Bio

Honors & Awards


  • Postdoctoral Fellowship, American Cancer Society (2013-present)
  • Dean's Fellowship, Stanford University School of Medicine (2012-2013)

Professional Education


  • Doctor of Philosophy, University of Oregon (2011)
  • Bachelor of Science, University of Washington (2004)

Stanford Advisors


Publications

Journal Articles


  • H. pylori virulence factor CagA increases intestinal cell proliferation by Wnt pathway activation in a transgenic zebrafish model. Disease models & mechanisms Neal, J. T., Peterson, T. S., Kent, M. L., Guillemin, K. 2013; 6 (3): 802-810

    Abstract

    Infection with Helicobacter pylori is a major risk factor for the development of gastric cancer, and infection with strains carrying the virulence factor CagA significantly increases this risk. To investigate the mechanisms by which CagA promotes carcinogenesis, we generated transgenic zebrafish expressing CagA ubiquitously or in the anterior intestine. Transgenic zebrafish expressing either the wild-type or a phosphorylation-resistant form of CagA exhibited significantly increased rates of intestinal epithelial cell proliferation and showed significant upregulation of the Wnt target genes cyclinD1, axin2 and the zebrafish c-myc ortholog myca. Coexpression of CagA with a loss-of-function allele encoding the ?-catenin destruction complex protein Axin1 resulted in a further increase in intestinal proliferation. Coexpression of CagA with a null allele of the key ?-catenin transcriptional cofactor Tcf4 restored intestinal proliferation to wild-type levels. These results provide in vivo evidence of Wnt pathway activation by CagA downstream of or in parallel to the ?-catenin destruction complex and upstream of Tcf4. Long-term transgenic expression of wild-type CagA, but not the phosphorylation-resistant form, resulted in significant hyperplasia of the adult intestinal epithelium. We further utilized this model to demonstrate that oncogenic cooperation between CagA and a loss-of-function allele of p53 is sufficient to induce high rates of intestinal small cell carcinoma and adenocarcinoma, establishing the utility of our transgenic zebrafish model in the study of CagA-associated gastrointestinal cancers.

    View details for DOI 10.1242/dmm.011163

    View details for PubMedID 23471915

  • beta-Catenin-Driven Cancers Require a YAP1 Transcriptional Complex for Survival and Tumorigenesis CELL Rosenbluh, J., Nijhawan, D., Cox, A. G., Li, X., Neal, J. T., Schafer, E. J., Zack, T. I., Wang, X., Tsherniak, A., Schinzel, A. C., Shao, D. D., Schumacher, S. E., Weir, B. A., Vazquez, F., Cowley, G. S., Root, D. E., Mesirov, J. P., Beroukhim, R., Kuo, C. J., Goessling, W., Hahn, W. C. 2012; 151 (7): 1457-1473

    Abstract

    Wnt/?-catenin signaling plays a key role in the pathogenesis of colon and other cancers; emerging evidence indicates that oncogenic ?-catenin regulates several biological processes essential for cancer initiation and progression. To decipher the role of ?-catenin in transformation, we classified ?-catenin activity in 85 cancer cell lines in which we performed genome-scale loss-of-function screens and found that ?-catenin active cancers are dependent on a signaling pathway involving the transcriptional regulator YAP1. Specifically, we found that YAP1 and the transcription factor TBX5 form a complex with ?-catenin. Phosphorylation of YAP1 by the tyrosine kinase YES1 leads to localization of this complex to the promoters of antiapoptotic genes, including BCL2L1 and BIRC5. A small-molecule inhibitor of YES1 impeded the proliferation of ?-catenin-dependent cancers in both cell lines and animal models. These observations define a ?-catenin-YAP1-TBX5 complex essential to the transformation and survival of ?-catenin-driven cancers.

    View details for DOI 10.1016/j.cell.2012.11.026

    View details for Web of Science ID 000312890300012

    View details for PubMedID 23245941

  • Identification of genetic modifiers of CagA-induced epithelial disruption in Drosophila. Frontiers in cellular and infection microbiology Reid, D. W., Muyskens, J. B., Neal, J. T., Gaddini, G. W., Cho, L. Y., Wandler, A. M., Botham, C. M., Guillemin, K. 2012; 2: 24-?

    Abstract

    Helicobacter pylori strains containing the CagA protein are associated with high risk of gastric diseases including atrophic gastritis, peptic ulcers, and gastric cancer. CagA is injected into host cells via a Type IV secretion system where it activates growth factor-like signaling, disrupts cell-cell junctions, and perturbs host cell polarity. Using a transgenic Drosophila model, we have shown that CagA expression disrupts the morphogenesis of epithelial tissues such as the adult eye. Here we describe a genetic screen to identify modifiers of CagA-induced eye defects. We determined that reducing the copy number of genes encoding components of signaling pathways known to be targeted by CagA, such as the epidermal growth factor receptor (EGFR), modified the CagA-induced eye phenotypes. In our screen of just over half the Drosophila genome, we discovered 12 genes that either suppressed or enhanced CagA's disruption of the eye epithelium. Included in this list are genes involved in epithelial integrity, intracellular trafficking, and signal transduction. We investigated the mechanism of one suppressor, encoding the epithelial polarity determinant and junction protein Coracle, which is homologous to the mammalian Protein 4.1. We found that loss of a single copy of coracle improved the organization and integrity of larval retinal epithelia expressing CagA, but did not alter CagA's localization to cell junctions. Loss of a single copy of the coracle antagonist crumbs enhanced CagA-associated disruption of the larval retinal epithelium, whereas overexpression of crumbs suppressed this phenotype. Collectively, these results point to new cellular pathways whose disruption by CagA are likely to contribute to H. pylori-associated disease pathology.

    View details for DOI 10.3389/fcimb.2012.00024

    View details for PubMedID 22919616

  • Epithelial cell proliferation in the developing zebrafish intestine is regulated by the Wnt pathway and microbial signaling via Myd88 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Cheesman, S. E., Neal, J. T., Mittge, E., Seredick, B. M., Guillemin, K. 2011; 108: 4570-4577

    Abstract

    Rates of cell proliferation in the vertebrate intestinal epithelium are modulated by intrinsic signaling pathways and extrinsic cues. Here, we report that epithelial cell proliferation in the developing zebrafish intestine is stimulated both by the presence of the resident microbiota and by activation of Wnt signaling. We find that the response to microbial proliferation-promoting signals requires Myd88 but not TNF receptor, implicating host innate immune pathways but not inflammation in the establishment of homeostasis in the developing intestinal epithelium. We show that loss of axin1, a component of the ?-catenin destruction complex, results in greater than WT levels of intestinal epithelial cell proliferation. Compared with conventionally reared axin1 mutants, germ-free axin1 mutants exhibit decreased intestinal epithelial cell proliferation, whereas monoassociation with the resident intestinal bacterium Aeromonas veronii results in elevated epithelial cell proliferation. Disruption of ?-catenin signaling by deletion of the ?-catenin coactivator tcf4 partially decreases the proliferation-promoting capacity of A. veronii. We show that numbers of intestinal epithelial cells with cytoplasmic ?-catenin are reduced in the absence of the microbiota in both WT and axin1 mutants and elevated in animals' monoassociated A. veronii. Collectively, these data demonstrate that resident intestinal bacteria enhance the stability of ?-catenin in intestinal epithelial cells and promote cell proliferation in the developing vertebrate intestine.

    View details for DOI 10.1073/pnas.1000072107

    View details for Web of Science ID 000288451300009

    View details for PubMedID 20921418

  • The Purkinje cell degeneration 5J mutation is a single amino acid insertion that destabilizes Nna1 protein MAMMALIAN GENOME CHAKRABARTI, L., Neal, J. T., Miles, M., Martinez, R. A., Smith, A. C., Sopher, B. L., La Spada, A. R. 2006; 17 (2): 103-110

    Abstract

    In the mouse, Purkinje cell degeneration (pcd) is a recessive mutation characterized by degeneration of cerebellar Purkinje cells, retinal photoreceptors, olfactory bulb mitral neurons, and certain thalamic neurons, and is accompanied by defective spermatogenesis. Previous studies of pcd have led to the identification of Nna1 as the causal gene; however, how loss of Nna1 function results in neurodegeneration remains unresolved. One useful approach for establishing which functional domains of a protein underlie a recessive phenotype has been to determine the genetic basis of the various alleles at the locus of interest. Because none of the pcd alleles analyzed at the time of the identification of Nna1 provided insight into the molecular basis of Nna1 loss-of-function, we obtained a recent pcd remutation--pcd5J, and after determining that its phenotype is comparable to existing pcd severe alleles, we sought its genetic basis by sequencing Nna1. In this article we report that pcd5J results from the insertion of a single GAC triplet encoding an aspartic acid residue at position 775 of Nna1. Although this insertion does not affect Nna1 expression at the RNA level, Nna1pcd-5J protein expression is markedly decreased. Pulse-chase experiments reveal that the aspartic acid insertion dramatically destabilizes Nna1pcd-5J protein, accounting for the observation that pcd5J is a severe allele. The presence of a readily detectable genetic mutation in pcd5J confirms that Nna1 loss-of-function alone underlies the broad pcd phenotype and will facilitate further studies of how Nna1 loss-of-function produces neurodegeneration and defective spermatogenesis in pcd mice.

    View details for DOI 10.1007/s00335-005-0096-x

    View details for Web of Science ID 000235219200002

    View details for PubMedID 16465590

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