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John G. Monroe, Ph.D.

John G. Monroe, Ph.D.

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Emeritus Professor of Pathology and Laboratory Medicine
Department: Pathology and Laboratory Medicine

Contact information
Room 311 BRB II/III
421 Curie Blvd
Philadelphia, PA 19104-6082
Office: (215) 898-2873
Fax: (215) 573-2014
Education:
B.S. (Biochemistry)
University of California, Los Angeles, California, 1975.
M.S. (Cell & Molecular Biology)
California State University, Northridge, California, 1979.
Ph.D. (Immunology)
Duke University, Durham, North Carolina, 1982.
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Description of Research Expertise

Research Interests
Genetic and biochemical regulation of lymphocyte development; signal transduction through lymphocyte antigen receptors.

Key words: Signal transdcution, cellular development, immunology, lymphocyte, tolerance

Description of Research
The interest of my laboratory is in defining the molecular basis for cell fate decisions triggered by plasma membrane receptors. In particular, we have focused on the translation of receptor-initiated signals as they relate to cell fate decisions leading to cell growth, survival and apoptosis. Each of these cellular processes when deregulated lead to the loss of the homeostatic balance necessary for normal tissue growth, renewal, and differentiation and, can result in cancer and autoimmunity.

Depending upon the activation state, the stage of development, or the strength of the signal, a signal generated through the B cell antigen receptor (BCR) results in very different B lymphocyte responses. For example, at the pre-B cell stage, BCR signaling triggers allelic exclusion, expansion of pre-B cells and developmental progression. In contrast, BCR signal transduction in immature-stage B cells leads either to apoptosis or editing and replacement of antigen reactive receptors. These latter processes are believed be the underlying mechanisms regulating negative selection against autoreactive specificities among immature B cells in the bone marrow and periphery. We study the molecular processes regulating the coupling of BCR signals to these specific cellular responses in order to define the processes in normal and disease prone mice that regulate positive and negative selection events during B cell development. Developmental-associated differences in BCR signal transduction and gene regulation are the laboratory's principle areas of focus in defining the biochemical and genetic processes regulating B cell development and selection.

In addition, we have recently discovered the ability of the antigen receptor on B cells to generate survival and differentiation signals independently of ligand. This ligand-independent or tonic signaling depends upon a specific protein sequence motif termed an ITAM. Signaling through ITAMs depends upon Src kinase-medicated phosphorylation of tyrosine residues encoded within these motifs. These ITAM-dependent tonic signals are held in check in hematopoietic tissues by a complex balance of positive and negative regulators whose expression are nearly exclusively restricted to cells of the hematopoietic system. The only known instances of ITAM-containing protein expression in tissues outside of the hematopoietic system are a handful of oncogenic viruses. These viruses encode transmembrane proteins that contain canonical ITAMs. Importantly, the expression of virus encoded ITAM proteins (or highly homologous sequences) have been associated with malignancies of predominately epithelial tissues in rodents and humans. In particular, Mouse Mammary Tumor Virus gp52 and homologous sequences isolated from human tumors possess these motifs and are associated with breast cancer. We have shown that ITAM-dependent signals are generated through MMTV Env and trigger early hallmarks of transformation of mouse and human mammary epithelial cells. These data suggest a heretofore unappreciated potential mechanism for the initiation of breast cancer and identify MMTV Env and ITAM-containing proteins in human breast tumors as probable oncoproteins. In addition, they represent potentially new targets for prognosis and therapy in human breast cancer. We are currently studying the molecular basis for ITAM-mediated transformation using both in vitro and in vivo experimental approaches.

Rotation Projects for 2006-2007
Regulation of formation and function of lipid rafts in lymphocyte signaling and B cell selection and development.
Integration of tyrosine kinase-based ITAM and integrin signaling in survival and transformation of hematopoietic and non-hematopoietic cells.
Role of transcription factor Pax5 in cellular fate decisions during early B lymphocyte development.
Mechanisms of B lymphocyte antigen receptor signal initiation and transduction.

Lab personnel:
Ezequiel Fuentes-Panana, Postdoctoral Fellow
Anand Jacob, Postdoctoral Fellow
Elad Katz, Postdoctoral Fellow
Leslie King, Research Specialist
Randall Brezsky, PhD Student
Shannon Grande, PhD student
Fred Karnell, PhD student
Jack Treml, PhD student
Michelle Bernardini, Research Technician
Wei Zhu, Research Technician

Selected Publications

Chung, J.B., Wells, A.D., Adler, S., Turka, L.A., and Monroe, J.G.: Incomplete activation of CD4 T cells by antigen presenting transitional immature B cells: implications for peripheral B and T cell responsiveness. J. Immunol. Notes: in press.

