T antigen (PyMT)-Ptn mouse breast cancers was first shown to induce rapid growth of morphologically identified foci of "scirrhous" carcinoma and to extensively remodel the microenvironment, including increased tumor angiogenesis and striking increases in mouse protocollagens Ialpha2, IValpha5, and XIalpha1, and elastin. Ectopic Ptn expression in MCF-7 (human breast cancer)-Ptn cell xenografts also was shown to markedly increase MCF-7-Ptn cell xenograft growth in nude mice; furthermore, it induced extensive remodeling of the microenvironment and tumor angiogenesis. In a coculture model of equal numbers of NIH 3T3 stromal fibroblasts and MCF-7-Ptn cells, PTN secreted from MCF-7-Ptn cells was then shown to induce a more malignant MCF-7-Ptn breast cancer cell phenotype and extensive remodeling of the MCF-7-Ptn/NIH 3T3 cell microenvironment; it up-regulated expression of markers of aggressive breast cancers, including PKCdelta and matrix metalloproteinase-9 in both MCF-7-Ptn and NIH 3T3 cells. The morphological phenotypes of MCF-7-Ptn cell xenografts and MCF-7-Ptn cell/NIH 3T3 cell cocultures closely resembled breast cancers in MMTV-PyMT-Ptn mice. Inappropriate expression of Ptn thus promotes breast cancer progression in mice; the data suggest that secretion of PTN through stimulation of the stromal cell microenvironment alone may be sufficient to account for significant features of breast cancer progression.
    Proceedings of the National Academy of Sciences 07/2007; 104(26):10888-93. DOI:10.1073/pnas.0704366104 · 9.81 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Pleiotrophin and midkine are two recently discovered growth factors that promote survival and differentiation of catecholaminergic neurons. Chronic opioid stimulation has been reported to induce marked alterations of the locus coeruleus-hippocampus noradrenergic pathway, an effect that is prevented when opioids are coadministered with the alpha2-adrenoceptor antagonist yohimbine. The present work tries to examine a possible link between yohimbine reversal of morphine effects and pleiotrophin/midkine activation in the rat hippocampus by studying the levels of expression of pleiotrophin and midkine in response to acute and chronic administration of morphine, yohimbine and combinations of both drugs. Pleiotrophin gene expression was not altered by any treatment; however midkine mRNA levels were increased after chronic treatment with morphine. Chronic administration of yohimbine alone also increased midkine expression levels, whereas yohimbine and morphine administered together exhibited summatory effects on the upregulation of midkine expression levels. The data suggest that midkine could play a role in the prevention of opioid-induced neuroadaptations in hippocampus by yohimbine.
    European Journal of Pharmacology 03/2007; 557(2-3):147-50. DOI:10.1016/j.ejphar.2006.11.024 · 2.68 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The alpha(2)-adrenoceptor antagonist yohimbine is known to oppose to several pharmacological effects of opioid drugs, but the consequences and the mechanisms involved remain to be clearly established. In the present study we have checked the effects of yohimbine on morphine-induced alterations of the expression of key proteins (glial fibrillary acidic protein, GFAP) and genes (alpha(2)-adrenoceptors) in rat brain areas known to be relevant in opioid dependence, addiction and individual vulnerability to drug abuse. Rats were treated with morphine in the presence or absence of yohimbine. The effects of the treatments on GFAP expression were studied by immunohistochemical staining in Locus Coeruleus (LC) and Nucleus of the Solitary Tract (NST), two important noradrenergic nuclei. In addition, drug effects on alpha(2)-adrenoceptor gene expression were determined by real time RT-PCR in the hippocampus, a brain area that receives noradrenergic input from the brainstem. Morphine administration increased GFAP expression both in LC and NST as it was previously reported in other brain areas. Yohimbine was found to efficiently prevent morphine-induced GFAP upregulation. Chronic (but not acute) morphine downregulated mRNA levels of alpha(2A)- and alpha(2C)-adrenoceptors in the hippocampus, while simultaneously increased the expression of the alpha(2B)-adrenoceptor gene. Again, yohimbine was able to prevent morphine-induced changes in the levels of expression of the three alpha(2)-adrenoceptor genes. These results correlate the well-established reduction of opioid dependence and addiction by yohimbine and suggest that this drug could interfere with the neural plasticity induced by chronic morphine in central noradrenergic pathways.
    Neuroscience Letters 02/2007; 412(2):163-7. DOI:10.1016/j.neulet.2006.11.002 · 2.06 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Pleiotrophin (PTN, Ptn) is an 18kDa secretory cytokine that is expressed in many human cancers, including glioblastoma. In previous experiments, interruption of the constitutive PTN signaling in human U87MG glioblastoma cells that inappropriately express endogenous Ptn reversed their rapid growth in vitro and their malignant phenotype in vivo. To seek a mechanism for the effect of the dominant-negative PTN, flow cytometry was used to compare the profiles of U87MG cells and four clones of U87MG cells that express the dominant-negative PTN (U87MG/PTN1-40 cells); here, we report that the dominant-negative PTN in U87MG cells induces tetraploidy and aneuploidy and arrests the tetraploid and aneuploid cells in the G1 phase of the cell cycle. The data suggest that PTN signaling may have a critical role in chromosomal segregation and cell cycle progression; the data suggest induction of tetraploidy and aneuploidy in U87MG glioblastoma cells may be an important mechanism that contributes to the loss of the malignant phenotype of U87MG cells.
    Biochemical and Biophysical Research Communications 01/2007; 351(2):336-9. DOI:10.1016/j.bbrc.2006.09.148 · 2.28 Impact Factor

Publication Stats

11k Citations
1,178.95 Total Impact Points


  • 2004–2013
    • The Scripps Research Institute
      • Department of Molecular and Experimental Medicine
      لا هویا, California, United States
  • 1978–2009
    • Washington University in St. Louis
      • • Division of Hematology and oncology
      • • Department of Medicine
      • • Department of Biochemistry and Molecular Biophysics
      • • Division of Biology and Biomedical Sciences
      Saint Louis, MO, United States
  • 2007
    • University Foundation San Pablo CEU
      Madrid, Madrid, Spain
  • 1997–2002
    • Beth Israel Deaconess Medical Center
      • Department of Medicine
      Boston, Massachusetts, United States
  • 1997–1999
    • Harvard University
      Cambridge, Massachusetts, United States
  • 1988–1996
    • Barnes Jewish Hospital
      San Luis, Missouri, United States
  • 1995
    • Wayne State University
      • Department of Pathology
      Detroit, MI, United States
  • 1993
    • University of Illinois at Chicago
      Chicago, Illinois, United States
  • 1990
    • St. Luke's Hospital (MO, USA)
      Saint Louis, Michigan, United States
  • 1983–1989
    • University of Missouri - St. Louis
      Saint Louis, Michigan, United States