|
Paul L. Fox, Ph.D.StaffDepartment of Cell Biology Professor
Lerner Research Institute / NC10 |
Areas of general research interest:
Translational control of inflammatory gene expression, endothelial cell migration, macrophage iron metabolism.
Current program:
• Membrane, Cytoskeleton, and RNA Polarization during Endothelial Cell Movement.
• Role of Ferroxidases in Iron Homeostasis, Inflammation, and Atherosclerosis.
• Translational Control of Gene Expression in Macrophages.
Investigators:
• Abul Arif, Ph.D., Research Associate
• Bakhautdin Bakytzhan, B.S., Graduate Student
• Erin Childers, Undergraduate Student
• Sandeepa M. Eswarappa, Ph.D., Postdoctoral Fellow
• Yi Fan, M.D., Ph.D., Postdoctoral Fellow
• Paroma Ghosh, Ph.D., Postdoctoral Fellow
• Prabar Kumar Ghosh, Ph.D., Research Associate
• Faye Jafarifar, B.S., Graduate Student
• Jie Jia, Ph.D., Research Associate
• Megan McCartney, Undergraduate Student
• Fulvia Terenzi, Ph.D., Research Associate
• Ashley Wallace, Undergraduate Student
• Peng Yao, Ph.D., Postdoctoral Fellow
Collaborators:
• Paul DiCorleto, Ph.D., Department of Cell Biology, CCF
• Donna Driscoll, Ph.D., Department of Cell Biology, CCF
• Linda Graham, M.D., Department of Vascular Surgery, CCF
• Maria Hatzoglou, Ph.D., Department of Nutrition, Case Western Reserve University
• Stanley Hazen, M.D., Ph.D., Department of Cell Biology, CCF
• Xiaoxia Li, Ph.D., Department of Immunology, CCF
• Chinmay Mukhopadhyay, Ph.D., Jawaharlal Nehru University, India
• Saul Nurko, M.D., Department of Hypertension & Nephrology, CCF
• Partho Sarothi Ray, Ph.D., Indian Institute of Science Education & Research, India
• Dennis Stuehr, Ph.D., Department of Pathobiology, CCF
Brief Description:
We have discovered a translational control pathway that selectively regulates inflammatory gene expression in myeloid cells, and may be an endogenous regulator of the duration and magnitude of the inflammatory response. IFN-gamma induces expression of certain pro-inflammatory mRNAs, e.g., vascular endothelial growth factor (VEGF)-A and ceruloplasmin (Cp), but synthesis of the proteins is limited by translational silencing. IFN-gamma induces assembly of the 4-protein, IFN-Gamma-Activated Inhibitor of Translation (GAIT) complex, that binds a 29-nt RNA element in the 3’untranslated region (UTR) of target mRNAs, and inhibits translation. The GAIT complex contains glutamyl-prolyl-tRNA synthetase (EPRS), NS1-associated protein, ribosomal protein L13a, and GAPDH. We have focused much of our attention on EPRS is central to the GAIT system because it is responsible for target mRNA recognition and binding. EPRS joins several other tRNA synthetases that exhibit important noncanonical functions unrelated to synthetase activity. Also, we are investigating the signal transduction pathway that leads to activation of the GAIT pathway, and the mechanisms by which EPRS and L13a escape their parent complexes.
In other major projects in the laboratory we are investigating the mechanism of endothelial cell (EC) movement, a critical and initiating event in the formation of new blood vessels and in the repair of injured vessels. We focus on the mechanisms by which membranes, cytoskeleton and mRNA become polarized in migrating cells. We also study the role of ferroxidases in cellular and whole-body iron metabolism, particularly during chronic renal failure and other inflammatory diseases. The diversity of these areas encourages investigation at multiple levels, and the laboratory actively pursues biomedical processes at the molecular, cellular, animal model, and human levels.
Key References:
Ray, P.S., Jia, J., Yao, P., Majumder, M., Hatzoglou, M., and Fox, P.L. A stress-responsive RNA switch regulates VEGFA expression. Nature 457: 915-919, 2009. PMID: 19098893
Arif, A., Jia, J., Mukhopadhyay, R., Willard, B., Kinter, M., and Fox, P. L. Two-site phosphorylation of EPRS coordinates multimodal regulation of noncanonical translational control activity. Mol. Cell, in press, 2009.
