David A Cheresh

University of California, San Diego, San Diego, California, United States

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Publications (284)2874.34 Total impact

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    Preview · Article · Jan 2003
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    Dwayne G Stupack · David A Cheresh
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    ABSTRACT: Programmed cell death is crucial for the development and maintenance of multicellular organisms. The decision to live, or to die, depends, at the cellular level, upon the cell's interaction with extracellular cues that trigger cell signaling pathways promoting survival or death. The extracellular matrix (ECM) influences the execution of the apoptotic program through the actions of adhesion receptors. Among these, integrins initiate a variety of downstream signaling events in response to ECM ligation. Integrins directly activate survival pathways via the PI 3-kinase and MAPK pathways and act as essential cofactors for their stimulation by growth factors. Conversely, elevated integrin expression in the absence of appropriate ligands, or in the presence of natural or synthetic antagonists, can promote apoptosis under otherwise permissive growth conditions. Integrins thus act in a crucial biosensory role, coordinating survival or death responses as a function of ECM composition. This dual function provides an elegant mechanism through which tissue-remodeling events may regulate cell death or survival in a temporal, ECM-governed manner.
    Full-text · Article · Nov 2002 · Journal of Cell Science
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    ABSTRACT: The first step of protein synthesis is catalyzed by aminoacyl-tRNA synthetases. In addition, certain mammalian tRNA synthetases link protein synthesis to cytokine signaling pathways. In particular, human tyrosyl-tRNA synthetase (TyrRS) can be split by proteolysis into two fragments having distinct cytokine activities. One of the TyrRS fragments (mini TyrRS) contains features identical to those in CXC chemokines (like interleukin-8) that also act as angiogenic factors. Here mini TyrRS (but not full-length TyrRS) is shown to stimulate chemotaxis of endothelial cells in vitro and stimulate angiogenesis in each of two in vivo animal models. The angiogenic activity of mini TyrRS can be opposed by anti-angiogenic chemokines like IP-10. Thus, a biological fragment of human tyrosyl-tRNA synthetase links protein synthesis to regulation of angiogenesis.
    Preview · Article · Jul 2002 · Journal of Biological Chemistry
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    ABSTRACT: Efforts to influence the biology of blood vessels by gene delivery have been hampered by a lack of targeting vectors specific for endothelial cells in diseased tissues. Here we show that a cationic nanoparticle (NP) coupled to an integrin alphavbeta3-targeting ligand can deliver genes selectively to angiogenic blood vessels in tumor-bearing mice. The therapeutic efficacy of this approach was tested by generating NPs conjugated to a mutant Raf gene, ATPmu-Raf, which blocks endothelial signaling and angiogenesis in response to multiple growth factors. Systemic injection of the NP into mice resulted in apoptosis of the tumor-associated endothelium, ultimately leading to tumor cell apoptosis and sustained regression of established primary and metastatic tumors.
    Full-text · Article · Jul 2002 · Science
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    ABSTRACT: Vascular endothelial growth factor (VEGF) promotes vascular permeability (VP) and neovascularization, and is required for development. We find that VEGF-stimulated Src activity in chick embryo blood vessels induces the coupling of focal adhesion kinase (FAK) to integrin alpha(v)beta5, a critical event in VEGF-mediated signaling and biological responsiveness. In contrast, FAK is constitutively associated with beta1 and beta3 integrins in the presence or absence of growth factors. In cultured endothelial cells, VEGF, but not basic fibroblast growth factor, promotes the Src-mediated phosphorylation of FAK on tyrosine 861, which contributes to the formation of a FAK/alpha(v)beta5 signaling complex. Moreover, formation of this FAK/alpha(v)beta5 complex is significantly reduced in pp60c-src-deficient mice. Supporting these results, mice deficient in either pp60c-src or integrin beta5, but not integrin beta3, have a reduced VP response to VEGF. This FAK/alpha(v)beta5 complex was also detected in epidermal growth factor-stimulated epithelial cells, suggesting a function for this complex outside the endothelium. Our findings indicate that Src can coordinate specific growth factor and extracellular matrix inputs by recruiting integrin alpha(v)beta5 into a FAK-containing signaling complex during growth factor-mediated biological responses.
    Full-text · Article · May 2002 · The Journal of Cell Biology
  • Glen R Nemerow · David A Cheresh
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    ABSTRACT: Human herpesvirus 8 (HHV-8), an agent associated with Kaposi's sarcoma, binds to integrin alpha(3)beta(1) through its gB envelope glycoprotein, and thus gains entry into human fibroblasts. Based on an analogy with other microbial pathogens, integrin interaction with HHV-8 may induce signalling events that promote cell entry and perhaps facilitate disease progression.
    No preview · Article · May 2002 · Nature Cell Biology
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    ABSTRACT: PAK1 is a protein kinase downstream of the small GTPases Rac and Cdc42 that previous work has implicated in endothelial cell migration via modulation of cell contraction. The first proline-rich region of PAK that binds to an SH3 domain from the adapter protein NCK was responsible for these dominant-negative effects. To test the role of PAK in angiogenesis, we prepared a peptide in which the proline-rich region was fused to the polybasic sequence from the HIV Tat protein to facilitate entry into cells. We show that the short peptide selectively binds NCK, whereas a mutant peptide does not. Treatment of cells with the PAK peptide but not the control peptide disrupts localization of PAK. This peptide specifically inhibited endothelial cell migration and contractility similarly to full-length dominant-negative PAK. In an in vitro tube-forming assay, the PAK peptide specifically blocked formation of multicellular networks. In an in vivo chick chorioallantoic membrane assay, the PAK peptide specifically blocked angiogenesis. These results, therefore, suggest a role for PAK in angiogenesis.
    Full-text · Article · May 2002 · Circulation Research
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    ABSTRACT: αv-Integrin antagonists block neovascularization in various species, whereas 20% of αv-integrin null mice are born with many normal looking blood vessels. Given that blockade of αv-integrins during angiogenesis induces p53 activity, we utilized p53 null mice to elucidate whether loss of p53 can compensate for αv-integrin function in neovascularization of the retina. Murine retinal vascularization was inhibited by systemic administration of an αv-integrin antagonist. In contrast, mice lacking p53 were refractory to this treatment, indicating that neovascularization in normal mice depends on αv-integrin-mediated suppression of p53. Blockade of αv-integrins during neovascularization resulted in an induction of p21CIP1 in wild type and, surprisingly, in p53 null retinas, indicating that αv-integrin ligation regulates p21CIP1 levels in a p53-independent manner. In conclusion, we demonstrate for the first time an in vivointracellular mechanism for compensation of integrin function and that p53 and αv-integrins act in concert during retinal neovascularization.
    Full-text · Article · May 2002 · Journal of Biological Chemistry
  • David A Cheresh · Dwayne G Stupack

