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Stephanie S. Watowich, Ph.D.

Present Title & Affiliation

Primary Appointment

Associate Professor, Department of Immunology, Division of Basic Science Research, The University of Texas MD Anderson Cancer Center, Houston, TX

Dual/Joint/Adjunct Appointment

Associate Dean of Graduate Education, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX

Research Interests


Hematopoiesis, dendritic cells, neutrophils, STAT transcription factors

 

Research in my laboratory is focused upon understanding the molecular mechanisms that control the development of two important cell types in the innate immune system, plasmacytoid dendritic cells (pDCs) and neutrophils, which are critically involved in responses to viral and bacterial pathogens, respectively.  The production of pDCs and neutrophils is under tight control by cytokines and cytokine-responsive STAT proteins, yet these pathways can be deregulated in certain immune diseases including severe congenital neutropenia and autoimmunity.  We use mice with genetic deletion of individual STAT genes as well as direct molecular techniques to investigate how cytokine-activated STAT pathways regulate pDC and neutrophil development.  We have uncovered roles for STAT5, STAT3 and STAT1 in cytokine-dependent regulation of pDC lineage-determination factors, including GM-CSF- and IFN-a-dependent control of the IRF8 transcription factor. Moreover, we have established a crucial role for STAT3 in G-CSF-dependent myeloid progenitor proliferation and neutrophil mobilization in vivo. Ongoing studies are aimed at defining the molecular mechanisms of STAT-mediated transcriptional regulation in hematopoietic progenitor cells, as well as the function of STAT signaling in mouse models of immune disease.

Office Address

The University of Texas MD Anderson Cancer Center
7455 Fannin Street
Unit Number: Unit 902
Houston, TX 77054
Room Number: SCR4.3023

Education & Training

Degree-Granting Education

1990 Northwestern University, Evanston, IL, PHD, Biochemistry, Molecular Biology and Cell Biology
1983 Carleton College, Northfield, MN, BA, Cum Laude, Biology

Postgraduate Training

9/1990-10/1995 Postdoctoral Fellow, Cellular and Molecular Biology, Whitehead Institute for Biomedical Research, Cambridge, MA, Dr. Harvey F. Lodish

Experience/Service

Academic Appointments

Member, Graduate Faculty, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, 2/1996-present

Administrative Appointments/Responsibilities

Co-Director, Center for Inflammation and Cancer, The University of Texas MD Anderson Cancer Center, Houston, TX, 9/2010-present
Director, Program in Immunology, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, 12/2004-4/2010

Other Appointments/Responsibilities

Organizer and Chair, Symposium, Experimental Biology Annual Meeting, Anaheim, CA, 2010
Chair, Block Symposium, American Association of Immunology, Annual Meeting, Baltimore, MD, 2010

Institutional Committee Activities

Member, Scientific Review Committee for Basic Research Projects, 2009-2012
Member, Odyssey Program Advisory Committee, 2009-2012
Member, Faculty Advisory Committee, South Campus Animal Facility, 2008-present
Member, Strategic Planning for Research Space Development-Transportation-People and Specimens Committee, 2008-2011
Member, Faculty Health Committee, 2008-2010

Honors and Awards

2010 John P. McGovern Outstanding Teacher Award, The University of Texas Graduate School of Biomedical Sciences at Houston
2009 Reappointment with Highest Commendation, The University of Texas Graduate School of Biomedical Sciences
2009 The William Randolph Hearst Foundation Faculty Achievement Award in Education, The University of Texas MD Anderson Cancer Center

