Selected Research Area: Gene Regulation
The coordinated regulation of genes is vital to numerous processes including cellular activation, growth and differentiation. Members of our department are investigating genome regulation by a variety of approaches that include transcriptome and epigenome analyses using next generation sequencing, single cell/molecule microscopy and genetic perturbation. By combining cutting-edge technologies with more traditional approaches these studies are providing insights into genome regulation in normal cells and its dysregulation in disease.
521A Physiology BldgBaltimore, MD 21205
Office Phone: 410-955-5759
Lab Phone: 410-955-3458
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The Fukunaga lab investigates the mechanism and biology of small silencing RNAs. We try to understand how small silencing RNAs, such as microRNAs (miRNAs), small interfering RNAs (siRNAs) and piwi-interacting RNAs (piRNAs), are produced and how they function. We use a combination of biochemistry, biophysics, fly genetics, cell culture, X-ray crystallography and next-generation sequencing, in order to understand the biogenesis and function of small silencing RNAs from the atomic to the organismal level.
miRNAs are 21-24 nt long RNA. In fruit fly Drosophila, miRNAs are transcribed as long primary transcripts called pri-miRNAs (Figure 1). The pri-miRNA is cleaved into pre-miRNA in the nucleus by the RNase III enzyme Drosha, aided by the dsRNA-binding partner protein Pasha. The Exportin-5/Ran-GTP complex transports pre-miRNA from the nucleus to the cytoplasm. In cytoplasm, Dicer-1, aided by the dsRNA-binding partner protein Loqs-PA or Loqs-PB, cleaves the pre-miRNA into miRNA duplex. miRNA is then loaded to Argonaute1 and binds target mRNAs through base complementarity of the miRNA sequence at positions 2-8 (called seed sequence). miRNA-Ago1 binding to the target mRNAs causes translational repression and mRNA degradation.
Loqs-PB, but not its alternative splicing isoform Loqs-PA, changes the nucleotide positions at which Dicer-1 cleaves pre-miRNA and produces miRNA with distinct length (Figure 2). These alternatively produced miRNAs can have distinct seed sequences and therefore regulate different target mRNAs. The mammalian Dicer partner protein TRBP, but not its paralogue PACT, changes the length and the seed sequence of miRNAs produced by Dicer in mammals. The Fukunaga lab investigates how Dicer partner proteins (Loqs-PB in fly and TRBP in mammals) change the miRNA length generated by the Dicer enzymes. We also try to uncover biological significance of the alternative miRNA production. Our hypothesis is that the alternative splicing of Loqs-PA/Loqs-PB in fly and the gene expression of TRBP/PACT in mammals are finely regulated in each tissue and developmental stage, leading to regulated production of distinct miRNA isoforms, and that such fine regulation is important for biology. For this end, we are trying to make miR-307a knockout flies and plan to analyze the molecular phenotypes. Furthermore, we are trying to discover novel factors and mechanisms regulating the miRNA production and function.
In another project, as collaboration with a physician scientist, Dr. Roselle Abraham at the Cardiology Division of Department of Medicine, we are studying functional effects of a miRNA SNP mutation found from Hypertrophic cardiomyopathy (HCM) patients. This project may lead to development of novel diagnosis and therapeutics for cardiovascular diseases including HCM in the future.
Drosophila Dicer-2 associates with the dsRNA-binding partner proteins Loqs-PD and R2D2 and produces 21 nt long siRNAs from long dsRNA (Figure 2). siRNA is loaded to Argonaute2 and silences highly complementary target RNAs by cleaving them—a process typically called RNAi. One of the biological functions of the siRNA pathway is to fight against exogenously derived viral infection and against genome encoded transposon invasion. In addition, Dicer-2 produces endogenous siRNAs (endo-siRNAs) derived from genome encoded long hairpin RNA or overlapping mRNAs. The biological functions of these classes of endo-siRNAs are not well understood. We are interested in how viral and endogenously derived RNAs are recognized and cleaved into siRNAs by Dicer-2 and how the produced siRNAs function in biology. We also try to identify and characterize novel factors involved in or regulating the siRNA pathways. We are also interested in understanding how the two Dicer enzymes achieve their respective substrate specificities (pre-miRNA for Dicer-1 and long dsRNA for Dicer-2). Recently, we found that physiological concentration of inorganic phosphate, a small molecule found in all the cells, restricts the substrate specificity of Dicer-2 to long dsRNA by inhibiting Dicer-2 from cleaving pre-miRNA, without affecting cleavage of long dsRNA (Figure 4). We propose that inorganic phosphate occupies the phosphate-binding pocket in Dicer-2 and thereby block access of pre-miRNA. Currently we are investigation the function of the phosphate-binding pocket.
