Growth Inhibition by the ARF Tumor Suppressor

Summary

Principal Investigator: DAWN QUELLE
Affiliation: University of Iowa
Country: USA
Abstract: INK4a/ARF encodes the ARF tumor suppressor protein and is the second most frequently inactivated gene in human cancers. ARF prevents oncogene-mediated transformation through protein-protein interactions in partially defined p53-dependent and p53-independent pathways. Numerous ARF-associated proteins have been identified but few besides the p53 antagonist, Mdm2, have a clearly defined role in ARF-mediated tumor suppression. Based on work from the previously funded project, we identified and characterized two novel ARF interacting proteins and showed they participate in ARF signaling. Parf (Partner of ARF) is required for ARF's p53-independent growth suppressive activity, whereas NIAM (Nuclear Interactor of ARF and Mdm2) activates p53 and collaborates with ARF to inhibit cell proliferation. Both proteins also act independent of ARF and p53 to maintain genomic stability, regulate DNA damage checkpoints, and suppress cancer cell proliferation, suggesting they have anticancer activities that intersect with ARF and other antiproliferative pathways. However, the underlying mechanisms by which Parf and NIAM regulate ARF signaling, genomic stability and cell proliferation are poorly understood. The specific objective of this research is to define the mechanistic and biological roles of these novel ARF interacting proteins in ARF signaling and carcinogenesis. Aim 1 will establish how NIAM enhances ARF signaling and its role in tumorigenesis. Aim 2 will define how Parf contributes to ARF signaling and tumor suppression. Molecular and biochemical approaches, as well as unique mouse models of cancer, will be utilized. These studies will advance our fundamental understanding of how the ARF tumor suppressor and its associated proteins prevent cancer. This is highly relevant to public health because loss of ARF figures prominently in the development of nearly all types of human tumors and we cannot effectively battle cancer until we know its molecular basis. This work is expected to identify new targets for anticancer strategies and new paradigms used by tumor suppressors to prevent tumorigenesis, and as such, it should improve our ability to diagnose, treat and ultimately prevent human cancer.
Funding Period: ----------------2001 - ---------------2012-
more information: NIH RePORT

Top Publications

  1. ncbi A novel nuclear interactor of ARF and MDM2 (NIAM) that maintains chromosomal stability
    Van S Tompkins
    Department of Pharmacology, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, 52242 1109, USA, and the Laboratoire de Genetique Cellulaire et Moleculaire, UPRES EA2622, Centre Hospitalier Universitaire de Poitiers, France
    J Biol Chem 282:1322-33. 2007
  2. pmc Generation and characterization of monoclonal antibodies to NIAM: a nuclear interactor of ARF and Mdm2
    Jussara Hagen
    Department of Pharmacology, The University of Iowa, College of Medicine, Iowa City, Iowa, USA
    Hybridoma (Larchmt) 27:159-66. 2008
  3. pmc RABL6A, a novel RAB-like protein, controls centrosome amplification and chromosome instability in primary fibroblasts
    Xuefeng Zhang
    Department of Pharmacology, University of Iowa, Iowa City, Iowa, United States of America
    PLoS ONE 8:e80228. 2013
  4. pmc Nuclear interactor of ARF and Mdm2 regulates multiple pathways to activate p53
    Sara M Reed
    Department of Pharmacology University of Iowa College of Medicine Iowa City, IA USA Medical Scientist Training Program University of Iowa College of Medicine Iowa City, IA USA
    Cell Cycle 13:1288-98. 2014
  5. pmc Residues in the alternative reading frame tumor suppressor that influence its stability and p53-independent activities
    Anne Di Tommaso
    Pole Biologie Sante, UMR 6187 CNRS, Pathologies Mol├ęculaire de l Adressage et de la Signalisation, Universite de Poitiers, Poitiers, France
    Exp Cell Res 315:1326-35. 2009
  6. pmc The ARF tumor suppressor inhibits tumor cell colonization independent of p53 in a novel mouse model of pancreatic ductal adenocarcinoma metastasis
    Viviane Palhares Muniz
    Molecular and Cellular Biology Graduate Program, The University of Iowa, Iowa City, Iowa 52242, USA
    Mol Cancer Res 9:867-77. 2011

Detail Information

Publications6

  1. ncbi A novel nuclear interactor of ARF and MDM2 (NIAM) that maintains chromosomal stability
    Van S Tompkins
    Department of Pharmacology, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, 52242 1109, USA, and the Laboratoire de Genetique Cellulaire et Moleculaire, UPRES EA2622, Centre Hospitalier Universitaire de Poitiers, France
    J Biol Chem 282:1322-33. 2007
    ..This study identifies a novel protein with tumor suppressor-like behaviors and functional links to ARF-MDM2-p53 signaling...
  2. pmc Generation and characterization of monoclonal antibodies to NIAM: a nuclear interactor of ARF and Mdm2
    Jussara Hagen
    Department of Pharmacology, The University of Iowa, College of Medicine, Iowa City, Iowa, USA
    Hybridoma (Larchmt) 27:159-66. 2008
    ..These MAbs are predicted to be important tools for evaluating the expression and physiological function of NIAM in normal versus neoplastic human cells and tissues...
  3. pmc RABL6A, a novel RAB-like protein, controls centrosome amplification and chromosome instability in primary fibroblasts
    Xuefeng Zhang
    Department of Pharmacology, University of Iowa, Iowa City, Iowa, United States of America
    PLoS ONE 8:e80228. 2013
    ..These findings demonstrate an essential role for RABL6A in centrosome regulation and maintenance of chromosome stability in non-transformed cells, key processes that ensure genomic integrity and prevent tumorigenesis. ..
  4. pmc Nuclear interactor of ARF and Mdm2 regulates multiple pathways to activate p53
    Sara M Reed
    Department of Pharmacology University of Iowa College of Medicine Iowa City, IA USA Medical Scientist Training Program University of Iowa College of Medicine Iowa City, IA USA
    Cell Cycle 13:1288-98. 2014
    ..Thus, NIAM regulates 2 critical pathways that control p53 function and are altered in human cancers, implying an important role for NIAM in tumorigenesis. ..
  5. pmc Residues in the alternative reading frame tumor suppressor that influence its stability and p53-independent activities
    Anne Di Tommaso
    Pole Biologie Sante, UMR 6187 CNRS, Pathologies Mol├ęculaire de l Adressage et de la Signalisation, Universite de Poitiers, Poitiers, France
    Exp Cell Res 315:1326-35. 2009
    ..Most intriguingly, this work reveals a novel and direct role for p14ARF in the p53-independent maintenance of genomic stability...
  6. pmc The ARF tumor suppressor inhibits tumor cell colonization independent of p53 in a novel mouse model of pancreatic ductal adenocarcinoma metastasis
    Viviane Palhares Muniz
    Molecular and Cellular Biology Graduate Program, The University of Iowa, Iowa City, Iowa 52242, USA
    Mol Cancer Res 9:867-77. 2011
    ..These findings establish a new bioluminescent mouse tumor model for rapidly assessing the biological significance of suspected PDAC metastasis genes. This system may also provide a valuable platform for testing innovative therapies...