Selected Publications

Peer-Reviewed Original Research Articles

1. Nurieva RI, Podd A, Chen Y, Alekseev AM, Yu M, Qi X, Huang H, Wen R, Wang J, Li HS, Watowich SS, Qi H, Dong C, Wang D. STAT5 negatively regulates T follicular helper (Tfh) cell generation and function. J Biol Chem 287(14):11234-9, 3/2012. e-Pub 2/2012. PMCID: PMC3322890.
2. Li HS, Greeley N, Sugimoto N, Liu YJ, Watowich SS. miR-22 controls Irf8 mRNA abundance and murine dendritic cell development. PLoS One 7(12):e52341, 2012. e-Pub 12/14/2012. PMCID: PMC3522651.
3. Li HS, Gelbard A, Martinez GJ, Esashi E, Zhang H, Nguyen-Jackson H, Liu YJ, Overwijk WW, Watowich SS. Cell-intrinsic role for IFN-α-STAT1 signals in regulating murine Peyer patch plasmacytoid dendritic cells and conditioning an inflammatory response. Blood 118(14):3879-89, 2011. PMCID: PMC3193265.
4. Yang CY, Best JA, Knell J, Yang E, Sheridan AD, Jesionek AK, Li HS, Rivera RR, Lind KC, D'Cruz LM, Watowich SS, Murre C, Goldrath AW. The transcriptional regulators Id2 and Id3 control the formation of distinct memory CD8+ T cell subsets. Nat Immunol 12(12):1221-9, 2011. PMID: 22057289.
5. Qualls JE, Neale G, Smith AM, Koo MS, DeFreitas AA, Zhang H, Kaplan G, Watowich SS, Murray PJ. Arginine usage in mycobacteria-infected macrophages depends on autocrine-paracrine cytokine signaling. Sci Signal 3(135):ra62, 2010. PMCID: PMC2928148.
6. Zhang H, Nguyen-Jackson H, Panopoulos AD, Li HS, Murray PJ, Watowich SS. STAT3 controls myeloid progenitor growth during emergency granulopoiesis. Blood 116(14):2462-71, 2010. PMCID: PMC2953883.
7. Nguyen-Jackson H, Panopoulos AD, Zhang H, Li HS, Watowich SS. STAT3 controls the neutrophil migratory response to CXCR2 ligands by direct activation of G-CSF-induced CXCR2 expression and via modulation of CXCR2 signal transduction. Blood 115(16):3354-63, 2010. PMCID: PMC2858484.
8. Hegde S, Ni S, He S, Yoon D, Feng GS, Watowich SS, Paulson RF, Hankey PA. Stat3 promotes the development of erythroleukemia by inducing Pu.1 expression and inhibiting erythroid differentiation. Oncogene 28(38):3349-59, 9/24/2009. e-Pub 7/6/2009. PMCID: PMC3086737.
9. Chung Y, Chang SH, Martinez GJ, Yang XO, Nurieva R, Kang HS, Ma L, Watowich SS, Jetten AM, Tian Q, Dong C. Critical regulation of early Th17 cell differentiation by interleukin-1 signaling. Immunity 30(4):576-87, 2009. PMCID: PMC2705871.
10. Speiran K, Bailey DP, Fernando J, Macey M, Barnstein B, Kolawole M, Curley D, Watowich SS, Murray PJ, Oskeritzian C, Ryan JJ. Endogenous suppression of mast cell development and survival by IL-4 and IL-10. J Leukoc Biol 85(5):826-36, 2009. PMCID: PMC2669408.
11. Yamazaki T, Yang XO, Chung Y, Fukunaga A, Nurieva R, Pappu B, Martin-Orozco N, Kang HS, Ma L, Panopoulos AD, Craig S, Watowich SS, Jetten AM, Tian Q, Dong C. CCR6 regulates the migration of inflammatory and regulatory T cells. J Immunol 181(12):8391-401, 2008. PMID: 19050256.
12. Nurieva RI, Chung Y, Hwang D, Yang XO, Kang HS, Ma L, Wang YH, Watowich SS, Jetten AM, Tian Q, Dong C. Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. Immunity 29(1):138-49, 2008. PMCID: PMC2556461.