piRNAs (26-31 nt) are mostly produced in gonads (ovaries and testes). Unlike miRNAs and siRNAs, Dicer enzymes are not involved in the piRNA production. piRNAs are produced in the primary processing pathway and the ping-pong pathway, which are not yet fully understood (Figure 5). piRNAs are loaded onto PIWI proteins and function in epigenetic and post-transcriptional gene silencing of transposons and other genetic elements in order to maintain genome integrity of germline cells. Interestingly, piRNAs are recently implicated also in sex determination, neuronal functions in brain, and tumorigenesis in cancer cells. We are interested in the mechanisms for biogenesis and function of piRNAs. We are trying to identify new factors involved in the piRNA pathway, using a fly reporter system.
4. RNA helicase
RNA helicases are involved in almost all the aspects in the RNA biology: RNA transcription, transport, translation, silencing, localization, structural rearrangement, decay, and so on. The Dicer enzymes also have a N-terminal 'helicase' domain. We are studying molecular and physiological roles of DEAD-box RNA helicases. Particularly, we are currently focusing on Drosophila belle, a DEAD-box RNA helicase that essential for fly viability and fertility and is conserved from yeast to human (Figure 6). We are making various mutant Belle and analyzing them genetically and biochemically.
Our lab uses multi-disciplinary approaches to understand the biogenesis and function of small silencing RNAs from the atomic to the organismal level. Small silencing RNAs play crucial roles in various aspects in biology. In fact, mutations in the small RNA genes or in the genes involved in the pathways cause many diseases in human including cancers. Our research projects will answer fundamental biological questions and also potentially lead to therapeutic application to human disease.
Postdoc and student positions are available. Please contact the PI if interested.
Fukunaga R, Colpan C, Han BW, Zamore PD, "Inorganic phosphate blocks binding of pre-miRNA to Dicer-2 via its PAZ domain" EMBO Journal, 18, 371-84, (2014)PubMed Reference
Fukunaga R, Han BW, Hung JH, Xu J, Weng Z, Zamore PD, "Dicer Partner Proteins Tune the Length of Mature miRNAs in Flies and Mammals" Cell, 151, 533-46, (2012)PubMed Reference
725 N. Wolfe StBaltimore, MD 21205
Office Phone: 410-955-5759
Lab Phone: 410-502-2571
For images of our work
Recent links to our work: Neuroscience Innovations
Videos showing increased mRNA repression (RNA-processing bodies) in live neurons responding to BDNF:Messenger RNA accumulates in a neuronBDNF-treated neuron
Huang*Y-WA, Ruiz*CR, Eyler ECH*, Lin K, and Meffert MK (2012). Dual regulation of miRNA biogenesis generates target specificity in neurotrophin-induced protein synthesis. Cell, 148(5); 933-946.PubMed Reference
Boersma* MC, Dresselhaus*EC, De Biase LM, Mihalas AB, Bergles DE, and Meffert MK (2011), A requirement for NF-kB in developmental and plasticity-associated synaptogenesis. J.Neurosci., 31; 5414-5425.PubMed Reference
Shrum CK, Defrancisco D, and Meffert MK. (2009) Stimulated nuclear translocation of NF-kB and shuttling differentially depend on dynein and the dynactin complex. PNAS, 106; 2647-2652.PubMed Reference
Boersma MC and Meffert MK (2008) Novel roles for the NF-kB signaling pathway in regulating neuronal function. Science Signaling 1, pe7.PubMed Reference
Shrum CK and Meffert MK (2008). The NF- kB Family in Learning and Memory. In J. David Sweatt(Ed.), Molecular Mechanisms of Memory. Vol.  of Learning and Memory: A Comprehensive Reference (J.Byrne Editor), pp. [567-586] Oxford: ElsevierScience Direct
Mattson MP and Meffert MK (2006). Roles for NF-kB in nerve cell survival, plasticity, and disease. Cell Death and Differentiation 13, 852-60.PubMed Reference
Meffert MK and Baltimore D (2005). Physiological functions for brain NF-kB. Trends in Neurosciences 28, 37-43.PubMed Reference
Meffert MK, Chang JM, Wiltgen BJ, Fanselow MS, Baltimore D (2003). NF-kB functions in synaptic signaling and behavior. Nature Neuroscience 6, 1072 - 1078.PubMed Reference
