Thomas V. O'Halloran
Charles E. and Emma H. Morrison Professor
Metalloregulatory proteins; molecular mechanisms of metal-responsive gene expression; protein-DNA interactions; oxygen activation by nonheme iron proteins; bioinorganic chemistry
We are exploring the cell and molecular biology of transition elements. One of our approaches is to isolate novel receptors and characterize their function, structure and chemical mechanism. In other strategies, we are interrogating the vesicular trafficking of these elements by developing vital fluorescent probes that are specific for metal ions such as Zn(II). Together, these types of experiments are delineating elemental aspects of microbial and mammalian biology.
Two new classes of metalloprotein have emerged from these studies. Metalloregulatory proteins such as MerR, Fur, Zur, PcoRS, and ZntR act as metal responsive genetic switches. Our goal in studies of these proteins is to understand the basis of metal ion recognition, establish the mechanisms by which metal binding alters gene expression and ultimately uses these insights to describe global aspects of metal metabolism.
Metallochaperones are diffusible metal ion receptors involved in intracellular metal trafficking. It has long been thought that metalloproteins are highly specific chelators that select available metal ions in the cytoplasm of the cell. Our recent studies indicate the opposite: the 'free' copper concentration is lower than one atom per cell; too low to allow a protein to acquire copper without assistance. Atxl, a prototypical metallochaperone, protects and guides Cu(I) to a specific target enzyme in the cytoplasm. In humans, Atxl delivers Cu(I) to proteins involved in fatal metal-based disorders such as Menkes' syndrome and Wilson disease. Characterization of CCS, copper chaperone for superoxide dismutase, is another challenge, but has payoffs in our understanding and treatment of severe neurodegenerative diseases such as ALS.
Allosteric transcriptional regulation via changes in the overall topology of the core promoter. Philips SJ, Canalizo-Hernandez M, Yildirim I, Schatz GC, Mondragón A, and O'Halloran TV. Science. 2015 August 21;349(6250):877-881.
Identification of a New Epitope in uPAR as a Target for the Cancer Therapeutic Monoclonal Antibody ATN-658, a Structural Homolog of the uPAR Binding Integrin CD11b (αM). Xu X, Cai Y, Wei Y, Donate F, Juarez J, Parry G, Chen L, Meehan EJ, Ahn RW, Ugolkov A, Dubrovskyi O, O'Halloran TV, Huang M, and Mazar AP. PLoS ONE. 2014 January 21;9(1):e85349.
Alignment of low-dose X-ray fluorescence tomography images using differential phase contrast. Hong YP, Gleber S-C, O'Halloran TV, Que EL, Bleher R, Vogt S, Woodruff TK, and Jacobsen C. Journal of Synchrotron Radiation. 2014 January;21(pt 1):229-234.
Urokinase Plasminogen Activator System–Targeted Delivery of Nanobins as a Novel Ovarian Cancer Therapy. Zhang Y, Kenny HA, Swindell EP, Mitra AK, Hankins PL, Ahn RW, Gwin K, Mazar AP, O'Halloran TV, and Lengyel E. Molecular Cancer Therapeutics. 2013 December;12(12):2628-2639.
Anticancer Activity of Small-Molecule and Nanoparticulate Arsenic(III) Complexes. Swindell EP, Hankins PL, Chen H, Miodragovic DU, and O'Halloran TV. Inorganic Chemistry. 2013 November 4;52(21):12292-12304.
Zinc, insulin, and the liver: a ménage à trois. O'Halloran TV, Kebede M, Philips SJ, and Attie AD. Journal of Clinical Investigation. 2013 October 1;123(10):4136-4139.
pH-Responsive Theranostic Polymer-Caged Nanobins: Enhanced Cytotoxicity and T1 MRI Contrast by Her2 Targeting. Hong BJ, Swindell EP, MacRenaris KW, Hankins PL, Chipre AJ, Mastarone DJ, Ahn RW, Meade TJ, O'Halloran TV, and Nguyen ST. Particle & Particle Systems Characterization. 2013 September;30(9):770-774.
A copper hyperaccumulation phenotype correlates with pathogenesis in Cryptococcus neoformans. Raja MR, Waterman SR, Qiu J, Bleher R, Williamson PR, and O'Halloran TV. Metallomics. 2013 April 1;5(4):363-371.
Nano-Encapsulation of Arsenic Trioxide Enhances Efficacy against Murine Lymphoma Model while Minimizing Its Impact on Ovarian Reserve In Vitro and In Vivo. Ahn RW, Barrett SL, Raja MR, Jozefik JK, Spaho L, Chen H, Bally MB, Mazar AP, Avram MJ, Winter JN, Gordon LI, Shea LD, O'Halloran TV, and Woodruff TK. PLoS ONE. 2013 March 20;8(3):e58491.
Improved anti-proliferative effect of doxorubicin-containing polymer nanoparticles upon surface modification with cationic groups. Krovi SA, Swindell EP, O'Halloran TV, and Nguyen ST. Journal of Materials Chemistry. 2012 December;22(48):25463-25470.
Role of CTR4 in the Virulence of Cryptococcus neoformans. Waterman SR, Park Y-D, Raja M, Qiu J, Hammoud DA, O'Halloran TV, and Williamson PR. mBio. 2012 October 2;3(5):e00285-12.
Zinc Maintains Prophase I Arrest in Mouse Oocytes Through Regulation of the MOS-MAPK Pathway. Kong BY, Bernhardt ML, Kim AM, O'Halloran TV, and Woodruff TK. Biology of Reproduction. 2012 July 1;87(1):11,1-12.
Fluxes in “Free” and Total Zinc Are Essential for Progression of Intraerythrocytic Stages of Plasmodium falciparum. Marvin RG, Wolford JL, Kidd MJ, Murphy S, Ward J, Que EL, Mayer ML, Penner-Hahn JE, Haldar K, and O'Halloran TV. Chemistry & Biology. 2012 June 22;19(6):731-741.
View all publications by Thomas V. O'Halloran in the National Library of Medicine (PubMed). Current and former IBiS students in blue.