13. Kennedy Norton S, Barnstein B, Brenzovich J, Bailey DP, Kashyap M, Speiran K, Ford J, Conrad D, Watowich S, Moralle MR, Kepley CL, Murray PJ, Ryan JJ. IL-10 suppresses mast cell IgE receptor expression and signaling in vitro and in vivo. J Immunol 180(5):2848-54, 2008. PMID: 18292506.
14. Yang X, Nurieva R, Martinez G, Kang H, Chung Y, Pappu B, Shah B, Chang S, Schluns K, Watowich S, Feng X, Jetten A, Dong C. Molecular Antagonism and Plasticity of Regulatory and Inflammatory T Cell Programs. Immunity 29(1):44-56, 2008. PMCID: PMC2630532.
15. Yang X, Pappu B, Nurieva R, Akimzhanov N, Kang H, Chung Y, Ma L, Shah B, Panopoulos A, Schluns K, Watowich S, Tian Q, Jetten A, Dong C. T helper 17 lineage differentiation is programmed by orphan nuclear receptors RORalpha and RORgamma. Immunity 28(1):29-39, 2008. PMCID: PMC2587175.
16. Esashi E, Wang YH, Perng O, Qin XF, Liu YJ, Watowich SS. The signal transducer STAT5 inhibits plasmacytoid dendritic cell development by suppressing transcription factor IRF8. Immunity 28(4):509-20, 2008. PMID: 18342552.
17. El Kasmi KC, Smith AM, Williams L, Neale G, Panopoulos AD, Panopolous A, Watowich SS, Häcker H, Foxwell BM, Murray PJ. Cutting edge: A transcriptional repressor and corepressor induced by the STAT3-regulated anti-inflammatory signaling pathway. J Immunol 179(11):7215-9, 2007. PMID: 18025162.
18. Nurieva R, Yang X, Panopoulos AD, Martinez G, Zhang Y, Ma L, Schluns K, Tian Q, Watowich SS, Jetten A, Dong C. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 448(7152):480-483, 2007. PMID: 17581589.
19. Kile BT, Panopoulos AD, Stirzaker, R, Hacking D, Tahtamouni L, Willson T, Mielke L, Henley K, Zhang JG, Wicks I, Stevenson W, Nurden P, Watowich SS, Justice MJ. Mutations in the cofilin partner Aip1/Wdr1 cause autoinflammatory disease and macrothrombocytopenia. Blood 110(7):2371-80, 2007. PMCID: PMC1988957.
20. Yang X, Panopoulos AD, Nurieva R, Chang SH, Wang D, Watowich SS, Dong C. STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J Biol Chem 282(13):9358-9363, 2007. PMID: 17277312.
21. El Kasmi K, Holst J, Coffre M, Mielke L, de Pauw A, Lhocine N, Smith A, Rutschman R, Kaushal D, Shen Y, Suda T, Donnelly R, Myers Jr M, Alexander W, Vignali D, Watowich SS, Ernst M, Hilton DJ, Murray PJ. General nature of the STAT3-activated anti-inflammatory response. J Immunol 177(11):7880-7888, 2006. PMID: 17114459.
22. Zhang L, Badgwell DB, Bevers 3rd JJ, Schlessinger K, Murray PJ, Levy DE, Watowich SS. IL-6 signaling via the STAT3/SOCS3 pathway: Functional analysis of the conserved STAT3 N-domain. Mol Cell Biochem 288:179-189, 2006. PMID: 16718380.
23. Trevino JG, Gray MJ, Nawrocki ST, Summy JM, Lesslie DP, Evans DB, Sawyer TK, Shakespeare WC, Watowich SS, Chiao PJ, McConkey DJ, Gallick GE. Src activation of Stat3 is an independent requirement from NF-kappaB activation for constitutive IL-8 expression in human pancreatic adenocarcinoma cells. Angiogenesis 9:101-110, 2006. PMID: 16871430.
24. Panopoulos AD, Zhang L, Snow JW, Jones DM, Smith AM, El Kasmi KC, Liu F, Goldsmith MA, Link DC, Murray PJ, Watowich SS. STAT3 governs distinct pathways in emergency granulopoiesis and mature neutrophils. Blood 108:3682-3690, 2006. PMID: 16888100.
