Mechanism of angiogenin-induced angiogenesis

Summary

Principal Investigator: Guo fu Hu
Abstract: DESCRIPTION (provided by applicant): Angiogenin (ANG) is a 14 kDa angiogenic ribonuclease that is upregulated in a variety of human cancers. Loss-of-function mutations in the coding region of ANG have recently been found in patients with amyotrophic lateral sclerosis (ALS). Studies carried out in the previous funding period have demonstrated an important role of ANG in ribosomal RNA (rRNA) synthesis, which is essential for many fundamental biological processes including cell growth, proliferation, and survival. We have created conditional Ang1 knockout mice and have shown that Ang1 null mice have reduced angiogenic response and increased susceptibility to stress-induced apoptosis. Mechanistically, we have demonstrated that the biological activity of ANG relies on its subcellular destination. Under growth condition, ANG is translocated to the nucleus where it stimulates ribosomal RNA (rRNA) transcription and processing thereby promoting cell growth and proliferation. Under stress, ANG is translocated to the stress granules where it enhances the production of tiRNA (tRNA-derived, stress-induced small RNA) that reprogram protein translation thereby promoting cell survival. We have also identified PlexinB2 as a functional ANG receptor that is both necessary and sufficient for mediating biological activity of ANG. We have shown that ANG and Semaphorin 4C (Sema4C), the other ligand of PlexinB2, bind at non-overlapping regions and trigger different signals. The objective of this proposal is to understand the mechanism of action of ANG in stimulating angiogenesis and cancer progression. This objective will be achieved by addressing the following four specific aims. (1) Assess the therapeutic activity of anti-ANG receptor (PlexinB2) antibody. We will examine the effect of anti-PlexinB2 monoclonal antibodies on angiogenesis and tumor progression in both xenograft and transgenic animal models. (2) Characterize the differential effect of ANG and Sema4C in angiogenesis and tumor progression. We will assess the effect of knockdown PlexinB2 and Sema4C on Akt- induced prostate intraepithelial (PIN) and compare the results with that from ANG knockdown. (3) Determine the role of ANG in stress-regulated protein translation and cell survival. We will identify the signals that direct translocation of ANG into stress granules and into nucleus. We will also characterize the role of ANG-mediated tiRNA in reprogramming protein translation and promoting cell survival. (4) Characterize the effect of Ang1 knockout and ANG overexpression in angiogenesis and tumor growth. We will examine the function of ANG in cancer susceptibility to oncogenic insults inflicted by environmental and genetic factors. We will also study autocrine vs. paracrine action of ANG and their respective contributions toward tumor angiogenesis and cancer cell proliferation. We anticipate that the results of these experiments will elucidate how ANG interacts with its cell surface receptor, how the signaling pathway is transduced, and how ANG promotes cell survival and proliferation. These results will provide a comprehensive understanding of the function and mechanism of ANG in angiogenesis and in cancer progression.
Funding Period: 2003-12-01 - 2016-05-31
more information: NIH RePORT

Top Publications

  1. pmc A therapeutic target for prostate cancer based on angiogenin-stimulated angiogenesis and cancer cell proliferation
    Norie Yoshioka
    Center for Biochemical and Biophysical Sciences and Medicine, Department of Pathology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 103:14519-24. 2006
  2. pmc Angiogenin inhibits nuclear translocation of apoptosis inducing factor in a Bcl-2-dependent manner
    Shuping Li
    Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts 02111, USA
    J Cell Physiol 227:1639-44. 2012
  3. pmc Emerging role of angiogenin in stress response and cell survival under adverse conditions
    Shuping Li
    Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111, USA
    J Cell Physiol 227:2822-6. 2012
  4. pmc Ribonuclease 4 protects neuron degeneration by promoting angiogenesis, neurogenesis, and neuronal survival under stress
    Shuping Li
    Molecular Oncology Research Institute, Tufts Medical Center, 800 Washington Street, Box 5069, Boston, MA 02111, USA
    Angiogenesis 16:387-404. 2013
  5. pmc Ribonuclease/angiogenin inhibitor 1 regulates stress-induced subcellular localization of angiogenin to control growth and survival
    Elio Pizzo
    Department of Biology, University of Naples Federico II, Complesso Universitario di Monte S Angelo, Via Cintia, Naples 80126, Italy
    J Cell Sci 126:4308-19. 2013
  6. pmc Angiogenin mediates androgen-stimulated prostate cancer growth and enables castration resistance
    Shuping Li
    Molecular Oncology Research Institute, Tufts Medical Center, 800 Washington Street, Boston, MA 02111
    Mol Cancer Res 11:1203-14. 2013
  7. pmc Angiogenin stimulates ribosomal RNA transcription by epigenetic activation of the ribosomal DNA promoter
    Jinghao Sheng
    Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts Institute of Environmental Medicine, Zhejiang University School of Medicine, Hangzhou, China
    J Cell Physiol 229:521-9. 2014
  8. pmc Amyloidogenic variant of apolipoprotein A-I elicits cellular stress by attenuating the protective activity of angiogenin
    R Del Giudice
    1 Department of Chemical Sciences, University of Naples Federico II, Via Cinthia 4, Naples 80126, Italy 2 Molecular Oncology Research Institute, Tufts Medical Center, 800 Washington Street, Boston, MA 02111, USA
    Cell Death Dis 5:e1097. 2014
  9. pmc Angiogenin prevents serum withdrawal-induced apoptosis of P19 embryonal carcinoma cells
    Shuping Li
    Department of Pathology, Harvard Medical School, Boston, MA, USA
    FEBS J 277:3575-87. 2010
  10. pmc Angiogenin-mediated ribosomal RNA transcription as a molecular target for treatment of head and neck squamous cell carcinoma
    Lili Chen
    Department of Stomatology, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
    Oral Oncol 46:648-53. 2010