Monroe JG.: ITAM-mediated tonic signalling through pre-BCR and BCR complexes. [Review] [111 refs] Nature Reviews Immunology: 6(4):283-94, 2006 Apr. Apr 2006.

Grande SM., Ross SR., Monroe JG.: Viral immunoreceptor-associated tyrosine-based activation motifs: potential players in oncogenesis. [Review] [62 refs] Future Oncology 2(2): 301-10, Apr 2006.

Grande SM., Katz E., Crowley JE., Bernardini MS., Ross SR., Monroe JG.: Cellular ITAM-containing proteins are oncoproteins in nonhematopoietic cells. Oncogene 25(19): 2748-57, May 4 2006.

Ross SR., Schmidt JW., Katz E., Cappelli L., Hultine S., Gimotty P., Monroe JG.: An immunoreceptor tyrosine activation motif in the mouse mammary tumor virus envelope protein plays a role in virus-induced mammary tumors. Journal of Virology 80(18): 9000-8, Sep 2006.

Fuentes-Panana, E.M., Bannish, G., Randall Brezski, and Monroe, J.G.: Lipid rafts are not required for preBCR-dependent developmental progression. Notes: Submitted.

Fuentes-Panana, E.M., Bannish, G., Randall Brezski, and Monroe, J.G.: Coordinated preBCR-dependent IgH allelic exclusion, light chain recombination, and developmental progression via Iga/Igb basal signaling. Notes: Submitted.

Fuentes-Pananá, E.M., Bannish, G., van der Voort, D., King, L.B. and Monroe, J.G.: Ig alpha/Ig beta complexes generate signals for B cell development independent of selective plasma membrane compartmentalization. J. Immunol 174: 1245-1252, 2005.

Kremyanskaya M., Monroe JG.: Ig-independent Ig beta expression on the surface of B lymphocytes after B cell receptor aggregation. Journal of Immunology 174(3): 1501-6, Feb 1 2005.

Katz E., Lareef MH., Rassa JC., Grande SM., King LB., Russo J., Ross SR., Monroe JG.: MMTV Env encodes an ITAM responsible for transformation of mammary epithelial cells in three-dimensional culture. Journal of Experimental Medicine 201(3): 431-9, Feb 7 2005.

Monroe JG.: Molecular mechanisms regulating B cell responsiveness and tolerance. [Review] [11 refs] Transplantation 79(3 Suppl): S12-3, Feb 15 2005.

Karnell FG., Brezski RJ., King LB., Silverman MA., Monroe JG.: Membrane cholesterol content accounts for developmental differences in surface B cell receptor compartmentalization and signaling. Journal of Biological Chemistry 280(27): 25621-8, Jul 8 2005.

Skalet AH., Isler JA., King LB., Harding HP., Ron D., Monroe JG.: Rapid B cell receptor-induced unfolded protein response in nonsecretory B cells correlates with pro- versus antiapoptotic cell fate. Journal of Biological Chemistry 280(48): 39762-71, Dec 2 2005.

Feng B., Cheng S., Hsia CY., King LB., Monroe JG., Liou HC.: NF-kappaB inducible genes BCL-X and cyclin E promote immature B-cell proliferation and survival. Cellular Immunology 232(1-2): 9-20, Nov-Dec 2004.

Monroe JG.: B-cell positive selection and peripheral homeostasis. [Review] [4 refs] Immunological Reviews 197: 5-9, Feb 2004.

Fuentes-Panana EM., Bannish G., Monroe JG.: Basal B-cell receptor signaling in B lymphocytes: mechanisms of regulation and role in positive selection, differentiation, and peripheral survival. [Review] [60 refs] Immunological Reviews 197: 26-40, Feb 2004.

Monroe JG.: Ligand-independent tonic signaling in B-cell receptor function. [Review] [47 refs] Current Opinion in Immunology 16(3): 288-95, Jun 2004.

Fuentes-Panana EM., Bannish G., Shah N., Monroe JG.: Basal Igalpha/Igbeta signals trigger the coordinated initiation of pre-B cell antigen receptor-dependent processes. Journal of Immunology 173(2): 1000-11, Jul 15 2004.