25. Nishimoto A, Yu Y, Lu Z, Mao X, Ren Z, Watowich SS, Mills GB, Liao WS, Chen X, Bast RC, Jr, Luo RZ. A Ras homologue member I directly inhibits signal transducers and activators of transcription 3 translocation and activity in human breast and ovarian cancer cells. Cancer Res 65:6701-10, 2005. PMID: 16061651.
26. Wang L, Arcasoy MO, Watowich SS, Forget BG. Cytokine signals through STAT3 promote expression of granulocyte secondary granule proteins in 32D cells. Exp Hematol 33:308-17, 2005. PMID: 15730854.
27. Gray MJ, Zhang J, Ellis LM, Semenza GL, Evans DB, Watowich SS, Gallick GE. HIF-1alpha, STAT3, CBP/p300 and Ref-1/APE are components of a transcriptional complex that regulates Src-dependent hypoxia-induced expression of VEGF in pancreatic and prostate carcinomas. Oncogene 24:3110-20, 2005. PMID: 15735682.
28. Butcher BA, Kim L, Panopoulos AD, Watowich SS, Murray PJ, Denkers EY. IL-10-independent STAT3 activation by Toxoplasma gondii mediates suppression of IL-12 and TNF-alpha in host macrophages. J Immunol 174:3148-52, 2005. PMID: 15749841.
29. Pauleau AL, Rutschman R, Lang R, Pernis A, Watowich SS, Murray PJ. Enhancer-mediated control of macrophage-specific arginase I expression. J Immunol 172:7565-73, 2004. PMID: 15187136.
30. Sarna MK, Ingley E, Busfield SJ, Cull VS, Lepere W, McCarthy DJ, Wright MJ, Palmer GA, Chappell D, Sayer MS, Alexander WS, Hilton DJ, Starr R, Watowich SS, Bittorf T, Klinken SP, Tilbrook PA. Differential regulation of SOCS genes in normal and transformed erythroid cells. Oncogene 22:3221-30, 2003. PMID: 12761492.
31. Yoon D, Watowich SS. Hematopoietic cell survival signals are elicited through non-tyrosine-containing sequences in the membrane-proximal region of the erythropoietin receptor (EPOR) by a Stat5-dependent pathway. Exp Hematol 31:1310-6, 2003. PMID: 14662339.
32. Panopoulos AD, Bartos D, Zhang L, Watowich SS. Control of myeloid-specific integrin alphaMbeta2 (CD11b/CD18) expression by cytokines is regulated by Stat3-dependent activation of PU.1. J Biol Chem 277:19001-7, 2002. PMID: 11889125.
33. Afrikanova I, Yeh E, Bartos D, Watowich SS, Longmore GD. Oncogene cooperativity in Friend erythroleukemia: erythropoietin receptor activation by the env gene of SFFV leads to transcriptional upregulation of PU.1, independent of SFFV proviral insertion. Oncogene 21:1272-84, 2002. PMID: 11850847.
34. Kubatzky KF, Ruan W, Gurezka R, Cohen J, Ketteler R, Watowich SS, Neumann D, Langosch D, Klingmuller U. Self assembly of the transmembrane domain promotes signal transduction through the erythropoietin receptor. Curr Biol 11:110-5, 2001. PMID: 11231127.
35. Wooten DK, Xie X, Bartos D, Busche RA, Longmore GD, Watowich SS. Cytokine signaling through Stat3 activates integrins, promotes adhesion, and induces growth arrest in the myeloid cell line 32D. J Biol Chem 275:26566-75, 2000. PMID: 10858439.
36. Cull V, Tilbrook PA, Adenan AS, Chappell D, Ingley E, Sarna MK, Palmer TN, Watowich SS, Klinken SP. Dominant action of mutated erythropoietin receptors on differentiation in vitro and erythroleukemia development in vivo. Oncogene 19:953-60, 2000. PMID: 10702804.
37. Watowich SS, Mikami A, Busche RA, Xie X, Pharr PN, Longmore GD. Erythropoietin receptors that signal through Stat5 or Stat3 support fetal liver and adult erythropoiesis: lack of specificity of Stat signals during red blood cell development. J Interferon Cytokine Res 20:1065-70, 2000. PMID: 11152572.
