Frederick W. Quelle, PhD

Portrait
Director of Graduate Studies
Associate Professor of Pharmacology
Associate Professor of Internal Medicine

Contact Information

Primary Office: 2-340F BSB
51 Newton Rd.
Iowa City, IA 52242
319-335-8539

Lab: 2-340 BSB
Iowa City, IA 52242
319-335-7769

Education

BA, Chemistry, Middlebury College
MS, Biochemistry, The Pennsylvania State University
PhD, Genetics, The Pennsylvania State University

Fellow, Biochemistry, St. Jude's Children's Research Hospital, Department of Biochemistry

Education/Training Program Affiliations

Interdisciplinary Graduate Program in Immunology

Research Summary

Cytokine Receptor Signal Transduction and Regulation of Cell Growth The growth of myeloid and lymphoid blood cells is governed by cytokine growth factors acting through Type I cytokine receptors. This receptor family functions through activation of Jak tyrosine kinases, which phosphorylate components of signaling pathways that control cell survival and proliferation. Blood cell development fails in the absence of Jak kinase activation resulting in anemias, whereas enhanced Jak kinase activity contributes to myeloid and lymphoid leukemias. Work in our laboratory is directed at defining mechanism by which cytokines regulated blood cell growth. Proper regulation of Jak kinase activity requires mechanisms controlling activation of the kinase that are balanced against mechanisms controlling its inactivation. Mechanisms inhibiting Jak kinase activity include its degradation, which is governed by ubiquitination mediated by SOCS proteins. We have shown that Jak kinases and cytokine receptors can also be ubiquitinated by a receptor-associated ubiquitin ligase, RUL. Inhibition of RUL activity limits the ability of cytokines to induce Jak-dependent phosphorylation of signaling proteins and inhibits cell growth, suggesting that Jak activity is enhanced by RUL-mediated ubiquitin ligation. The finding that RUL-mediated ubiquitination enhances Jak signaling is novel, and forms the basis for our hypothesis that different mediators of Jak ubiquitination exert distinct influences on its kinase activity. Thus, a major focus of work in our laboratory is to define the role of RUL in regulating Jak kinase activity, and test the concept that competing ubiquitination between a promoter (e.g., RUL) and inhibitor (e.g., SOCS1) regulates the activity of Jak kinases in vivo. The lack of proliferation by hematopoietic cells deprived of cytokine is associated with their accumulation in G1 phase of the cell cycle. This implies a direct link between the activities of cytokine receptors and regulators of cell cycle progression. However the specific roles of signaling pathways activated by cytokine receptors in promoting G1 phase progression has not been clearly defined. We have shown that cytokine-treatment overrides G1 and G2/M phase growth arrest in hematopoietic cells exposed to DNA damaging agents. Blockade of these growth arrest checkpoints is dependent on activation of phosphoinositide 3-kinase (PI3K) signaling pathways, and correlates with the appearance of a Cdk2 activating kinase (CAK) activity in lysates of irradiated cells. These observations define a signaling pathway connecting cytokine-induced PI3K and regulated Cdk2 activity in hematopoietic cells. Thus a second focus of work in our laboratory is to define the molecular mechanisms that govern this PI3K-mediated signaling pathway, and ultimately to determine the general parameters required for cytokine-dependent blockade of DNA damage checkpoints. These studies will advance our fundamental understanding of cytokine signaling pathways, and will help to establish important paradigms of cell cycle regulation, DNA damage checkpoints, and their regulation by extracellular signals.

Publications

Woll, A. W., Quelle, F. W. & Sigmund, C. D. (2017). PPAR? and retinol binding protein 7 form a regulatory hub promoting antioxidant properties of the endothelium. Physiological genomics, 49(11), 653-658. PMID: 28916634.

Hu, C., Keen, H. L., Lu, K., Wu, J., Davis, D. R., Ibeawuchi, S. C., Vogel, S., Quelle, F. W., Sigmund, C. D. (2017). Retinol-binding protein 7 is an endothelium-specific PPAR? cofactor mediating an antioxidant response through adiponectin. JCI Insight, 2(6), e91736. PMID: 28352663.