Meffert MK, Calakos NC, Scheller RH, Schulman H (1996). Nitric oxide modulates synaptic vesicle docking / fusion reactions. Neuron 16, 1229-1236.PubMed Reference
Meffert*MK, Haley*JE, Schuman EM, Schulman H, and Madison DV (1994). Inhibition of hippocampal heme oxygenase, nitric oxide synthase and long-term potentiation by metalloporphyrins. Neuron 13, 1225-1233.PubMed Reference
Meffert MK, Premack BA, and Schulman H (1994). Nitric oxide stimulates calcium-independent synaptic vesicle release. Neuron 12, 1235-1244.PubMed Reference
Schuman EM, Meffert MK, Schulman H, Madison DV (1994). An ADP-Ribosyltransferase as a Target for Nitric Oxide Action in Long-Term Potentiation. Proceedings of the National Academy of Sciences 91, 11958-11962.PubMed Reference
733 N. BroadwayBaltimore, MD 21205
Office Phone: 443-287-3109
Lab Phone: 443-287-3104
Jattani RP, Tritapoe JM, Pomerantz JL. Cooperative Control of Caspase Recruitment Domain-Containing Protein 11 (CARD11) Signaling by an Unusual Array of Redundant Repressive Elements. J. Biol Chem. 2016. 291(16):8324-8336.PubMed Reference
Jattani RP, Tritapoe JM, Pomerantz JL. Intramolecular Interactions and Regulation of Cofactor Binding by the Four Repressive Elements in the Caspase Recruitment Domain-Containing Protein 11 (CARD11) Inhibitory Domain. J. Biol Chem. 2016. 291(16):8338-8348. PubMed Reference
Hamblet CE, Makowski SL, Tritapoe JM, Pomerantz JL. NK Cell Maturation and Cytotoxicity are Controlled by the Intramembrane Aspartyl Protease SPPL3. J. Immunol. 2016;196:2614-2626.PubMed Reference
Pedersen SM, Chan W, Jattani RP, Mackie dS, Pomerantz JL. Negative Regulation of CARD11 Signaling and Lymphoma Cell Survival by the E3 Ubiquitin Ligase RNF181. Mol Cell Biol. 2016; 36:794-808.PubMed Reference
Makowski, SL, Wang, Z, Pomerantz JL. A Protease-independent Function for SPPL3 in NFAT Activation. Mol Cell Biol. 2015. 35(2):451–467.PubMed Reference
Chan, W., Schaeffer TB, Pomerantz JL. A quantitative signaling screen identifies CARD 11 mutations in the CARD and LATCH domains tht induce Bc110 ubiquitination and human lymphoma cell survival. Mol Cell Biol. 2013. 33(2): 429-443.PubMed Reference
Lamason, R.L., Lew SM, and Pomerantz JL. 2010. Transcriptional target-based expression cloning of immunoregulatory molecules. Immunol. Res. 47:172-178.PubMed Reference
Lamason, R.L., McCully RR, Lew SM, and Pomerantz JL. 2010. Oncogenic CARD11 mutations induce hyperactive signaling by disrupting autoinhibition by the PKC-responsive inhibitory domain. Biochemistry 49:8240-8250.PubMed Reference
Lamason, R.L., Kupfer A, and Pomerantz JL. 2010. The dynamic distribution of CARD11 at the immunological synapse is regulated by the inhibitory kinesin GAKIN. Mol. Cell 40:798-809.PubMed Reference
Yang, H.-C., Shen L, Siliciano RF, and Pomerantz JL. 2009. Isolation of a cellular factor that can reactivate latent HIV-1 without T cell activation. Proc. Natl. Acad. Sci.USA, 106: 6321-6326.PubMed Reference
McCully, R.R. and Pomerantz JL. 2008. The Protein Kinase C-responsive inhibitory domain of CARD11 functions in NF-κB activation to regulate the association of multiple signaling cofactors that differentially depend on Bcl10 and MALT1 for association. Molecular and Cellular Biology 28:5668-5686.PubMed Reference
Sommer, K., Guo B, Pomerantz JL, Bandaranayake AD, Moreno-Garcia ME, Ovechkina YL, and Rawlings DJ. 2005. Phosphorylation of the CARMA1 linker controls NF-kappaB activation. Immunity 23, 561-574.PubMed Reference
Wurtz, N.R., Pomerantz JL, Baltimore D, and Dervan PB. (2002) Inhibition of DNA binding by NF-kB with pyrrole-imidazole polyamides. Biochemistry, 41, 7604-7609.PubMed Reference Pomerantz, J.L., and Baltimore D. (2002) Two pathways to NF-kB. Mol. Cell, 10, 693-695.PubMed Reference Pomerantz, J.L., Denny EM, and Baltimore D. (2002) CARD11 mediates factor-specific activation of NF-kB by the T cell receptor complex. EMBO J., 21, 5184-5194.PubMed Reference