38. Watowich SS, Xie X, Klingmuller U, Kere J, Lindlof M, Berglund S, de la Chapelle A. Erythropoietin receptor mutations associated with familial erythrocytosis cause hypersensitivity to erythropoietin in the heterozygous state. Blood 94:2530-2, 1999. PMID: 10498627.
39. Watowich SS, Liu KD, Xie X, Lai SY, Mikami A, Longmore GD, Goldsmith MA. Oligomerization and scaffolding functions of the erythropoietin receptor cytoplasmic tail. J Biol Chem 274:5415-21, 1999. PMID: 10026152.
40. Levin I, Cohen J, Supino-Rosin L, Yoshimura A, Watowich SS, Neumann D. Identification of a cytoplasmic motif in the erythropoietin receptor required for receptor internalization. FEBS Lett 427:164-70, 1998. PMID: 9607304.
41. Tarr K, Watowich SS, Longmore GD. Cell surface organization of the erythropoietin receptor complex differs depending on its mode of activation. J Biol Chem 272:9099-107, 1997. PMID: 9083037.
42. Hilton DJ, Watowich SS, Katz L, Lodish HF. Saturation mutagenesis of the WSXWS motif of the erythropoietin receptor. J Biol Chem 271:4699-708, 1996. PMID: 8617735.
43. Murray PJ, Watowich SS, Lodish HF, Young RA, Hilton DJ. Epitope tagging of the human endoplasmic reticulum HSP70 protein, BiP, to facilitate analysis of BiP--substrate interactions. Anal Biochem 229:170-9, 1995. PMID: 7485969.
44. Hilton DJ, Watowich SS, Murray PJ, Lodish HF. Increased cell surface expression and enhanced folding in the endoplasmic reticulum of a mutant erythropoietin receptor. Proc Natl Acad Sci U S A 92:190-4, 1995. PMID: 7816815.
45. Watowich SS, Hilton DJ, Lodish HF. Activation and inhibition of erythropoietin receptor function: role of receptor dimerization. Mol Cell Biol 14:3535-49, 1994. PMID: 8196600.
46. Longmore G, SS Watowich, P Pharr, D Neumann, HF Lodish. Activation of the erythropoietin receptor and leukemia induction in mice. Leukemia 7 Suppl.S113-116, 1993. PMID: 8361212.
47. Neumann D, Wikstrom L, Watowich SS, Lodish HF. Intermediates in degradation of the erythropoietin receptor accumulate and are degraded in lysosomes. J Biol Chem 268:13639-13649, 1993. PMID: 8514796.
48. Ng DT, Watowich SS, Lamb RA. Analysis in vivo of GRP78-BiP/substrate interactions and their role in induction of the GRP78-BiP gene. Mol Biol Cell 3:143-155, 1992. PMID: 1550958.
49. Watowich SS, Yoshimura A, Longmore GD, Hilton DJ, Yoshimura Y, Lodish HF. Homodimerization and constitutive activation of the erythropoietin receptor. Proc Natl Acad Sci U S A 89:2140-2144, 1992. PMID: 1312714.
50. Lodish HF, Hilton DJ, Longmore G, Watowich SS, Yoshimura A. The erythropoietin receptor: dimerization, activation, and tumorigenesis. Cold Spring Harb Symp Quant Biol 57:95-106, 1992. PMID: 1339709.
51. Watowich SS, Morimoto RI, Lamb RA. Flux of the paramyxovirus hemagglutinin-neuraminidase glycoprotein through the endoplasmic reticulum activates transcription of the GRP78-BiP gene. J Virol 65:3590-3597, 1991. PMID: 2041085.
52. Watowich SS, Morimoto RI. Complex regulation of heat shock- and glucose-responsive genes in human cells. Mol Cell Biol 8:393-405, 1988. PMID: 3275876.