Research Grants

Detail Information

Publications21

  1. pmc A therapeutic target for prostate cancer based on angiogenin-stimulated angiogenesis and cancer cell proliferation
    Norie Yoshioka
    Center for Biochemical and Biophysical Sciences and Medicine, Department of Pathology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 103:14519-24. 2006
    ..Blocking nuclear translocation of angiogenin could have a combined benefit of antiangiogenesis and chemotherapy in treating prostate cancer...
  2. pmc Angiogenin inhibits nuclear translocation of apoptosis inducing factor in a Bcl-2-dependent manner
    Shuping Li
    Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts 02111, USA
    J Cell Physiol 227:1639-44. 2012
    ..ANG inhibits serum withdrawal-induced apoptosis by attenuating a series of Bcl-2-dependent events including caspase-3 activation, poly ADP-ribose polymerase-1 (PARP-1) cleavage, and AIF nuclear translocation...
  3. pmc Emerging role of angiogenin in stress response and cell survival under adverse conditions
    Shuping Li
    Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA 02111, USA
    J Cell Physiol 227:2822-6. 2012
    ..Thus, ANG-mediated tiRNA reprogram protein translation, save anabolic energy, and promote cell survival. This recently uncovered function of ANG presents a novel mechanism of action in regulating cell growth and survival...
  4. pmc Ribonuclease 4 protects neuron degeneration by promoting angiogenesis, neurogenesis, and neuronal survival under stress
    Shuping Li
    Molecular Oncology Research Institute, Tufts Medical Center, 800 Washington Street, Box 5069, Boston, MA 02111, USA
    Angiogenesis 16:387-404. 2013
    ..Importantly, systemic treatment with RNASE4 protein slowed weight loss and enhanced neuromuscular function of SOD1 (G93A) mice...
  5. pmc Ribonuclease/angiogenin inhibitor 1 regulates stress-induced subcellular localization of angiogenin to control growth and survival
    Elio Pizzo
    Department of Biology, University of Naples Federico II, Complesso Universitario di Monte S Angelo, Via Cintia, Naples 80126, Italy
    J Cell Sci 126:4308-19. 2013
    ..Knockdown of RNH1 abolished stress-induced relocalization of ANG and decreased cell growth and survival...
  6. pmc Angiogenin mediates androgen-stimulated prostate cancer growth and enables castration resistance
    Shuping Li
    Molecular Oncology Research Institute, Tufts Medical Center, 800 Washington Street, Boston, MA 02111
    Mol Cancer Res 11:1203-14. 2013
    ....
  7. pmc Angiogenin stimulates ribosomal RNA transcription by epigenetic activation of the ribosomal DNA promoter
    Jinghao Sheng
    Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts Institute of Environmental Medicine, Zhejiang University School of Medicine, Hangzhou, China
    J Cell Physiol 229:521-9. 2014
    ..These data suggest that one of the mechanisms by which ANG stimulates rRNA transcription is through an epigenetic activation of rDNA promoter...
  8. pmc Amyloidogenic variant of apolipoprotein A-I elicits cellular stress by attenuating the protective activity of angiogenin
    R Del Giudice
    1 Department of Chemical Sciences, University of Naples Federico II, Via Cinthia 4, Naples 80126, Italy 2 Molecular Oncology Research Institute, Tufts Medical Center, 800 Washington Street, Boston, MA 02111, USA
    Cell Death Dis 5:e1097. 2014
    ..Consistently, we also find that addition of exogenous ANG protects cells from L75P-ApoA-I-induced apoptosis. ..
  9. pmc Angiogenin prevents serum withdrawal-induced apoptosis of P19 embryonal carcinoma cells
    Shuping Li
    Department of Pathology, Harvard Medical School, Boston, MA, USA
    FEBS J 277:3575-87. 2010
    ..Thus, angiogenin prevents stress-induced cell death through both the Bcl-2 and Nf-kappab pathways...
  10. pmc Angiogenin-mediated ribosomal RNA transcription as a molecular target for treatment of head and neck squamous cell carcinoma
    Lili Chen
    Department of Stomatology, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
    Oral Oncol 46:648-53. 2010
    ..As the role of ANG in HNSCC is being unveiled, the therapeutic potential of ANG inhibitors in HNSCC is expected...
  11. ncbi Ornithine decarboxylase antizyme upregulates DNA-dependent protein kinase and enhances the nonhomologous end-joining repair of DNA double-strand breaks in human oral cancer cells
    Takanori Tsuji
    Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA
    Biochemistry 46:8920-32. 2007
    ..Plasmid end-joining assays confirmed that antizyme enhances the ability of UM1 cells to repair DNA double-strand breaks by the nonhomologous end-joining pathway...
  12. pmc Angiogenin loss-of-function mutations in amyotrophic lateral sclerosis
    David Wu
    Department of Pathology, Brigham and Women s Hospital, Boston, MA 02114, USA
    Ann Neurol 62:609-17. 2007
    ..However, the role of ANG in motor neuron physiology and the functional consequences of these mutations are unknown. We searched for new mutations and sought to define the functional consequences of these mutations...
  13. pmc Targeting angiogenin in therapy of amyotropic lateral sclerosis
    Hiroko Kishikawa
    Harvard Medical School, Department of Pathology, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
    Expert Opin Ther Targets 12:1229-42. 2008
    ....
  14. pmc Epithelial-mesenchymal transition induced by growth suppressor p12CDK2-AP1 promotes tumor cell local invasion but suppresses distant colony growth
    Takanori Tsuji
    Department of Pathology, Harvard Medical School and Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts 02115, USA
    Cancer Res 68:10377-86. 2008
    ..We thus hypothesize that EMT cells are responsible for degrading the surrounding matrix to lead the way of invasion and intravasation. Non-EMT cells then enter the blood stream and reestablish colonies in the secondary sites...
  15. pmc Angiogenin-stimulated rRNA transcription is essential for initiation and survival of AKT-induced prostate intraepithelial neoplasia
    Soichiro Ibaragi
    Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA
    Mol Cancer Res 7:415-24. 2009
    ..All three types of the ANG inhibitor suppress rRNA transcription of the prostate luminal epithelial cells and inhibit AKT-induced PIN, indicating an essential role of ANG in AKT-mediated cell proliferation and survival...
  16. pmc Neamine inhibits prostate cancer growth by suppressing angiogenin-mediated rRNA transcription
    Soichiro Ibaragi
    Department of Pathology, Harvard Medical School, Boston, MA 02115, USA
    Clin Cancer Res 15:1981-8. 2009
    ..The purpose of this study is to assess the antitumor activity of neamine, a nontoxic degradation product of neomycin that blocks nuclear translocation of ANG...
  17. pmc Characterization of the angiogenic activity of zebrafish ribonucleases
    Daria M Monti
    Department of Structural and Functional Biology, University of Naples Federico II, Italy
    FEBS J 276:4077-90. 2009
    ....
  18. pmc Epithelial-mesenchymal transition and cell cooperativity in metastasis
    Takanori Tsuji
    Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
    Cancer Res 69:7135-9. 2009
    ..Here, we discuss an alternative model for the role of EMT in cancer metastasis in which EMT and non-EMT cells cooperate to complete the entire process of spontaneous metastasis...
  19. pmc Transcription of angiogenin and ribonuclease 4 is regulated by RNA polymerase III elements and a CCCTC binding factor (CTCF)-dependent intragenic chromatin loop
    Jinghao Sheng
    From the Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts 02111 and
    J Biol Chem 289:12520-34. 2014
    ..Furthermore, our data indicate that a CTCF-dependent chromatin loop is able to differentially regulate transcription of genes that share the same promoters. ..