, Lu, K., Guo, D. F., Wu, J., Keen, H. L., Liu, X., Ketsawatsomkron, P., Stump, M., Rahmouni, K., Quelle, F. W. & Sigmund, C. D. (2017). Hypertension-Causing Mutation in Peroxisome Proliferator-Activated Receptor ? Impairs Nuclear Export of Nuclear Factor-?B p65 in Vascular Smooth Muscle. Hypertension, 70(1), 174-182. PMID: 28507170.

Mukohda, M., Stump, M., Ketsawatsomkron, P., Hu, C., Qulle, F. W. & Sigmund, C. D. (2016). Endothelial PPAR-? provides vascular protection from IL-1ß-induced oxidative stress. Am J Physiol Heart Circ Physiol, 310(1), H39-H48. PMID: 26566726.

Agbor, L. N., Ibeawuchi, S. C., Hu, C., Wu, J., Davis, D. R., Keen, H. L., Quelle, F. W. & Sigmund, C. D. (2016). Cullin-3 mutation causes arterial stiffness and hypertension through a vascular smooth muscle mechanism. JCI Insight, 1(19), e91015. PMID: 27882355.

Ibeawuchi, S. R., Agbor, L. N., Quelle, F. W. & Sigmund, C. D. (2015). Hypertension-causing mutations in Cullin3 protein impair RhoA protein ubiquitination and augment the association with substrate adaptors. J Biol Chem, 290(31), 19208-17. PMID: 26100637.

Reed, S. M., Hagen, J., Tompkins, V. S., Thies, K., Quelle, F. W. & Quelle, D. E. (2014). Nuclear interactor of ARF and Mdm2 regulates multiple pathways to activate p53. Cell Cycle, 13(8), 1288-98. PMID: 24621507.

Reed, S. M., Quelle, F. W. & Quelle, D. E. (2014). ARF sees Pdgfrß through the miR. Cell Cyle, 13(10), 1520-1521. PMID: 24755551.

Hagen, J., Muniz, V. P., Falls, K. C., Reed, S. M., Taghiyev, A. F., Quelle, F. W., Gourronc, F. A., Klingelhutz, A. J., Major, H. J., Askeland, R. W., Sherman, S. K., O'Dorisio, T. M., Bellizzi, A. m., Howe, J. R., Darbro, B. W. & Quelle, D. E. (2014). RABL6A promotes G1-S phase progression and pancreatic neuroendocrine tumor cell proliferation in an Rb1-dependent manner. PMID: 25273089.

Quelle, F. W., Sigmund, C. D. (2013). PPARgamma: no SirT, no service. Circulation Research, 112(3), 411-4. PMID: 23371897.

Lei, H., Quelle, F. W. (2009). FOXO transcription factors enforce cell cycle checkpoints and promote survival of hematopoietic cells after DNA damage. Molecular cancer research : MCR, 7(8), 1294-303. PMID: 19671690.

Lei, H., Quelle, F. W. (2008). FOXO transcription factors are required for DNA damage-induced growth arrest checkpoints in hematopoietic cells. (Vols. 22). pp. 637.4. FASEB Journal.

Nimbalkar, D., Quelle, F. W. (2008). Phosphoinositide 3-kinase signaling overrides a G2 phase arrest checkpoint and promotes aberrant cell cycling and death of hematopoietic cells after DNA damage. Cell cycle (Georgetown, Tex.), 7(18), 2877-85. PMID: 18769155.

Quelle, F. W. (2007). Cytokine signaling to the cell cycle. Immunologic Research, 39(1-3), 173-84. PMID: 17917064.

Korgaonkar, C., Hagen, J., Tompkins, V., Frazier, A. A., Allamargot, C., Quelle, F. W. & Quelle, D. E. (2005). Nucleophosmin (B23) targets ARF to nucleoli and inhibits its function. Molecular and cellular biology, 25(4), 1258-71. PMID: 15684379.

Chakravarti, P., Henry, M. K. & Quelle, F. W. (2005). Prolactin and heregulin override DNA damage-induced growth arrest and promote phosphatidylinositol-3 kinase-dependent proliferation in breast cancer cells. International journal of oncology, 26(2), 509-14. PMID: 15645137.