Invited Articles

1. Watowich SS. The erythropoietin receptor: molecular structure and hematopoietic signaling pathways. J Investig Med 59(7):1067-72, 2011. PMCID: PMC3134576.
2. Watowich SS, Liu YJ. Mechanisms regulating dendritic cell specification and development. Immunol Rev 238(1):76-92, 2010. PMCID: PMC3039024.
3. Esashi E, Watowich SS. Dendritic cells: transcriptional control of plasmacytoid dendritic cell development by E2-2. Immunol Cell Biol 87(1):1-2, 2009. PMID: 19048021.
4. Panopoulos A, Watowich S. Granulocyte colony-stimulating factor: molecular mechanisms of action during steady state and 'emergency' hematopoiesis. Cytokine 42(3):277-288, 2008. e-Pub 4/2008. PMID: 18400509.
5. Watowich SS. Activation of erythropoietin signaling by receptor dimerization. Int J Biochem Cell Biol 31:1075-88, 1999. PMID: 10582340.
6. Watowich SS, Wu H, Socolovsky M, Klingmuller U, Constantinescu SN, Lodish HF. Cytokine receptor signal transduction and the control of hematopoietic cell development. Annu Rev Cell Dev Biol 12:91-128, 1996. PMID: 8970723.
7. Lodish HF, Hilton DJ, Klingmuller U, Watowich SS, Wu H. The erythropoietin receptor: biogenesis, dimerization, and intracellular signal transduction. Cold Spring Harb Symp Quant Biol 60:93-104, 1995. PMID: 8824381.
8. Longmore GD, Watowich SS, Hilton DJ, Lodish HF. The erythropoietin receptor: its role in hematopoiesis and myeloproliferative diseases. J Cell Biol 123:1305-8, 1993. PMID: 8253831.

Book Chapters

1. Nguyen-Jackson H, Zhang H, Watowich SS. G-CSF receptor structure, function and intracellular signal transduction. In: 20 Years of G-CSF: Clinical and Nonclinical Discoveries. Ed(s) Graham Molineux, Tara Arvedson, MaryAnn Foote. Birkhäuser Verlag AG: Basel, Switzerland, 2012. ISBN: 978-3-0348-0217-8.
2. Watowich SS. Erythropoietin. In: Colony Stimulating Factors Molecular and Cellular Biology, 2. Ed(s) JM Garland, PJ Quesenberry, DJ Hilton. M Dekker: New York, 291-313, 1996.
3. Hilton DJ, Watowich SS. The Erythropoietin Receptor. In: Guidebook to Cytokines and their Receptors. Ed(s) N Nicola. Oxford University Press: New York, 155-157, 1994.

Grant & Contract Support

Title: Julia Jones Matthews Cancer Research Graduate Scholar Training Program
Funding Source: The Legett Foundation, The Still Water Foundation, and The Kickapoo Springs Foundation
Role: Principal Investigator
Duration: 8/1/2012 - 8/31/2014
 
Title: The Future of Cancer Research: Training Program for Basic and Translational Scientists
Funding Source: CPRIT
Role: Principal Investigator
Duration: 8/1/2010 - 7/31/2015
 
Title: Transcriptomic and Epigenomic Basis of Helper T cell Specification and Plasticityand Development
Funding Source: NIH/NIAMS
Role: Co-Principal Investigator
Duration: 9/30/2009 - 8/31/2011
 
Title: Regulation of Hematopoietic Stem Cell Function by STAT3 Stem Cell and Development
Funding Source: The University of Texas MD Anderson Cancer Center, Center for Stem Cell and Developmental Biology
Role: Principal Investigator
Duration: 9/1/2009 - 8/31/2010
 
Title: Cytokine Regulation of Dendritic Cell Development
Funding Source: NIH/NIAID
Role: Principal Investigator
Duration: 12/1/2007 - 11/30/2009
 
Title: STAT Function in Myeloid Progenitors and Their Response to Granulocyte Colony-Stimulating Factor (G-CSF)
Funding Source: Amgen, Inc.
Role: Principal Investigator
Duration: 9/18/2006 - 9/18/2009
 
Title: Predoctoral Training Program in Cancer Immunobiology
Funding Source: NIH/NCI
Role: Co-Investigator
Principal Investigator: Honnavara N. Ananthaswamy, Ph.D
Duration: 4/27/2000 - 2/28/2005

Last updated: 8/26/2013