    No preview · Article · Apr 2002 · Nature Medicine
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    Dwayne G Stupack · David A Cheresh
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    ABSTRACT: The process of angiogenesis is a dynamic one. Vascular endothelial cells are changing at the same time the extracellular matrix is being remodeled. Stupack and Cheresh discuss how remodeling of the extracellular matrix (ECM) and changes in the endothelial cell protein production and integrin expression contribute to the complex process of new blood vessel growth from an existing vascular bed.
    Full-text · Article · Mar 2002 · Science s STKE
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    John D Hood · David A Cheresh
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    ABSTRACT: As cancer cells undergo metastasis--invasion and migration of a new tissue--they penetrate and attach to the target tissue's basal matrix. This allows the cancer cell to pull itself forward into the tissue. The attachment is mediated by cell-surface receptors known as integrins, which bind to components of the extracellular matrix. Integrins are crucial for cell invasion and migration, not only for physically tethering cells to the matrix, but also for sending and receiving molecular signals that regulate these processes.
    Full-text · Article · Mar 2002 · Nature reviews. Cancer
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    ABSTRACT: Modulation of the balance between pro- and antiangiogenic factors holds great promise for the treatment of a broad spectrum of human disease ranging from ischemic heart disease to cancer. This requires both the identification of angiogenic regulators and their efficient delivery to target organs. Here, we demonstrate the use of a noncatalytic fragment of matrix metalloproteinase 2 (termed PEX) delivered by lentiviral vectors in different angiogenesis models. Transduction of human endothelial cells with PEX virus suppressed endothelial invasion and formation of capillary-like structures without affecting chemotaxis in vitro. Lentiviral delivery of PEX blocked basic fibroblast growth factor-induced matrix metalloproteinase 2 activation and angiogenesis on chicken chorioallantoic membranes. PEX expression also inhibited tumor-induced angiogenesis and tumor growth in a nude mouse model. Thus, our study shows that lentiviral vectors can deliver sufficient quantities of antiangiogenic substances to achieve therapeutic effects in vivo.
    No preview · Article · Feb 2002 · Annals of Hematology
  • J.D. HOOD · D.A. CHERESH