Henry, M. K., Nimbalkar, D., Hohl, R. J. & Quelle, F. W. (2004). Cytokine-induced phosphoinositide 3-kinase activity promotes Cdk2 activation in factor-dependent hematopoietic cells. Experimental cell research, 299(1), 257-66. PMID: 15302592.

Chandrashekhar, K., Hagen, J., Tompkins, V., Quelle, F. W. & Quelle, D. E. (2004). Nucleophosmin (NPM/B23) targets ARF to nucleoli and inhibits its function. AACR.

Korgaonkar, C., Hagen, J., Tompkins, V., Quelle, F. W. & Quelle, D. E. (2004). Nucleophosmin (NPM/B23) targets ARF to nucleoli and inhibits its function. Cold Spring Harbor meeting on Cancer Genetics and Tumor Suppressor Genes.

Nimbalkar, D., Quelle, F. W. (2003). Effect of DNA damaging agents on hematopoietic cell. Experimental Biology.

Friedman, A. D., Nimbalkar, D. & Quelle, F. W. (2003). Erythropoietin receptors associate with a ubiquitin ligase, p33RUL, and require its activity for erythropoietin-induced proliferation. The Journal of biological chemistry, 278(29), 26851-61. PMID: 12746455.

Nimbalkar, D., Henry, M. K. & Quelle, F. W. (2003). Cytokine activation of phosphoinositide 3-kinase sensitizes hematopoietic cells to cisplatin-induced death. Cancer research, 63(5), 1034-9. PMID: 12615719.

Henry, M. K., Lynch, J. T., Eapen, A. K. & Quelle, F. W. (2001). DNA damage-induced cell-cycle arrest of hematopoietic cells is overridden by activation of the PI-3 kinase/Akt signaling pathway. Blood, 98(3), 834-41. PMID: 11468186.

Henry, M. K., Eapen, A. K. & Quelle, F. W. (2001). PI-3 Kinase Signaling Pathways Activate cdk2 and Override DNA Damage-induced Growth Arrest in Hematopoietic Cells. The Molecular Basis of Cancer.

Eapen, A. K., Henry, M. K., Quelle, D. E. & Quelle, F. W. (2001). DNA damage-induced G(1) arrest in hematopoietic cells is overridden following phosphatidylinositol 3-kinase-dependent activation of cyclin-dependent kinase 2. Molecular and cellular biology, 21(18), 6113-21. PMID: 11509654.

Henry, M. K., Quelle, F. W. (1999). Cytokine rescue of DNA damage-induced cell cycle arrest is mediated by a PI-3 kinase-dependent signaling pathway. Oncogene Networks in Signal Transduction.

Eapen, A. K., Quelle, F. W. (1999). DNA damage-induced expression of p27kip1 and cell cycle arrest are suppressed by cytokine stimulation. pp. 15. FASEB Journal.

Quelle, F. W., Wang, J., Feng, J., Wang, D., Cleveland, J. L., Ihle, J. N. & Zambetti, G. P. (1998). Cytokine rescue of p53-dependent apoptosis and cell cycle arrest is mediated by distinct Jak kinase signaling pathways. Genes & development, 12(8), 1099-107. PMID: 9553040.

Ihle, J. N., Nosaka, T., Thierfelder, W., Quelle, F. W. & Shimoda, K. (1997). Jaks and Stats in cytokine signaling. Stem cells (Dayton, Ohio), 15 Suppl 1, 105-11; discussion 112. PMID: 9368330.

Quelle, F. W., Wang, D., Nosaka, T., Thierfelder, W. E., Stravopodis, D., Weinstein, Y. & Ihle, J. N. (1996). Erythropoietin induces activation of Stat5 through association with specific tyrosines on the receptor that are not required for a mitogenic response. Molecular and cellular biology, 16(4), 1622-31. PMID: 8657137.

Shimoda, K., van Deursen, J., Sangster, M. Y., Sarawar, S. R., Carson, R. T., Tripp, R. A., Chu, C., Quelle, F. W., Nosaka, T., Vignali, D. A., Doherty, P. C., Grosveld, G., Paul, W. E. & Ihle, J. N. (1996). Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted Stat6 gene. Nature, 380(6575), 630-3. PMID: 8602264.

