James J.-D. Hsieh, M.D., Ph.D.

Jim Hsieh
  • Assistant Professor
    • Department of Medicine
      • Oncology Division
        • Medical Oncology Section
        • Molecular Oncology Section
  • Clinical interests
    • Lung cancer
    • GU cancer
    • Leukemia
  • Research interests
    • Epigenetics
    • Gene regulation
    • Development
    • Proteases
    • Leukemogenesis

Research

Our laboratory focuses on understanding how Taspase1 and MLL regulate critical biological pathways with a special emphasis on cancer biology. Specifically, we'd like to utilize combined biochemical and genetic approaches to investigate how the evolutionarily conserved protease, Taspase1, and its substrates such as MLL coordinate essential cellular and developmental processes.

Recurrent human chromosome band 11q23 translocations disrupting MLL gene lead to altered HOX gene expression and human leukemia. We showed that MLL undergoes routine proteolysis generating N-terminal 320kDa and C-terminal 180kDa fragments. We subsequently purified the responsible protease and named it, Taspase1. The discovery of Taspase1 founded a novel class of protesases. In addition to MLL proteins, we also identified precursor TFIIA family proteins as well as the Drosophila HCF protein as bona fide Taspase1 substrates.

MLL is a 500kD nuclear coactivator which plays critical roles in embryonic development, hematopoiesis, stem cells, and cell cycle. We plan to extend our knowledge on MLL beyond Hox gene regulation and study the deregulations of respective signalings caused by leukemogenic MLL-Fusions. The ultimate goal is to provide a detailed blueprint of the MLL regulatory network for a molecular reconstruction of the MLL leukemia.

To investigate Taspase1's functions in vivo, we generated Taspase1 knockout mice. Our in vivo studies uncover an essential role of Taspase1 in cell cycle regulation. Taspase1-/- MEFs exhibit impaired proliferation. The un-cleaved precursor MLL displays a reduced histone H3 methyl transferase activity in vitro and in vivo. Our data are consistent with a model in which precursor MLLs, activated by Taspase1, target to Cyclins through E2Fs to methylate histone H3 at K4, leading to activation. Lastly, Taspase1-/- cells are resistant to oncogenic transformation and Taspase1 is over-expressed in many cancer cell lines. Thus, Taspase1 may serve as a target for future cancer therapeutics. Accordingly, we are in the process of developing Taspase1 inhibitors for potential cancer therapeutics.

Taspase1

A schematic model depicts the intramolecular proteolysis of Taspase1 followed by MLL processing required for proper HOX gene expression

Biographical Sketch

Education

1990 MD, Taipei Medical College, Taiwan
1996 PhD (pharmacology and molecular sciences), Johns Hopkins University, Baltimore, MD

Post-graduate Training

1990-1992 Physician, Obligatory Military Service in Taiwan
1992-1996 Graduate Student, Department of Pharmacology and Molecular Sciences, School of Medicine, The Johns Hopkins University (Dr. S. Diane Hayward, advisor; dissertation research in characterizing the molecular mechanisms involved in Epstein-Barr virus immortalization of B lymphocytes)
1996-1997 Postdoctoral Fellow, School of Medicine, The Johns Hopkins University, Baltimore, MD
1997-1999 House Staff, Department of Medicine, Barnes Hospital, Washington University, St. Louis, MO
1999-2000 Oncology Fellow, Barnes Hospital, Department of Medicine, Washington University, St. Louis, MO
2000-2003 Adult Oncology Fellow, Dana-Farber Cancer Institute, Boston, MA
2000-2003 Clinical Fellow, Brigham and Women's Hospital, Boston, MA

Academic Positions

2003-2004 Instructor in Medicine, Harvard Medical School, Boston, MA
2004-present Assistant Professor, Medicine, Washington University, St. Louis, MO

Board Certification

2000 Internist, American Board of Internal Medicine
2003 Medical Oncologist, American Board of Internal Medicine

Honors & Awards

1990 Graduated with highest honors from Taipei Medical College, Taiwan
1992-1996 Scholarship sponsored by the Johns Hopkins University, School of Medicine
1996 Nineteenth Annual Young Investigators Award, School of Medicine, Johns Hopkins University, Baltimore, MD
1996 Phi Beta Kappa
2000-2003 Physician-Scientist Award, Howard Hughes Medical Institute
2003-2008 Howard Temin Award, K01, National Cancer Institute
2005-2008 Edward Mallinckrodt Jr. Foundation Award
2006-2009 Basic Research Scholar Award, American Society of Hematology