    No preview · Article · Feb 2002 · Cold Spring Harbor Symposia on Quantitative Biology
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    ABSTRACT: Aminoacyl-tRNA synthetases catalyze the first step of protein synthesis. It was shown recently that human tyrosyl-tRNA synthetase (TyrRS) can be split into two fragments having distinct cytokine activities, thereby linking protein synthesis to cytokine signaling pathways. Tryptophanyl-tRNA synthetase (TrpRS) is a close homologue of TyrRS. A natural fragment, herein designated as mini TrpRS, was shown by others to be produced by alternative splicing. Production of this fragment is reported to be stimulated by IFN-gamma, a cytokine that also stimulates production of angiostatic factors. Mini TrpRS is shown here to be angiostatic in a mammalian cell culture system, the chicken embryo, and two independent angiogenesis assays in the mouse. The full-length enzyme is inactive in the same assays. Thus, protein synthesis may be linked to the regulation of angiogenesis by a natural fragment of TrpRS.
    Full-text · Article · Feb 2002 · Proceedings of the National Academy of Sciences
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    ABSTRACT: Pathological angiogenesis contributes directly to profound loss of vision associated with many diseases of the eye. Recent work suggests that human tyrosyl- and tryptophanyl-tRNA synthetases (TrpRS) link protein synthesis to signal transduction pathways including angiogenesis. In this study, we show that a recombinant form of a COOH-terminal fragment of TrpRS is a potent antagonist of vascular endothelial growth factor-induced angiogenesis in a mouse model and of naturally occurring retinal angiogenesis in the neonatal mouse. The angiostatic activity is dose-dependent in both systems. The recombinant fragment is similar in size to one generated naturally by alternative splicing and can be produced by proteolysis of the full-length protein. In contrast, the full-length protein is inactive as an antagonist of angiogenesis. These results suggest that fragments of TrpRS, as naturally occurring and potentially nonimmunogenic anti-angiogenics, can be used for the treatment of neovascular eye diseases.
    Full-text · Article · Feb 2002 · Proceedings of the National Academy of Sciences
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    Preview · Article · Jan 2002
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    Brian P Eliceiri · David A Cheresh
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    ABSTRACT: Recent work from several laboratories indicates that the coordination of endothelial cell adhesion events with growth factor receptor inputs regulates endothelial cell responses during angiogenesis. Analyses of the signaling pathways downstream of integrins, cadherins and growth-factor receptors are providing an insight into the molecular basis of known anti-angiogenic strategies, as well as into the design of novel therapies.
    Full-text · Article · Nov 2001 · Current Opinion in Cell Biology
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    ABSTRACT: Integrin-mediated adhesion promotes cell survival in vitro, whereas integrin antagonists induce apoptosis of adherent cells in vivo. Here, we demonstrate that cells adherent within a three-dimensional extracellular matrix undergo apoptosis due to expression of unligated integrins, the beta subunit cytoplasmic domain, or its membrane proximal sequence KLLITIHDRKEF. Integrin-mediated death requires initiator, but not stress, caspase activity and is distinct from anoikis, which is caused by the loss of adhesion per se. Surprisingly, unligated integrin or beta integrin tails recruit caspase-8 to the membrane, where it becomes activated in a death receptor-independent manner. Integrin ligation disrupts this integrin-caspase containing complex and increases survival, revealing an unexpected role for integrins in the regulation of apoptosis and tissue remodeling.
    Full-text · Article · Nov 2001 · The Journal of Cell Biology
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    ABSTRACT: This study analyzed the expression of integrins alpha(v)beta3 and alpha(v)beta5 in glioma tissue and focused on the periphery of high-grade gliomas. The analysis was performed with Western blot, immunohistochemistry, and immunofluorescence, by use of two monoclonal antibodies able to recognize the functional integrin heterodimer. The expression of integrin-related ligands and growth factors also was studied. Sections from the tumor periphery were classified as either tumor periphery (light tumor infiltrate or scant visible cells) or peritumor (heavy tumor infiltration). Our data on glioma tissues demonstrated that both integrins were expressed in glioma cells and vasculature and their expression correlated with the histological grade. Alpha(v)beta3 expression was prominent in astrocytic tumors. Both integrins were markers of tumor vasculature, particularly of endothelial proliferation. A high-grade glioma periphery demonstrated a prominent expression of integrin alpha(v)beta3. Cells demonstrating alpha(v)beta3 positivity were identified as tumor astrocytes and endothelial cells by double imaging. The same cells were surrounded by some alpha(v)beta3 ligands and co-localized fibroblast growth factor 2. Matrix metalloproteinase 2 also was found to be co-localized with alpha(v)beta3 in the same cells. Alpha(v)beta3 expression was more relevant in tumor astrocytes. Alpha(v)beta3 integrin and vascular endothelial growth factor expression increased from the periphery to the tumor center. Our data support the role of integrins alpha(v)beta3 and alpha(v)beta5 in glioma-associated angiogenesis. In addition, they suggest a role for integrin alpha(v)beta3 in neoangiogenesis and cell migration in high-grade glioma periphery.
    No preview · Article · Sep 2001 · Neurosurgery
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    ABSTRACT: OBJECTIVE: This study analyzed the expression of integrins αvβ3 and αvβ5 in glioma tissue and focused on the periphery of high-grade gliomas. METHODS: The analysis was performed with Western blot, immunohistochemistry, and immunofluorescence, by use of two monoclonal antibodies able to recognize the functional integrin heterodimer. The expression of integrin-related ligands and growth factors also was studied. Sections from the tumor periphery were classified as either tumor periphery (light tumor infiltrate or scant visible cells) or peritumor (heavy tumor infiltration). RESULTS: Our data on glioma tissues demonstrated that both integrins were expressed in glioma cells and vasculature and their expression correlated with the histological grade. αvβ3 expression was prominent in astrocytic tumors. Both integrins were markers of tumor vasculature, particularly of endothelial proliferation. A high-grade glioma periphery demonstrated a prominent expression of integrin αvβ3. Cells demonstrating αvβ3 positivity were identified as tumor astrocytes and endothelial cells by double imaging. The same cells were surrounded by some αvβ3 ligands and co-localized fibroblast growth factor 2. Matrix metalloproteinase 2 also was found to be co-localized with αvβ3 in the same cells. αvβ3 expression was more relevant in tumor astrocytes. αvβ3 integrin and vascular endothelial growth factor expression increased from the periphery to the tumor center. CONCLUSION: Our data support the role of integrins αvβ3 and αvβ5 in glioma-associated angiogenesis. In addition, they suggest a role for integrin αvβ3 in neoangiogenesis and cell migration in high-grade glioma periphery.
    No preview · Article · Aug 2001 · Neurosurgery

