Mechanism of the Transcriptional Response to Transition Metals

Summary

Principal Investigator: MICHAEL THOMAS MARR
Abstract: Essential divalent transition metals such as zinc, copper, and iron play important structural and catalytic roles in over 300 proteins. However, these and other transition metals also pose a potential threat to an organism. Left unchecked these metals can catalyze the generation of free radicals that damage all types of biological molecules. Transition metals must be kept in a physiological window. Diseases like Wilson's disease and Menke's disease demonstrate that either too much or too little metal can lead to pathologies of the liver, kidney, nervous system and connective tissues. Clearly metal homeostasis is an important aspect of cellular function. A major part of this control occurs at the level of transcription. One of the central players in this regulation is the metal response element binding protein (MTF-1). MTF-1 is a sequence specific DNA binding protein that perceives the metal status of a cell and activates genes accordingly. A good deal is known about MTF-1 itself, but very little is known about the protein co-factors that help MTF-1 efficiently activate transcription. We will use an RNAi based screen, in the Drosophila model system, to determine what protein co-factors are required for metal stimulated transcription. In addition we will characterize the physical and functional interactions between MTF-1 and these protein co-factors using a combination of cell based and in vitro assays. Finally we will identify the MTF-1 binding sites across the Drosophila genome to define the MTF-1 regulon that responds to metal stimuli. The long-term objective of our studies is to understand how a cell, in response to a diverse set of metals, differentially regulates the appropriate metal responsive genes to control metal homeostasis.
Funding Period: 2009-08-01 - 2014-05-31
more information: NIH RePORT

Top Publications

  1. pmc Efficient metal-specific transcription activation by Drosophila MTF-1 requires conserved cysteine residues in the carboxy-terminal domain
    Sharon K Marr
    Department of Biology and Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, MA, USA
    Biochim Biophys Acta 1819:902-12. 2012
  2. pmc Single nucleotide in the MTF-1 binding site can determine metal-specific transcription activation
    Hillel I Sims
    Department of Biology, Brandeis University, Waltham, MA 02454, USA
    Proc Natl Acad Sci U S A 109:16516-21. 2012

Research Grants

  1. POTENTIATED STATE OF THE HSP70 HEAT SHOCK GENE
    DAVID SCOTT GILMOUR; Fiscal Year: 2013
  2. HORMONAL REGULATION OF BLOOD PRESSURE
    Michal Laniado Schwartzman; Fiscal Year: 2013
  3. Elucidating Risks: From Exposure and Mechanism to Outcome
    James A Swenberg; Fiscal Year: 2013
  4. Puerto Rico Testsite for Exploring Contamination Threats (PRoTECT)
    Akram N Alshawabkeh; Fiscal Year: 2013
  5. BIOMARKERS OF EXPOSURE TO HAZARDOUS SUBSTANCES
    Bruce D Hammock; Fiscal Year: 2013
  6. Semi-volatile PCBs: Sources, Exposures, Toxicities
    Larry W Robertson; Fiscal Year: 2013
  7. TOXIC SUBSTANCES IN THE ENVIRONMENT
    Martyn T Smith; Fiscal Year: 2013
  8. Nutritional Copper Signaling and Homeostasis
    Sabeeha Merchant; Fiscal Year: 2013
  9. Protein Dynamics in Enzymatic Catalysis
    Robert Callender; Fiscal Year: 2013

Detail Information

Publications2

  1. pmc Efficient metal-specific transcription activation by Drosophila MTF-1 requires conserved cysteine residues in the carboxy-terminal domain
    Sharon K Marr
    Department of Biology and Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, MA, USA
    Biochim Biophys Acta 1819:902-12. 2012
    ..In addition, both metal specific domains are autorepressive in the absence of metal and contribute to the low level of basal transcription from metal inducible promoters...
  2. pmc Single nucleotide in the MTF-1 binding site can determine metal-specific transcription activation
    Hillel I Sims
    Department of Biology, Brandeis University, Waltham, MA 02454, USA
    Proc Natl Acad Sci U S A 109:16516-21. 2012
    ..We also find that the type of binding site chosen is an important component of the capability to induce the metal-specific transcription activation...

Research Grants30

  1. POTENTIATED STATE OF THE HSP70 HEAT SHOCK GENE
    DAVID SCOTT GILMOUR; Fiscal Year: 2013
    ..DSIF and P-TEFb both contribute to transcription of the HIV provirus, and an inhibitor of P-TEFb is in phase 2 clinical trials for cancer therapy. ..
  2. HORMONAL REGULATION OF BLOOD PRESSURE
    Michal Laniado Schwartzman; Fiscal Year: 2013
    ..ular tone, in the pathophysiology of hypertension and cardiovascular disease. ..
  3. Elucidating Risks: From Exposure and Mechanism to Outcome
    James A Swenberg; Fiscal Year: 2013
    ..This Program is highly relevant to Superfund by addressing high-priority chemicals and by focusing on mechanisms underlying health effects, exposure assessment, and remediation to mitigate exposure and toxicity. ..
  4. Puerto Rico Testsite for Exploring Contamination Threats (PRoTECT)
    Akram N Alshawabkeh; Fiscal Year: 2013
    ..The cross-disciplinary approach will employ the data-rich centralized data repository and integrated modeling/analysis capabilities to better understand complex interrelationships between multiple risk factors. ..
  5. BIOMARKERS OF EXPOSURE TO HAZARDOUS SUBSTANCES
    Bruce D Hammock; Fiscal Year: 2013
    ..abstract_text> ..
  6. Semi-volatile PCBs: Sources, Exposures, Toxicities
    Larry W Robertson; Fiscal Year: 2013
    ..These data and dietary studies in the last Aim will provide a scientific basis for risk assessment and advice for stakeholders with the ultimate goal to protect highly-exposed individuals and populations. ..
  7. TOXIC SUBSTANCES IN THE ENVIRONMENT
    Martyn T Smith; Fiscal Year: 2013
    ..The program will be overseen and coordinated by an Administration core (A). ..
  8. Nutritional Copper Signaling and Homeostasis
    Sabeeha Merchant; Fiscal Year: 2013
    ..In Aim 3, we will distinguish the mechanism of regulation of the corresponding genes, identify zinc response elements, and use gain-of-function mutants (by over-expression) to deduce whether they are zinc chaperones. ..
  9. Protein Dynamics in Enzymatic Catalysis
    Robert Callender; Fiscal Year: 2013
    ..The Equipment Core (Core A) supports the specialized comprehensive suite of instrumentation for the Program. The Administrative Core (Core B) administers the Program Project. ..