Pomerantz, J.L. and Baltimore D. (2000) Signal transduction ï¿½ A cellular rescue team. Nature, 406, 26-29.PubMed Reference
Pomerantz, J.L. and Baltimore D. (1999) NF-kB activation by a signaling complex containing TRAF2, TANK, and TBK1, a novel IKK-related kinase. EMBO J., 18, 6694-6704.PubMed Reference
Pomerantz, J.L., Wolfe SA, and C.O. Pabo CO. (1998) Structure-based design of a dimeric zinc finger protein. Biochemistry, 37, 965-970.PubMed Reference
Pomerantz, J.L., Pabo CO, and Sharp PA. (1995) Analysis of homeodomain function by structure-based design of a transcription factor. Proc. Natl. Acad. Sci.USA, 92, 9752-9756.PubMed Reference
Pomerantz, J.L., and Sharp PA. (1994) Homeodomain determinants of major groove recognition. Biochemistry, 33, 10851-10858.PubMed ReferencePomerantz, J.L., Kristie TM, and Sharp PA. (1992) Recognition of the surface of a homeo domain protein. Genes & Development 6, 2047-2057.PubMed Reference
Pomerantz, J.L., Mauxion Yoshida FM, Greene WC, and Sen R. (1989) A second sequence element located 3' to the NF-kB binding site regulates IL-2 receptor-alpha gene induction. Journal of Immunology 143, 4275-4281.PubMed Reference Rothenberg, M.E., Pomerantz JL, Owen WF, Jr., Avraham S, Soberman RJ, Austen KF, and Stevens RL. (1988) Characterization of a human eosinophil proteoglycan, and augmentation of its biosynthesis and size by interleukin 3, interleukin 5, and granulocyte/macrophage colony stimulating factor. Journal of Biological Chemistry 263, 13901-13908.PubMed Reference
Rangos 574Baltimore, MD 21205
Understanding the cell biology of genomes and how nuclear architecture controls gene expression is necessary to truly understand biological processes such as development and disease. Although sequencing of the genome and comparative genome analysis have yielded insights into the regulation and dis-regulation of genetic information, these efforts shed little light into how genomes actually work in vivo. The impact of architectural and cellular organization of genomes on gene activity is a next step to unlocking genetic and epigenetic mechanisms in development and disease. Recent evidence is emerging that the non-random organization in the nucleus is a contributing factor in regulating genes important to multiple developmental processes. Moreover, some studies suggest that the non-random organization in the nucleus is a contributing factor in initiating translocations. In mammalian nuclei, chromatin is organized into structural domains by association with distinct nuclear compartments. Such interactions are likely to bring together coordinately regulated genes and to focus proteins and enzymes that regulate DNA based activities such as transcription, recombination, replication and repression. While evidence mounts that genes are regulated by association with distinct nuclear compartments, relatively little is known about how specific loci are directed to different domains. I hypothesize that such “nuclear addressing” requires specific cis elements that interact with a set of sequestered proteins (trans factors) to establish and maintain nuclear architecture and functionality. Such self-reinforcing interactions likely lie at the heart of nuclear structure and function. My recent work has demonstrated that one such compartment that is important for both nuclear structure and gene regulation is the nuclear periphery. In addition to regulation of Immunoglobulin Heavy Chain loci, the nuclear envelope (NE) is also implicated in regulating, among other things, muscle specific genes. The focus of the research in my lab is to begin to understand how the nuclear periphery and other subcompartments contribute to general nuclear architecture and to specific gene regulation. These questions comprise three complementary areas of research: understanding how genes are regulated at the nuclear periphery, deciphering how genes are localized (or “addressed”) to specific nuclear compartments and, finally, how these processes are utilized in development and corrupted in disease.