Research Grants30

  1. Prostate cancer chemoprevention by penta-galloyl-glucose
    Junxuan Lu; Fiscal Year: 2013
    ..These multiple targeting activities plus published work supporting anti- angiogenesis activity provide strong rationale for testing the efficacy of PGG for prostate cancer chemoprevention. ..
  2. Angiogenin-induced RNA cleavage in cancer
    Paul J Anderson; Fiscal Year: 2013
    ..The proposed research is innovative because it focuses on the direct target of ANG, its RNA substrates, and attempts to determine how tRNA cleavage promotes tumorigenesis. ..
  3. Role of 11q23 Chromosome Abnormalities in the Causation of Acute Leukemia
    Carlo M Croce; Fiscal Year: 2013
    ..abstract_text> ..
  4. Interrogating Epigenetic Changes in Cancer Genomes
    Tim H M Huang; Fiscal Year: 2013
    ..abstract_text> ..
  5. Molecular Mechanisms of Prostate Cancer Chemoprevention by Apigenin
    Sanjay Gupta; Fiscal Year: 2013
    ....
  6. Mechanisms of GVHD
    Joseph H Antin; Fiscal Year: 2013
    ..Ultimately we envision an integrated genomic profile that will determine the type of GVHD prophylaxis that will be most effective. ..