Ihle, J. N., Witthuhn, B. A., Quelle, F. W., Yamamoto, K. & Silvennoinen, O. (1995). Signaling through the hematopoietic cytokine receptors. Annual Review of Immunology, 13, 369-98. PMID: 7612228.

Quelle, F. W., Shimoda, K., Thierfelder, W., Fischer, C., Kim, A., Ruben, S. M., Cleveland, J. L., Pierce, J. H., Keegan, A. D. & Nelms, K. (1995). Cloning of murine Stat6 and human Stat6, Stat proteins that are tyrosine phosphorylated in responses to IL-4 and IL-3 but are not required for mitogenesis. Molecular and cellular biology, 15(6), 3336-43. PMID: 7760829.

Azam, M., Erdjument-Bromage, H., Kreider, B. L., Xia, M., Quelle, F., Basu, R., Saris, C., Tempst, P., Ihle, J. N. & Schindler, C. (1995). Interleukin-3 signals through multiple isoforms of Stat5. The EMBO journal, 14(7), 1402-11. PMID: 7537213.

Quelle, F. W., Thierfelder, W., Witthuhn, B. A., Tang, B., Cohen, S. & Ihle, J. N. (1995). Phosphorylation and activation of the DNA binding activity of purified Stat1 by the Janus protein-tyrosine kinases and the epidermal growth factor receptor. The Journal of biological chemistry, 270(35), 20775-80. PMID: 7657660.

Copeland, N. G., Gilbert, D. J., Schindler, C., Zhong, Z., Wen, Z., Darnell, J. E., Mui, A. L., Miyajima, A., Quelle, F. W. & Ihle, J. N. (1995). Distribution of the mammalian Stat gene family in mouse chromosomes. Genomics, 29(1), 225-8. PMID: 8530075.

Yin, T., Keller, S. R., Quelle, F. W., Witthuhn, B. A., Tsang, M. L., Lienhard, G. E., Ihle, J. N. & Yang, Y. C. (1995). Interleukin-9 induces tyrosine phosphorylation of insulin receptor substrate-1 via JAK tyrosine kinases. The Journal of biological chemistry, 270(35), 20497-502. PMID: 7544789.

Ihle, J. N., Witthuhn, B., Tang, B., Yi, T. & Quelle, F. W. (1994). Cytokine receptors and signal transduction. Bailliere's clinical haematology, 7(1), 17-48. PMID: 7518712.

Stahl, N., Boulton, T. G., Farruggella, T., Ip, N. Y., Davis, S., Witthuhn, B. A., Quelle, F. W., Silvennoinen, O., Barbieri, G. & Pellegrini, S. (1994). Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6 beta receptor components. Science (New York, N.Y.), 263(5143), 92-5. PMID: 8272873.

Ihle, J. N., Witthuhn, B. A., Quelle, F. W., Yamamoto, K., Thierfelder, W. E., Kreider, B. & Silvennoinen, O. (1994). Signaling by the cytokine receptor superfamily: JAKs and STATs. Trends in biochemical sciences, 19(5), 222-7. PMID: 8048164.

Ihle, J. N., Witthuhn, B. A., Quelle, F. W., Silvennoinen, O., Tang, B. & Yi, T. (1994). Protein tyrosine phosphorylation in the regulation of hematopoiesis by receptors of the cytokine-receptor superfamily. Blood cells, 20(1), 65-80; discussion 80-2. PMID: 7994062.

Yamamoto, K., Quelle, F. W., Thierfelder, W. E., Kreider, B. L., Gilbert, D. J., Jenkins, N. A., Copeland, N. G., Silvennoinen, O. & Ihle, J. N. (1994). Stat4, a novel gamma interferon activation site-binding protein expressed in early myeloid differentiation. Molecular and cellular biology, 14(7), 4342-9. PMID: 8007943.

