The ATM/E2F1 Pathway in DNA Damage and Growth Control

Summary

Principal Investigator: Weei Chin Lin
Abstract: The transcription factor E2F1 plays a pivotal role in the control of cell proliferation and apoptosis. Recently we uncovered a novel pocket proteins-independent pathway involving PI3K/Akt and a BRCT domain-containing protein TopBP1 in the control of E2F1 Our preliminary data further demonstrate E2F can be regulated by another BRCT domain-containing protein, MCPH1/BRIT1. The pRb family members have long been considered to be the major regulators for E2F. TopBP1 and MCPH1 appear to be a new class of E2F regulators. They both contain multiple BRCT motifs and interact with the N- terminus of E2F1 through their BRCT motifs. TopBP1 is a negative regulator, whereas, MCPH1 is a positive regulator of E2F1 target genes in checkpoint/repair and apoptosis. Both proteins are also directly involved in DNA damage checkpoint activation. In this proposal, we aim to characterize the functions and mechanisms of these novel regulations governing E2F1 protein activity and stability. First, We will elucidate the mechanism by which growth factor signalings control E2F1 through TopBP1. Second, We will determine how MCPH1 regulates E2F1. How TopBP1 and MCPH1 respond to environmental milieu and regulate E2F1 activity will also be investigated. Lastly, we will investigate how E2F1 protein is induced in response to ATM phosphorylation. Upon completion of this project, we will elucidate how the proliferative and pro-apoptotic activities of E2F1 are differentially regulated. Understanding the control of E2F1 activity and stability in growth and DNA damage may provide novel approaches in harness E2F1 pro-apoptotic activity to enhance chemosensitivity. PUBLIC HEALTH RELEVANCE: Proper balance between proliferation and cell death is essential for normal growth. Recent studies have established a role for E2F1 in this control, especially upon DNA damage. During our last grant period, we discovered a novel class of E2F1 regulators. We will elucidate the mechanisms of regulation and the implications to clinical application in enhancing E2F1-induced cell killing in cancer therapy.
Funding Period: 2003-04-01 - 2015-02-28
more information: NIH RePORT

Top Publications

  1. pmc Regulation of TopBP1 oligomerization by Akt/PKB for cell survival
    Kang Liu
    Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
    EMBO J 25:4795-807. 2006
  2. pmc TRIP6 regulates p27 KIP1 to promote tumorigenesis
    Victor T G Lin
    Department of Medicine, Section of Hematology Oncology, Baylor College of Medicine, Houston, Texas, USA
    Mol Cell Biol 33:1394-409. 2013
  3. pmc Regulation of E2F1 by APC/C Cdh1 via K11 linkage-specific ubiquitin chain formation
    Varija N Budhavarapu
    Section of Hematology Oncology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
    Cell Cycle 11:2030-8. 2012
  4. pmc TopBP1 mediates mutant p53 gain of function through NF-Y and p63/p73
    Kang Liu
    Section of Hematology Oncology, Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA
    Mol Cell Biol 31:4464-81. 2011
  5. pmc EDD inhibits ATM-mediated phosphorylation of p53
    Shiyun Ling
    Section of Hematology Oncology, Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA
    J Biol Chem 286:14972-82. 2011
  6. pmc 14-3-3Tau regulates Beclin 1 and is required for autophagy
    Bing Wang
    Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
    PLoS ONE 5:e10409. 2010
  7. pmc 14-3-3Tau regulates ubiquitin-independent proteasomal degradation of p21, a novel mechanism of p21 downregulation in breast cancer
    Bing Wang
    Division of Hematology and Oncology, Department of Medicine, 1 Medical Statistics Section, University of Alabama at Birmingham, Birmingham, Alabama 35294 2182, USA
    Mol Cell Biol 30:1508-27. 2010
  8. pmc Regulation of E2F1-induced apoptosis by the nucleolar protein RRP1B
    Jason C Paik
    Division of Hematology Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA
    J Biol Chem 285:6348-63. 2010
  9. pmc Regulation of p53 by TopBP1: a potential mechanism for p53 inactivation in cancer
    Kang Liu
    Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294 3300, USA
    Mol Cell Biol 29:2673-93. 2009
  10. pmc MCPH1/BRIT1 cooperates with E2F1 in the activation of checkpoint, DNA repair and apoptosis
    Shan Zhong Yang
    Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294 3300, USA
    EMBO Rep 9:907-15. 2008

Research Grants

  1. Mechanisms of Atherogenesis in Insulin Resistance
    IRA A TABAS; Fiscal Year: 2013
  2. MECHANISMS OF BREAST DEVELOPMENT AND CARCINOGENESIS
    Robert A Weinberg; Fiscal Year: 2013
  3. IAP Family Proteins and Cancer
    Guy S Salvesen; Fiscal Year: 2013