Harr, J.C, Luperchio, T.R., Wong, X.,
Cohen, E., Sheelan, S.J. and Reddy, K.L. (2015) Directed targeting of
chromatin to the nuclear lamina is mediated by chromatin state and
A-type lamins, Journal of Cell Biology, vol 208(1), 33-52.PubMed Reference
Wong, X., Luperchio, T. R., & Reddy KL. (2014). NET gains and losses: the role of changing nuclear envelope proteomes in genome regulation. Current Opinion in Cell Biology, 28C, 105–120.PubMed Reference
Luperchio, T. R., Wong, X., & Reddy KL. (2014). Genome regulation at the peripheral zone: lamina associated domains in development and disease. Current Opinion in Genetics & Development, 25C, 50–61.PubMed Reference
Mohammad H, Luperchio, T. R., Cutler , J, Mitchell, C. J., Kim, M-S, Pandey, A, Sollner-Webb, B.and Reddy KL (2014) Prediction of Gene Activity in Early B Cell Development Based on an Integrative Multi-Omics Analysis. Journal of Proteomics & Bioinformatics.Link
Harr J. and Reddy KL. (2013) Live Cell imaging of Nuclear Dynamics. Encyclopedia of Biological Chemistry, 2nd Ed., p. 749Link
Reddy KL, & Feinberg, A. P. (2013). Higher order chromatin organization in cancer. Semin Cancer Biol, 23(2), 109–115.PubMed Reference
Zullo, J. M., Demarco, I. a, Piqué-Regi, R., Gaffney, D. J., Epstein, C. B., Spooner, C. J., Reddy KL and Singh, H. (2012). DNA sequence-dependent compartmentalization and silencing of chromatin at the nuclear lamina. Cell, 149(7), 1474–87.PubMed Reference
Mewborn, S. K., Puckelwartz, M. J., Abuisneineh, F., Fahrenbach, J. P., Zhang, Y., MacLeod, H., Dellefave L, Pytel P, Selig S, Labno CM, Reddy KL, Singh H, McNally E. (2010). Altered chromosomal positioning, compaction, and gene expression with a lamin A/C gene mutation. PloS One, 5(12), e14342.PubMed ReferenceJohnson, K., Reddy, KL, & Singh, H. (2009). Molecular pathways and mechanisms regulating the recombination of immunoglobulin genes during B-lymphocyte development. Adv Exp Med Biol, 650(Journal Article), 133–147.PubMed Reference Reddy KL, & Singh, H. (2008). Using molecular tethering to analyze the role of nuclear compartmentalization in the regulation of mammalian gene activity. Methods (San Diego, Calif.), 45(3), 242–251.MethodsReddy KL, Zullo, J. M., Bertolino, E., & Singh, H. (2008). Transcriptional repression mediated by repositioning of genes to the nuclear lamina. Nature, 452(7184), 243–7. doi:10.1038/nature06727PubMed ReferenceReynaud, D., A, Demarco, I., L Reddy KL, Schjerven, H., Bertolino, E., Chen, Z., Reddy, K. L. (2008). Regulation of B cell fate commitment and immunoglobulin heavy-chain gene rearrangements by Ikaros. Nature Immunology, 9(8), 927–936.PubMed ReferenceSchlimgen, R. J., Reddy KL, Singh, H., & Krangel, M. S. (2008). Initiation of allelic exclusion by stochastic interaction of Tcrb alleles with repressive nuclear compartments. Nature Immunology, 9(7), 802–809.PubMed Reference
855 N. Wolfe St.Baltimore, MD 21205
Office Phone: 410-614-8033
Lab Phone: 443-287-7214
Our laboratory is interested in understanding the metabolic properties of neurons and glia at a mechanistic level in situ. Some of the most interesting, enigmatic and understudied cells in metabolic biochemistry are those of the nervous system. Defects in these pathways can lead to devastating neurological disease. Conversely, altering the metabolic properties of the nervous system can have surprisingly beneficial effects on the progression of some diseases. However, the mechanisms of these interactions are largely unknown.
