Caroline C. Philpott, M.D. : NIDDK

Caroline C. Philpott, M.D.

NIDDK, National Institutes of Health
Building 10, Room 9B16A
10 Center Dr.
Bethesda, MD 20892
Tel: 301-435-4018
Fax: 301-402-0491

Education / Previous Training and Experience:
B.A., Duke University, 1983
M.D., Duke University, 1987

Research Statement:

Dysregulated iron metabolism and iron overload are features of a growing number of human diseases, yet only a few of the cellular proteins that are required for iron utilization and homeostasis have been identified and the cellular responses to iron limitation and iron excess are largely unknown. Mechanisms of iron acquisition have emerged as important virulence factors in pathogenic bacteria and fungi, and microbial systems of iron uptake and utilization are therefore significant targets of antibiotic drug development. We have constructed genetic models of iron deficiency and iron overload in yeast by generating strains in which the major iron-dependent transcription factor is either deleted or present as the constitutively active allele. Using cDNA microarrays representing the entire yeast genome, we have identified the genes in budding yeast that are regulated by iron and have functionally characterized numerous novel genes identified through the arrays. Our research efforts have led to the discovery of: new genes involved in iron metabolism, novel systems of iron uptake, and unexpected interactions with other metabolic pathways.

We have identified and functionally characterized the systems of siderophore iron uptake in yeast, a process that is important in the virulence of pathogenic fungi. The controlled intracellular trafficking of transporter molecules has emerged as an important mechanism for regulating transport activity in both mammalian and fungal systems, yet the molecular events that control this trafficking are largely unknown. We study the siderophore transport systems of yeast with an emphasis on the intracellular trafficking of the transporters. Our array work indicates that the global response to iron deprivation in yeast includes shutting off non-essential metabolic pathways that consume iron and shifting to parallel iron-independent pathways. We are studying how this shift is controlled at the transcriptional level. As we explore yeast iron homeostasis in further detail, we are also using the versatility of the yeast system to explore novel systems of iron homeostasis in pathogenic fungi. Studies of metal homeostasis in yeast have had a tremendous impact on our understanding of metal homeostasis in humans. We plan to extend this impact in our newest research area by exploiting the differences in the iron-handling systems of yeast and human cells to identify human genes of iron metabolism.

Indirect immunofluorescence of the iron-regulated cell wall mannoprotein FIT1?
Indirect immunofluorescence of the iron-regulated cell wall mannoprotein FIT1
Image of Iron uptake systems of S. cerevisiae
Iron uptake systems of S. cerevisiae
Image of Iron Uptake in Mammals
Iron Uptake in Mammals
(Click to enlarge images)

Selected Publications:

Kim Y, Lampert SM, Philpott CC A receptor domain controls the intracellular sorting of the ferrichrome transporter, ARN1. EMBO J (24): 952-62, 2005. [Full Text/Abstract]

Shakoury-Elizeh M Tiedeman J Rashford J Ferea T Demeter J Garcia E Rolfes R Brown PO Botstein D Philpott CC Transcriptional remodeling in response to iron deprivation in Saccharomyces cerevisiae. Mol Biol Cell (15): 1233-43, 2004. [Full Text/Abstract]

Pelletier B Beaudoin J Philpott CC Labbe S Fep1 represses expression of the fission yeast Schizosaccharomyces pombe siderophore-iron transport system. Nucleic Acids Res (31): 4332-44, 2003. [Full Text/Abstract]

Protchenko O Philpott CC Regulation of intracellular heme levels by HMX1, a homologue of heme oxygenase, in Saccharomyces cerevisiae. J Biol Chem (278): 36582-7, 2003. [Full Text/Abstract]

Moore RE Kim Y Philpott CC The mechanism of ferrichrome transport through Arn1p and its metabolism in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A (100): 5664-9, 2003. [Full Text/Abstract]

Kim Y Yun CW Philpott CC Ferrichrome induces endosome to plasma membrane cycling of the ferrichrome transporter, Arn1p, in Saccharomyces cerevisiae. EMBO J (21): 3632-42, 2002. [Full Text/Abstract]

Philpott CC Molecular aspects of iron absorption: Insights into the role of HFE in hemochromatosis. Hepatology (35): 993-1001, 2002. [Full Text/Abstract]

Philpott CC Protchenko O Kim YW Boretsky Y Shakoury-Elizeh M The response to iron deprivation in Saccharomyces cerevisiae: expression of siderophore-based systems of iron uptake. Biochem Soc Trans (30): 698-702, 2002. [Full Text/Abstract]

Yun CW Bauler M Moore RE Klebba PE Philpott CC The role of the FRE family of plasma membrane reductases in the uptake of siderophore-iron in Saccharomyces cerevisiae. J Biol Chem (276): 10218-23, 2001. [Full Text/Abstract]

Protchenko O Ferea T Rashford J Tiedeman J Brown PO Botstein D Philpott CC Three cell wall mannoproteins facilitate the uptake of iron in Saccharomyces cerevisiae. J Biol Chem (276): 49244-50, 2001. [Full Text/Abstract]

Yun CW Ferea T Rashford J Ardon O Brown PO Botstein D Kaplan J Philpott CC Desferrioxamine-mediated iron uptake in Saccharomyces cerevisiae. Evidence for two pathways of iron uptake. J Biol Chem (275): 10709-15, 2000. [Full Text/Abstract]

Yun CW Tiedeman JS Moore RE Philpott CC Siderophore-iron uptake in saccharomyces cerevisiae. Identification of ferrichrome and fusarinine transporters. J Biol Chem (275): 16354-9, 2000. [Full Text/Abstract]

Page last updated: December 17, 2008

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