Detail Information

Publications11

  1. pmc Regulation of TopBP1 oligomerization by Akt/PKB for cell survival
    Kang Liu
    Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
    EMBO J 25:4795-807. 2006
    ..Together, this study defines a novel pathway involving PI3K-Akt-TopBP1 for specific control of E2F1 apoptosis, in parallel with cyclin-Cdk-Rb for general control of E2F activities...
  2. pmc TRIP6 regulates p27 KIP1 to promote tumorigenesis
    Victor T G Lin
    Department of Medicine, Section of Hematology Oncology, Baylor College of Medicine, Houston, Texas, USA
    Mol Cell Biol 33:1394-409. 2013
    ..As TRIP6 is upregulated in gliomas and its levels correlate with poor clinical outcomes in a dose-dependent manner, it may represent a novel prognostic marker and therapeutic target in gliomas...
  3. pmc Regulation of E2F1 by APC/C Cdh1 via K11 linkage-specific ubiquitin chain formation
    Varija N Budhavarapu
    Section of Hematology Oncology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
    Cell Cycle 11:2030-8. 2012
    ..The data suggest that DNA damage signaling processes do not inhibit APC/C (Cdh1) to ubiquitinate E2F1. Instead, they block the proteasomal degradation of Ub-K11-linked E2F1, and therefore lead to its accumulation...
  4. pmc TopBP1 mediates mutant p53 gain of function through NF-Y and p63/p73
    Kang Liu
    Section of Hematology Oncology, Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA
    Mol Cell Biol 31:4464-81. 2011
    ..Since TopBP1 is often overexpressed in cancer cells and is recruited to cooperate with mutant p53 for tumor progression, TopBP1/mutant p53 interaction may be a new therapeutic target in cancer...
  5. pmc EDD inhibits ATM-mediated phosphorylation of p53
    Shiyun Ling
    Section of Hematology Oncology, Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA
    J Biol Chem 286:14972-82. 2011
    ..Thus, through binding to p53, EDD actively inhibits p53 phosphorylation by ATM and plays a role in ensuring smooth G(1)/S progression...
  6. pmc 14-3-3Tau regulates Beclin 1 and is required for autophagy
    Bing Wang
    Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
    PLoS ONE 5:e10409. 2010
    ..14-3-3 proteins mediate many cellular signaling processes, but its role in autophagy has not been investigated. We hypothesize that 14-3-3tau could regulate Beclin 1 expression through E2F1 and thus regulate autophagy...
  7. pmc 14-3-3Tau regulates ubiquitin-independent proteasomal degradation of p21, a novel mechanism of p21 downregulation in breast cancer
    Bing Wang
    Division of Hematology and Oncology, Department of Medicine, 1 Medical Statistics Section, University of Alabama at Birmingham, Birmingham, Alabama 35294 2182, USA
    Mol Cell Biol 30:1508-27. 2010
    ..Together, the findings of our studies strongly suggest a novel oncogenic role of 14-3-3tau by downregulating p21 in breast cancer. Therefore, 14-3-3tau may be a potential therapeutic target in breast cancer...
  8. pmc Regulation of E2F1-induced apoptosis by the nucleolar protein RRP1B
    Jason C Paik
    Division of Hematology Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA
    J Biol Chem 285:6348-63. 2010
    ..Thus, E2F1 makes use of its transcriptional target RRP1B to activate other genes directly involved in apoptosis. Our data also suggest an underappreciated role for nucleolar proteins in transcriptional regulation...
  9. pmc Regulation of p53 by TopBP1: a potential mechanism for p53 inactivation in cancer
    Kang Liu
    Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294 3300, USA
    Mol Cell Biol 29:2673-93. 2009
    ..Thus, a physiological level of TopBP1 is essential for normal G(1)/S transition, but a pathological level of TopBP1 in cancer may perturb p53 function and contribute to an aggressive tumor behavior...
  10. pmc MCPH1/BRIT1 cooperates with E2F1 in the activation of checkpoint, DNA repair and apoptosis
    Shan Zhong Yang
    Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294 3300, USA
    EMBO Rep 9:907-15. 2008
    ..Taken together, MCPH1 cooperates with E2F1 to regulate genes involved in DNA repair, checkpoint and apoptosis, and might participate in the maintenance of genomic integrity...
  11. pmc Akt switches TopBP1 function from checkpoint activation to transcriptional regulation through phosphoserine binding-mediated oligomerization
    Kang Liu
    Section of Hematology Oncology, Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
    Mol Cell Biol 33:4685-700. 2013
    ....

Research Grants30

  1. Mechanisms of Atherogenesis in Insulin Resistance
    IRA A TABAS; Fiscal Year: 2013
    ..End of Abstract) ..
  2. MECHANISMS OF BREAST DEVELOPMENT AND CARCINOGENESIS
    Robert A Weinberg; Fiscal Year: 2013
    ..abstract_text> ..
  3. IAP Family Proteins and Cancer
    Guy S Salvesen; Fiscal Year: 2013
    ....