Monroe JG., Allman D.: Keeping track of pro-B cells: a new model for the effects of IL-7 during B cell development.[comment] European Journal of Immunology 34(10): 2642-6, Oct 2004.

Monroe, J.G. and Turka, L.A.: Regulation of activation of B and T lymphocytes. Hematology: Basic Principles and Practice. Hoffman, R., Benz, E.J., Shattil, S.J., Furie, B., Cohen,H.J.,Silberstein, L.E., McGlave, P. (eds.). Churchill Livingstone, 2003.

Yu D., Allman D., Goldschmidt MH., Atchison ML., Monroe JG., Thomas-Tikhonenko A.: Oscillation between B-lymphoid and myeloid lineages in Myc-induced hematopoietic tumors following spontaneous silencing/reactivation of the EBF/Pax5 pathway. Blood 101(5): 1950-5, Mar 1 2003.

Chung JB., Silverman M., Monroe JG.: Transitional B cells: step by step towards immune competence. [Review] [62 refs] Trends in Immunology 24(6): 343-9, Jun 2003.

Monroe JG., Bannish G., Fuentes-Panana EM., King LB., Sandel PC., Chung J., Sater R.: Positive and negative selection during B lymphocyte development. [Review] [70 refs] Immunologic Research 27(2-3): 427-42, 2003.

Chung JB., Wells AD., Adler S., Jacob A., Turka LA., Monroe JG.: Incomplete activation of CD4 T cells by antigen-presenting transitional immature B cells: implications for peripheral B and T cell responsiveness. Journal of Immunology 171(4): 1758-67, Aug 15 2003.

Chung, J.B., Sater, R.A., Fields, M.L., Erikson, J. and Monroe, J.G.: CD23 defines two distinct subsets of immature B cells which differ in their responses to T cell help signals. Int. Immunol. 14: 157-166, 2002.

Monroe, J.G., Bannish, G., Fuentes-Panana, E.M., King, L.B., Sandel, P.C., Chung, J.B., and Sater, R.A.: Positive and negative selection during B-lymphocyte development. Immunologic Res. 2002 Notes: In press.

Chung JB., Baumeister MA., Monroe JG.: Cutting edge: differential sequestration of plasma membrane-associated B cell antigen receptor in mature and immature B cells into glycosphingolipid-enriched domains. Journal of Immunology 166(2): 736-40, Jan 15 2001.

Bannish, G., Cambier, J.C., Pear, W.S., and Monroe, J.G: Plasma membrane localization of Iga/Igb is sufficient for positive selection of developing B cells. J. Exp. Med. 194: 1583-1596, 2001.

Fuentes-Panana, E.M. and Monroe, J.G.: Ligand-dependent and –independent processes in BCR mediated signaling. Sem. Immunopath. 23/4: New aspects of antibody generation and function. R. Zubler (eds.). Springer, 2001 Notes: in press.

Monroe, J.G.: Review: Signaling and Gene Expression in the Immune System. Quart. Rev. Biol. 76: 486-487, 2001.

Fuentes-Panana EM., Monroe JG.: Ligand-dependent and -independent processes in B-cell-receptor-mediated signaling. [Review] [73 refs] Springer Seminars in Immunopathology 23(4): 333-50, Dec 2001.

Bannish G., Fuentes-Panana EM., Cambier JC., Pear WS., Monroe JG.: Ligand-independent signaling functions for the B lymphocyte antigen receptor and their role in positive selection during B lymphopoiesis. Journal of Experimental Medicine 194(11): 1583-96, Dec 3 2001.

Chiang MY., Monroe JG.: Role for transcription Pax5A factor in maintaining commitment to the B cell lineage by selective inhibition of granulocyte-macrophage colony-stimulating factor receptor expression. Journal of Immunology 166(10): 6091-8, May 15 2001.

Sandel PC., Gendelman M., Kelsoe G., Monroe JG.: Definition of a novel cellular constituent of the bone marrow that regulates the response of immature B cells to B cell antigen receptor engagement. Journal of Immunology 166(10): 5935-44, May 15 2001.

King LB., Monroe JG.: Immunology. B cell receptor rehabilitation--pausing to reflect.[comment] Science 291(5508): 1503-5, Feb 23 2001.

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Last updated: 01/11/2007
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