Publication Stats

42k Citations
2,874.34 Total Impact Points

Institutions

  • 1990-2015
    • University of California, San Diego
      • • Moores Cancer Center/Oncology
      • • Department of Pathology
      San Diego, California, United States
    • University of Southern California
      • Department of Medicine
      Los Angeles, California, United States
  • 2013
    • University of Kentucky
      Lexington, Kentucky, United States
  • 2005-2011
    • National University (California)
      San Diego, California, United States
  • 1988-2009
    • The Scripps Research Institute
      • • Skaggs Institute for Chemical Biology
      • • Department of Molecular and Experimental Medicine
      La Jolla, California, United States
  • 1995-2003
    • La Jolla Institute for Allergy & Immunology
      La Jolla, California, United States
    • University of Alabama at Birmingham
      • Division of Neuropathology
      Birmingham, Alabama, United States
  • 2002
    • Karolinska Institutet
      Сольна, Stockholm, Sweden
  • 2001
    • Salk Institute
      La Jolla, California, United States
  • 1997
    • University of Illinois at Chicago
      • Department of Physiology and Biophysics (Chicago)
      Chicago, Illinois, United States
  • 1993
    • Barnes Jewish Hospital
      San Luis, Missouri, United States
  • 1991
    • State University of New York
      New York, New York, United States
  • 1989
    • Michigan State University
      • Department of Biochemistry and Molecular Biology
      East Lansing, Michigan, United States
  • 1987
    • National Cancer Institute (USA)
      • Laboratory of Experimental Immunology
      베서스다, Maryland, United States