Miura, O., Miura, Y., Nakamura, N., Quelle, F. W., Witthuhn, B. A., Ihle, J. N. & Aoki, N. (1994). Induction of tyrosine phosphorylation of Vav and expression of Pim-1 correlates with Jak2-mediated growth signaling from the erythropoietin receptor. Blood, 84(12), 4135-41. PMID: 7527668.

Miura, O., Nakamura, N., Quelle, F. W., Witthuhn, B. A., Ihle, J. N. & Aoki, N. (1994). Erythropoietin induces association of the JAK2 protein tyrosine kinase with the erythropoietin receptor in vivo. Blood, 84(5), 1501-7. PMID: 8068943.

Quelle, F. W., Sato, N., Witthuhn, B. A., Inhorn, R. C., Eder, M., Miyajima, A., Griffin, J. D. & Ihle, J. N. (1994). JAK2 associates with the beta c chain of the receptor for granulocyte-macrophage colony-stimulating factor, and its activation requires the membrane-proximal region. Molecular and cellular biology, 14(7), 4335-41. PMID: 8007942.

Ihle, J. N., Quelle, F. W. & Miura, O. (1993). Signal transduction through the receptor for erythropoietin. Seminars in immunology, 5, 375-89. PMID: 8260653.

Silvennoinen, O., Witthuhn, B. A., Quelle, F. W., Cleveland, J. L., Yi, T. & Ihle, J. N. (1993). Structure of the murine Jak2 protein-tyrosine kinase and its role in interleukin 3 signal transduction. Proceedings of the National Academy of Sciences of the United States of America, 90(18), 8429-33. PMID: 8378315.

Witthuhn, B. A., Quelle, F. W., Silvennoinen, O., Yi, T., Tang, B., Miura, O. & Ihle, J. N. (1993). JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietin. Cell, 74(2), 227-36. PMID: 8343951.

Watling, D., Guschin, D., Muller, M., Silvennoinen, O., Witthuhn, B. A., Quelle, F. W., Rogers, N. C., Schindler, C., Stark, G. R. & Ihle, J. N. (1993). Complementation by the protein tyrosine kinase JAK2 of a mutant cell line defective in the interferon-gamma signal transduction pathway. Nature, 366(6451), 166-70. PMID: 7901766.

Quelle, F. W., Quelle, D. E. & Wojchowski, D. M. (1992). Interleukin 3, granulocyte-macrophage colony-stimulating factor, and transfected erythropoietin receptors mediate tyrosine phosphorylation of a common cytosolic protein (pp100) in FDC-ER cells. The Journal of biological chemistry, 267(24), 17055-60. PMID: 1324920.

Quelle, F. W., Egerton, M., Samelson, L. E. & Wojchowski, D. M. (1992). Cytokine-induced phosphorylation of pp100 in FDC-ER cells is at tyrosine residues. Biochemical and biophysical research communications, 188(3), 1040-6. PMID: 1280128.

Quelle, D. E., Quelle, F. W. & Wojchowski, D. M. (1992). Mutations in the WSAWSE and cytosolic domains of the erythropoietin receptor affect signal transduction and ligand binding and internalization. Molecular and cellular biology, 12(10), 4553-61. PMID: 1406645.

Quelle, F. W., Wojchowski, D. M. (1991). Proliferative action of erythropoietin is associated with rapid protein tyrosine phosphorylation in responsive B6SUt.EP cells. The Journal of biological chemistry, 266(1), 609-14. PMID: 1985918.

Schweisguth, D. C., Quelle, F. W., Wachob, G. & Hammerstedt, R. H. (1989). Isolation and characterization of brain lipids by solid phase extraction and thin layer chromatography. J Biochem Educ, 17, 211-213.

Quelle, F. W., Caslake, L. F., Burkert, R. E. & Wojchowski, D. M. (1989). High-level expression and purification of a recombinant human erythropoietin produced using a baculovirus vector. Blood, 74(2), 652-7. PMID: 2752139.

Quelle, F. W., Smith, R. V., Hrycyna, C. A., Kaliban, T. D., Crooks, J. A. & O'Brien, J. M. (1988). [3H]dexamethasone binding to plasma membrane-enriched fractions from liver of nonadrenalectomized rats. Endocrinology, 123(3), 1642-51. PMID: 2841103.