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DEVELOPMENTAL GENE REGULATION OF THE IMMUNE SYSTEM
     

Keiko Ozato, Ph.D., Principal Investigator
Tomohiko Tamura, M.D., Ph.D., Staff Scientist
Anup K. Dey, Ph.D., Research Fellow
Celine Gongora, Ph.D., Postdoctoral Fellow
Andrea Farina, Ph.D., Postdoctoral Fellow
Moon Kyoo Jang, Ph.D., Postdoctoral Fellow
Hee Heong Kong, Ph.D., Postdoctoral Fellow
Akira Nishiyama, Ph.D., Postdoctoral Fellow
Selvaggia Sciortino, Ph.D., Postdoctoral Fellow
Hideki Tsujimura, M.D., Ph.D., Postdoctoral Fellow
Asim A. Abbasi, B.A., Predoctoral Fellow
Pramita Thotakura, B.S., Predoctoral Fellow
Leopoldo Laricchia-Robbio, Ph.D., Courtesy Contract
Tomohiko Kanno, M.D., Ph.D., Guest Researcher
Yuka Kanno, M.D., Ph.D., Guest Researcher
Tomonori Uno, Ph.D., Guest Researcher

For More Information
Keiko Ozato's photograph
 

The section works on ICSBP (also IRF-8), an immune system-specific member of the IRF family. ICSBP is a nuclear protein of about 55 kDa that is expressed in macrophages in response to interferon (IFN)-gamma and bacterial lipopolysaccharides (LPS). ICSBP-/- mice display a syndrome similar to chronic myelogenous leukemia (CML) with abnormal expansion of granulocytes. They are also immunodeficient. CML is a malignancy of myeloid progenitor cells that is caused by a c-abl-BCR fusion protein created by chromosomal translocation. To investigate the role of ICSBP in the CML, the ICSBP gene was introduced into ICSBP-/- bone marrow myeloid progenitor cells by means of a MSCV retrovirus vector. ICSBP transduction led to macrophage differentiation that accompanied induction of cytokine production and phagocytosis. The cells ceased to divide and expressed a number of macrophage-specific genes; they also repressed granulocyte-specific genes. Recent data demonstrated that ICSBP also regulates the development of dendritic cells (DC) important for innate immunity. The results indicate that ICSBP plays a critical role in the differentiation of myeloid progenitor cells into antigen-presenting cells, thereby negatively affecting CML pathogenesis.

FIGURE 36

Control of DNA Replication
Dey, Farina, Ozato, Sciortino
In addition to studying ICSBP, the section is particularly interested in proteins that modulate chromatin. Screening a library for a conserved bromodomain motif believed to be involved in interacting with chromatin, researchers identified a novel protein of 200 kD named Brd4. Brd4 carries two bromodomains and belongs to the BET subgroup of bromodomain proteins. Although BET group proteins share a conserved domain composition, their function is unknown. However, Brd4 interacts with a conserved replication factor C, and, when Brd4 is ectopically expressed in NIH-3T3 cells, cell-cycle progression from G1 to S is blocked, indicating that Brd4 plays a critical role in the initiation of DNA replication.

 

PUBLICATIONS

  1. Blanco JC, Contursi C, Salkowski CA, DeWitt DL, Ozato K, Vogel SN. Interferon regulatory factor (IRF)-1 and IRF-2 regulate interferon gamma-dependent cyclooxygenase 2 expression. J Exp Med 2000;191:2131-2144.
  2. Dey A, Ellenberg J, Farina A, Coleman AE, Maruyama T, Sciortino S, Lippincott-Schwartz J, Ozato K. A bromodomain protein, MCAP, associates with mitotic chromosomes and affects G(2)-to-M transition. Mol Cell Biol 2000;20:6537-6549.
  3. Katagiri Y, Takeda K, Yu ZX, Ferrans VJ, Ozato K, Guroff G. Modulation of retinoid signalling through NGF-induced nuclear export of NGFI-B. Nat Cell Biol 2000;2:435-440.
  4. Kawagishi-Kobayashi M, Cao C, Lu J, Ozato K, Dever T. Pseudosubstrate inhibition of protein kinase PKR by swine pox virus C8L gene product. Virology 2000;276:424-434.
  5. Kuwata T, Wang IM, Tamura T, Ponnamperuma RM, Levine R, Holmes KL, Morse HC, De Luca LM, Ozato K. Vitamin A deficiency in mice causes a systemic expansion of myeloid cells. Blood 2000;95:3349-3356.
  6. Li M, Damania B, Alvarez X, Ogryzko V, Ozato K, Jung JU. Inhibition of p300 histone acetyltransferase by viral interferon regulatory factor. Mol Cell Biol 2000;20:8254-8263.
  7. Masumi A, Ozato K. Coactivator p300 acetylates the interferon regulatory factor-2 in U937 cells following phorbol ester treatment. J Biol Chem 2001;276:20973-20980.
  8. Morse HC, Qi CF, Chattopadhyay SK, Hori M, Taddesse-Heath L, Ozato K, Hartley JW, Taylor BA, Ward JM, Jenkins NA, Copeland NG, Fredrickson TN. Combined histologic and molecular features reveal previously unappreciated subsets of lymphoma in AKXD recombinant inbred mice. Leuk Res 2001;25:719-733.
  9. Nagamura-Inoue T, