Bio

Professional Education


  • Doctor of Philosophy, Loyola University Of Chicago (2010)
  • B.S., Illinois State University, Chemistry and Biochem/Mol Bio (2004)

Stanford Advisors


Teaching

Publications

Journal Articles


  • Analysis of p53 transactivation domain mutants reveals Acad11 as a metabolic target important for p53 pro-survival function. Cell reports Jiang, D., Lagory, E. L., Kenzelmann Brož, D., Bieging, K. T., Brady, C. A., Link, N., Abrams, J. M., Giaccia, A. J., Attardi, L. D. 2015; 10 (7): 1096-1109

    Abstract

    The p53 tumor suppressor plays a key role in maintaining cellular integrity. In response to diverse stress signals, p53 can trigger apoptosis to eliminate damaged cells or cell-cycle arrest to enable cells to cope with stress and survive. However, the transcriptional networks underlying p53 pro-survival function are incompletely understood. Here, we show that in oncogenic-Ras-expressing cells, p53 promotes oxidative phosphorylation (OXPHOS) and cell survival upon glucose starvation. Analysis of p53 transcriptional activation domain mutants reveals that these responses depend on p53 transactivation function. Using gene expression profiling and ChIP-seq analysis, we identify several p53-inducible fatty acid metabolism-related genes. One such gene, Acad11, encoding a protein involved in fatty acid oxidation, is required for efficient OXPHOS and cell survival upon glucose starvation. This study provides new mechanistic insight into the pro-survival function of p53 and suggests that targeting this pathway may provide a strategy for therapeutic intervention based on metabolic perturbation.

    View details for DOI 10.1016/j.celrep.2015.01.043

    View details for PubMedID 25704813

  • Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Rankin, E. B., Fuh, K. C., Castellini, L., Viswanathan, K., Finger, E. C., Diep, A. N., Lagory, E. L., Kariolis, M. S., Chan, A., Lindgren, D., Axelson, H., Miao, Y. R., Krieg, A. J., Giaccia, A. J. 2014; 111 (37): 13373-13378
  • Cross-talk between hypoxia and insulin signaling through Phd3 regulates hepatic glucose and lipid metabolism and ameliorates diabetes NATURE MEDICINE Taniguchi, C. M., Finger, E. C., Krieg, A. J., Wu, C., Diep, A. N., Lagory, E. L., Wei, K., McGinnis, L. M., Yuan, J., Kuo, C. J., Giaccia, A. J. 2013; 19 (10): 1325-?

    Abstract

    Signaling initiated by hypoxia and insulin powerfully alters cellular metabolism. The protein stability of hypoxia-inducible factor-1 alpha (Hif-1α) and Hif-2α is regulated by three prolyl hydroxylase domain-containing protein isoforms (Phd1, Phd2 and Phd3). Insulin receptor substrate-2 (Irs2) is a critical mediator of the anabolic effects of insulin, and its decreased expression contributes to the pathophysiology of insulin resistance and diabetes. Although Hif regulates many metabolic pathways, it is unknown whether the Phd proteins regulate glucose and lipid metabolism in the liver. Here, we show that acute deletion of hepatic Phd3, also known as Egln3, improves insulin sensitivity and ameliorates diabetes by specifically stabilizing Hif-2α, which then increases Irs2 transcription and insulin-stimulated Akt activation. Hif-2α and Irs2 are both necessary for the improved insulin sensitivity, as knockdown of either molecule abrogates the beneficial effects of Phd3 knockout on glucose tolerance and insulin-stimulated Akt phosphorylation. Augmenting levels of Hif-2α through various combinations of Phd gene knockouts did not further improve hepatic metabolism and only added toxicity. Thus, isoform-specific inhibition of Phd3 could be exploited to treat type 2 diabetes without the toxicity that could occur with chronic inhibition of multiple Phd isoforms.

