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Paul L. Fox, Ph.D.Staff
Department of Cell Biology |
Area of general research interest:
Endothelial cell migration, translational control of gene expression, iron metabolism, macrophage inflammation.
Current program:
- Role of Plasma Membrane in Regulation of Endothelial Cell Motility.
- Membrane Polarization during Cell Movement.
- Role of Ferroxidases in Inflammation and Atherosclerosis.
- Role of Ceruloplasmin and Hephaestin in Iron Homeostasis.
- Translational Control of Gene Expression in Macrophages.
Investigators:
- Arif, Abul, Ph.D., Fellow
- Bakytzhan Bakhautdin, Graduate Student
- Piyali Chatterjee, Ph.D., Fellow
- Lisa Dieter (for Dr Nurko)
- Yi Fan, MS., Graduate Student
- Paroma Ghosh, Ph.D., Fellow
- Prabar Kumar Ghosh, Ph.D., Research Associate
- Faye Jafarifar, Graduate Student
- Jie Jia, Ph.D., Fellow
- Katie McConnell, Student
- Rupak Mukhopadhyay, Ph.D., Fellow
- Sirisha Vadlamani, Graduate Student
Collaborators:
- Kwaku Dayie, Ph.D., Department of Molecular Genetics, CCF
- Donna Driscoll, Ph.D., Department of Cell Biology, CCF
- Linda Graham, M.D., Department of Vascular Surgery, CCF
- Stanley Hazen, M.D., Ph.D., Department of Cell Biology, CCF
- Barsanjit Mazumder, Ph.D., Department of Biology, Cleveland State University
- Chinmay Mukhopadhyay, Ph.D., , Jawaharlal Nehru University, India
- Saul Nurko, M.D., Department of Hypertension & Nephrology, 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, but synthesis of the proteins is limited by translational silencing. IFN gamma induces assembly of the four-protein IFN gamma-activated inhibitor of translation (GAIT) complex, which binds a specific RNA element in the 3’ untranslated region 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 because it is responsible for target mRNA recognition and binding. We are investigating the signal transduction pathways that lead to activation of the GAIT system and the mechanisms by which EPRS and L13a escape their parent complexes. Finally, we are taking a ribonomic approach to elucidate the family of targets silenced by this pathway.
In other major projects, we are investigating the mechanism of endothelial cell movement, a critical and initiating event in the formation of new blood vessels and in the repair of injured vessels. We also study the role of ferroxidases in cellular and whole-body iron metabolism, particularly during renal failure.
Key References:
Ray, P.S., Fox, P.L. A post-transcriptional pathway represses monocyte VEGF-A expression and angiogenic activity. EMBO J. 26: 3360-3372, 2007.
Ray, P.S., Arif, A., and Fox, P.L. Macromolecular complexes as depots for releasable regulatory proteins . Trends Biochem. Sci. 32: 158-164, 2007.
Kapasi, P., Chaudhuri, S., Vyas, K., Baus, D., Komar, A.A., Fox, P.L., Merrick , W.C., and Mazumder, B. L13a blocks 48S assembly: Role of a general initiation factor in mRNA-specific translational control. Mol. Cell 25: 113-126, 2007.
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.
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.
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.
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.
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.
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.
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.
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.
Mazumder, B., Seshadri, V., Imataka, H., Sonenberg, N., and Fox, P.L. Translational silencing of ceruloplasmin requires the essential elements of mRNA circularization: Poly(A) tail, poly(A)-binding protein, and eukaryotic translation initiation factor 4G. Mol. Cell. Biol. 21: 6440-6449, 2001.