Bio

Honors & Awards


  • St. Baldrick's Foundation Fellow, St. Baldrick's Foundation

Professional Education


  • Doctor of Medicine, Indiana-Purdue University Indianapolis (2008)
  • Bachelor of Arts, University of Notre Dame (2000)
  • Doctor of Philosophy, Indiana-Purdue University Indianapolis (2006)

Stanford Advisors


Research & Scholarship

Current Research and Scholarly Interests


Using genome engineering to model infant leukemia

Lab Affiliations


Teaching

Graduate and Fellowship Programs


  • Pediatric Hem/Onc (Fellowship Program)

Publications

Journal Articles


  • SIMPL Enhancement of Tumor Necrosis Factor-alpha Dependent p65-MED1 Complex Formation Is Required for Mammalian Hematopoietic Stem and Progenitor Cell Function PLOS ONE Zhao, W., Breese, E., Bowers, A., Hoggatt, J., Pelus, L. M., Broxmeyer, H. E., Goebl, M., Harrington, M. A. 2013; 8 (4)

    Abstract

    Significant insight into the signaling pathways leading to activation of the Rel transcription factor family, collectively termed NF-κB, has been gained. Less well understood is how subsets of NF-κB-dependent genes are regulated in a signal specific manner. The SIMPL protein (signaling molecule that interacts with mouse pelle-like kinase) is required for full Tumor Necrosis Factor-α (TNFα) induced NF-κB activity. We show that SIMPL is required for steady-state hematopoiesis and the expression of a subset of TNFα induced genes whose products regulate hematopoietic cell activity. To gain insight into the mechanism through which SIMPL modulates gene expression we focused on the Tnf gene, an immune response regulator required for steady-state hematopoiesis. In response to TNFα SIMPL localizes to the Tnf gene promoter where it modulates the initiation of Tnf gene transcription. SIMPL binding partners identified by mass spectrometry include proteins involved in transcription and the interaction between SIMPL and MED1 was characterized in more detail. In response to TNFα, SIMPL is found in p65-MED1 complexes where SIMPL enhances p65/MED1/SIMPL complex formation. Together our results indicate that SIMPL functions as a TNFα-dependent p65 co-activator by facilitating the recruitment of MED1 to p65 containing transcriptional complexes to control the expression of a subset of TNFα-induced genes.

    View details for DOI 10.1371/journal.pone.0061123

    View details for Web of Science ID 000317911500019

    View details for PubMedID 23630580

  • Anti-N-Methyl-D-Aspartate Receptor Encephalitis: Early Treatment is Beneficial PEDIATRIC NEUROLOGY Breese, E. H., Dalmau, J., Lennon, V. A., Apiwattanakul, M., Sokol, D. K. 2010; 42 (3): 213-214

    Abstract

    Anti-N-methyl-D-aspartate receptor antibody has been associated with a severe stereotypic form of subacute encephalitis, often found in women with ovarian teratoma. Reported here is the diagnosis of anti-N-methyl-D-aspartate receptor encephalitis in a 5-year-old girl who presented with subacute encephalopathy and movement disorder without evidence of malignancy. Early diagnosis and treatment with immune globulin and steroids resulted in near-complete recovery.

    View details for DOI 10.1016/j.pediatrneurol.2009.10.003

    View details for Web of Science ID 000276969000009

    View details for PubMedID 20159432

  • The disordered amino-terminus of SIMPL interacts with members of the 70-kDa heat-shock protein family DNA AND CELL BIOLOGY Breese, E. H., Uversky, V. N., Georgiadis, M. M., Harrington, M. A. 2006; 25 (12): 704-714

    Abstract

    The p65 coactivator SIMPL is a small protein that lacks any conserved domains of known function. To better understand regulation of SIMPL activity, we sought to identify novel SIMPL interacting proteins using mass spectrometry analysis of SIMPL containing complexes. Two members of the 70-kDa heat-shock protein family, Hsp70 and Hsc70, were identified as SIMPL binding proteins. Subsequent immunocomplexing assays confirmed this interaction and demonstrated that the amino-terminus of SIMPL is required for this interaction. Using a combination of amino acid composition analysis, PONDR VL-XT prediction, charge-hydropathy plots, and cumulative distribution functions, the amino-terminal region of both mouse and human SIMPL proteins was predicted to be intrinsically disordered. These data, taken together, suggest that Hsp70/Hsc70 bind the intrinsically disordered amino-terminal region of SIMPL to stabilize the protein and thereby regulate its activity. Understanding the regulation of SIMPL through its interaction with Hsp70/Hsc70 may serve as a novel means of modulating tumor necrosis factor alpha signaling.

    View details for Web of Science ID 000243115700007

    View details for PubMedID 17233114

  • Tumor necrosis factor alpha induction of NF-kappa B requires the novel coactivator SIMPL MOLECULAR AND CELLULAR BIOLOGY Kwon, H. J., Breese, E. H., Vig-Varga, E., Luo, Y., Lee, Y. L., Goebl, M. G., Harrington, M. A. 2004; 24 (21): 9317-9326

    Abstract

    A myriad of stimuli including proinflammatory cytokines, viruses, and chemical and mechanical insults activate a kinase complex composed of IkappaB kinase beta (IKK-beta), IKK-alpha, and IKK-gamma/N, leading to changes in NF-kappaB-dependent gene expression. However, it is not clear how the NF-kappaB response is tailored to specific cellular insults. Signaling molecule that interacts with mouse pelle-like kinase (SIMPL) is a signaling component required for tumor necrosis factor alpha (TNF-alpha)-dependent but not interleukin-1-dependent NF-kappaB activation. Herein we demonstrate that nuclear localization of SIMPL is required for type I TNF receptor-induced NF-kappaB activity. SIMPL interacts with nuclear p65 in a TNF-alpha-dependent manner to promote endogenous NF-kappaB-dependent gene expression. The interaction between SIMPL and p65 enhances p65 transactivation activity. These data support a model in which TNF-alpha activation of NF-kappaB dependent-gene expression requires nuclear relocalization of p65 as well as nuclear relocalization of SIMPL, generating a TNF-alpha-specific induction of gene expression.

    View details for DOI 10.1128/MCB.24.21.9317-9326.2004

    View details for Web of Science ID 000224943300006

    View details for PubMedID 15485901

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