    View details for DOI 10.1038/nm.3294

    View details for Web of Science ID 000325531700033

    View details for PubMedID 24037093

  • A low-carb diet kills tumor cells with a mutant p53 tumor suppressor gene: The Atkins diet suppresses tumor growth Comment on: Rodriguez OC, et al. Cell Cycle 2012; 11:4436-46; PMID:23151455; http://dx.doi.org/10.4161/cc.22778 CELL CYCLE Lagory, E. L., Giaccia, A. J. 2013; 12 (5): 718-719

    View details for DOI 10.4161/cc.22778

    View details for Web of Science ID 000315522200008

  • VHL loss in renal cell carcinoma leads to up-regulation of CUB domain-containing protein 1 to stimulate PKC delta-driven migration PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Razorenova, O. V., Finger, E. C., Colavitti, R., Chernikova, S. B., Boiko, A. D., Chan, C. K., Krieg, A., Bedogni, B., LaGory, E., Weissman, I. L., Broome-Powell, M., Giaccia, A. J. 2011; 108 (5): 1931-1936

    Abstract

    A common genetic mutation found in clear cell renal cell carcinoma (CC-RCC) is the loss of the von Hippel-Lindau (VHL) gene, which results in stabilization of hypoxia-inducible factors (HIFs), and contributes to cancer progression and metastasis. CUB-domain-containing protein 1 (CDCP1) was shown to promote metastasis in scirrhous and lung adenocarcinomas as well as in prostate cancer. In this study, we established a molecular mechanism linking VHL loss to induction of the CDCP1 gene through the HIF-1/2 pathway in renal cancer. Also, we report that Fyn, which forms a complex with CDCP1 and mediates its signaling to PKC?, is a HIF-1 target gene. Mechanistically, we found that CDCP1 specifically regulates phosphorylation of PKC?, but not of focal adhesion kinase or Crk-associated substrate. Signal transduction from CDCP1 to PKC? leads to its activation, increasing migration of CC-RCC. Furthermore, patient survival can be stratified by CDCP1 expression at the cell surface of the tumor. Taken together, our data indicates that CDCP1 protein might serve as a therapeutic target for CC-RCC.

    View details for DOI 10.1073/pnas.1011777108

    View details for Web of Science ID 000286804700036

    View details for PubMedID 21233420

  • The Protein Kinase C delta Catalytic Fragment Is Critical for Maintenance of the G(2)/M DNA Damage Checkpoint JOURNAL OF BIOLOGICAL CHEMISTRY Lagory, E. L., Sitailo, L. A., Denning, M. F. 2010; 285 (3): 1879-1887

    Abstract

    Protein kinase Cdelta (PKCdelta) is an essential component of the intrinsic apoptotic program. Following DNA damage, such as exposure to UV radiation, PKCdelta is cleaved in a caspase-dependent manner, generating a constitutively active catalytic fragment (PKCdelta-cat), which is necessary and sufficient for keratinocyte apoptosis. We found that in addition to inducing apoptosis, expression of PKCdelta-cat caused a pronounced G(2)/M cell cycle arrest in both primary human keratinocytes and immortalized HaCaT cells. Consistent with a G(2)/M arrest, PKCdelta-cat induced phosphorylation of Cdk1 (Tyr(15)), a critical event in the G(2)/M checkpoint. Treatment with the ATM/ATR inhibitor caffeine was unable to prevent PKCdelta-cat-induced G(2)/M arrest, suggesting that PKCdelta-cat is functioning downstream of ATM/ATR in the G(2)/M checkpoint. To better understand the role of PKCdelta and PKCdelta-cat in the cell cycle response to DNA damage, we exposed wild-type and PKCdelta null mouse embryonic fibroblasts (MEFs) to UV radiation. Wild-type MEFs underwent a pronounced G(2)/M arrest, Cdk1 phosphorylation, and induction of apoptosis following UV exposure, whereas PKCdelta null MEFs were resistant to these effects. Expression of PKCdelta-green fluorescent protein, but not caspase-resistant or kinase-inactive PKCdelta, was able to restore G(2)/M checkpoint integrity in PKCdelta null MEFs. The function of PKCdelta in the DNA damage-induced G(2)/M cell cycle checkpoint may be a critical component of its tumor suppressor function.

    View details for DOI 10.1074/jbc.M109.055392

    View details for Web of Science ID 000273429100034

    View details for PubMedID 19917613

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