Fan, Y., Gong, Y., Ghosh, P.K., Graham, L.M. and Fox, P.L. Spatial coordination of actin polymerization and ILK–Akt2 activity during endothelial cell migration. Dev. Cell, in press, 2009.
Mukhopadhyay, R., Jia, J., Arif, A., Ray, P.S., and Fox, P. L. The GAIT system: A gatekeeper of inflammatory gene expression. Trends Biochem. Sci., in press, 2009.
Mukhopadhyay, R., Ray, P.S., Arif, A., Brady, A.K., Kinter, M., and Fox, P.L. DAPK-ZIPK-L13a axis constitutes a negative-feedback module regulating inflammatory gene expression. Mol. Cell 32: 371-382, 2008. PMID: 18995835
Jia, J., Arif, A., Ray, P.S. and Fox, P.L. WHEP domains direct noncanonical function of glutamyl-prolyl tRNA synthetase in translational control of gene expression. Mol. Cell 29: 679-690, 2008. PMID: 18374644
Ray, P.S., Arif, A., and Fox, P.L. Macromolecular complexes as depots for releasable regulatory proteins. Trends Biochem. Sci. 32: 158-164, 2007. PMID: 17321138
Ray, P.S. and Fox, P.L. A post-transcriptional pathway represses monocyte VEGF-A expression and angiogenic activity. EMBO J. 26: 3360-3372, 2007. PMID: 17611605
Cherukuri, S., Potla, R., Sarkar, J., Nurko, S., Harris, Z.L., and Fox, P.L. Unexpected role of ceruloplasmin in intestinal iron absorption. Cell Metab. 2: 309-319, 2005. PMID: 16271531
Sampath, P., Mazumder, B., Seshadri, V., Gerber, C.A., Chavatte, L., Kinter, M., Ting, S.M., Dignam, J.D., Kim, S., Driscoll, D.M., and Fox, P.L. Noncanonical function of glutamyl-prolyl-tRNA synthetase: Gene-specific silencing of translation. Cell 119: 195-208, 2004. PMID: 15479637
Vasanji, A., Ghosh, P.K., Graham, L.M., Eppell, S.J., and Fox, P.L. Polarization of plasma membrane microviscosity during endothelial cell migration. Dev. Cell 6: 29-41, 2004. PMID: 14723845
Mazumder, B., Sampath, P., Seshadri, V., Maitra, R.K., DiCorleto, P.E., and Fox, P.L. Regulated release of L13a from the 60S ribosomal subunit as a mechanism of transcript-specific translational control. Cell 115: 187-198, 2003. PMID: 14567916
Sampath, P., Mazumder, B., Seshadri, V., and Fox, P.L. Transcript-selective translational silencing by gamma interferon is directed by a novel structural element in the ceruloplasmin mRNA 3’ UTR. Mol. Cell. Biol. 23: 1509-1519, 2003. PMID: 12588972
Parat, M.O., Anand-Apte, B., and Fox, P.L. Differential caveolin-1 polarization in endothelial cells during migration in 2- and 3-dimensions. Mol. Biol. Cell 14: 3156-3168, 2003. PMID: 12925753
Sarkar, J., Seshadri, V., Tripoulas, N.A., Ketterer, M.E., and Fox, P.L. Role of ceruloplasmin in macrophage iron efflux during hypoxia. J. Biol. Chem. 278: 44018-44024, 2003. PMID: 12952974
Mazumder, B., Seshadri, V., and Fox, P.L. Translational control by the 3’-UTR: the ends specify the means. Trends Biochem. Sci. 28: 91-98, 2003. PMID: 12575997
Ghosh, P.K., Vasanji, A., Murugesan, G., Eppell, S.J., Graham, L.M., and Fox, P.L. Membrane microviscosity regulates endothelial cell motility. Nat. Cell Biol. 4: 894-900, 2002. PMID: 12402046