We utilize biochemical and molecular genetic techniques to understand the molecular mechanisms that the nervous system uses to sense and respond to metabolic cues. We have uncovered novel neuronal nutrient sensing paradigms that act through unique metabolic enzymes to control body weight and diabetes susceptibility. We continue to explore novel neuron-specific enzyme function in metabolic processes as well as uncovering novel roles of canonical metabolic pathways in the nervous system. Furthermore, the unique makeup of the nervous system requires our laboratory to develop new technology and assays to facilitate our work.
Below are the broad areas that we are currently focusing on.
Ellis JM, Wong GW & Wolfgang MJ. Acyl Coenzyme A Thioesterase 7 regulates neuronal fatty acid metabolism to prevent neurotoxicity. Mol Cell Biol. 2013; 33(9) 1869-1882.PubMed Reference
Miyamoto T, DeRose R, Suarez A, Ueno T, Chen M, Sun T, Wolfgang MJ, Mukherjee C, Meyers DJ and Inoue T. Generation of Intracellular Logic Gates with Two Orthogonal Chemically Inducible Systems. Nature Chemical Biology 2012, Mar 25;8(5):465-70.PubMed Reference
Rodriguez S & Wolfgang MJ. Targeted chemical-genetic regulation of protein stability in vivo. Chemistry & Biology 2012, Mar 23;19(3):391-8.PubMed Reference
Reamy AA & Wolfgang MJ. Carnitine Palmitoyltransferase-1C gain-of-function in the brain results in postnatal microencephaly. Journal of Neurochemistry. 2011 Aug; 118(3) 388-98.PubMed Reference
Cha SH, Wolfgang M, Tokutake Y, Chohnan S, Lane MD. Differential effects of central fructose and glucose on hypothalamic malonyl-CoA and food intake. Proc Natl Acad Sci USA. 2008;105(44):16871-5.PubMed Reference
Wolfgang MJ, Cha SH, Millington DS, Cline G, Shulman GI, Suwa A, Asaumi M, Kurama T, Shimokawa, T & Lane MD. Brain-specific carnitine palmitoyltransferase-1c: Role in CNS fatty acid metabolism, food intake and body weight. J Neurochem 2008; May;105(4):1550-9.PubMed Reference
Wolfgang MJ, Cha SH, Sidhaye A, Chohnan S, Cline G, Shulman GI & Lane MD. Regulation of hypothalamic malonyl-CoA by central glucose and leptin. Proc Natl Acad Sci USA. 2007 Dec; 104(49): 19285-19290.PubMed Reference
Chakravarthy MV, Zhu Y, López M, Yin L, Wozniak DF, Coleman T, Hu Z, Wolfgang M, Vidal-Puig A, Lane MD & Semenkovich CF. Brain fatty acid synthase activates PPARa to maintain energy homeostasis. J Clin Invest. 2007; 117: 2539-2552.PubMed Reference
Wolfgang MJ & Lane MD. The role of hypothalamic malonyl-CoA in energy homeostasis. J. Biol. Chem. 2006; 281(49): 37265-37269.PubMed Reference
Wolfgang MJ, Kurama T, Dai Y, Suwa A, Asaumi M, Matsumoto S, Cha SH, Shimokawa T & Lane MD. The brain-specific carnitine palmitoyltransferase-1c regulates energy homeostasis. Proc. Natl. Acad. Sci. USA 2006 May; 103(19): 7282-7287.PubMed Reference
Gao Q*, Wolfgang MJ*, Neschen S, Morino K, Horvath, TL, Shulman GI, & Fu XY. Disruption of neural signal transducer and activator of transcription 3 causes obesity, diabetes, infertility and thermal dysregulation. Proc. Natl. Acad. Sci. USA 2004 March; 101(13): 4661-4666. (*equal contribution).PubMed Reference
Kano A*, Wolfgang MJ*, Gao Q*, Jacoby J, Chai GX, Hansen W, Iwamoto Y, Pober JS, Flavell RA, & Fu XY. Endothelial cells require STAT3 for protection against endotoxin-induced inflammation. J Exp Med. 2003; 198(10): 1517-1525. (*equal contribution).PubMed Reference