James J.-D. Hsieh, M.D., Ph.D.
- Assistant Professor
- Department of Medicine
- Oncology Division
- Medical Oncology Section
- Molecular Oncology Section
- Oncology Division
- Department of Medicine
- Clinical interests
- Lung cancer
- GU cancer
- Leukemia
- Research interests
- Epigenetics
- Gene regulation
- Development
- Proteases
- Leukemogenesis
Research
Active expression and suppression of subsets of genes confers various fates to cells despite their sharing the same DNA sequences. Cells must have the ability to remember who they are by judiciously maintaining the expression of lineage specification genes such as Hox genes. Deregulation of Hox code causes transformation of segmental identities during development and contributes to human disorders, including malignancy. The maintenance of appropriate Hox gene expression requires Mixed Lineage Leukemia (MLL) protein, a trithorax group protein. Chromosome segment 11q23 translocation disrupting MLL gene leads to human leukemia. We have demonstrated that MLL is normally processed at conserved cleavage sites and this cleavage regulates its stability thus controls target gene expression. Recently, we have purified and cloned the responsible protease, Taspase1, that initiates a novel class of proteases that utilize Threonine as active site nucleophile to cleave polypeptide substrates after Aspartate.
Our laboratory has generated mice carrying noncleavable MLL alleles to elucidate the role of MLL processing in target gene expression, hematopoiesis, and development. Understanding the mechanism by which MLL amino-terminus is degraded will help design specific therapeutics for MLL leukemia.
Taspase1 first appears at the emergence of Arthropoda and Chordata from Metazoa suggesting that Taspase1 originated to regulate complex body plans in higher organisms. The biological significance of Taspase1 and its regulation will be further pursued with combined biochemical and genetic approaches. Proteomic analysis utilizing Taspase1 null cells further addresses whether there are yet identified Taspase1 substrates. Finally, we are in the process of developing Taspase1 inhibitors for potential cancer therapeutics.
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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 |
Updated: April 23, 2008
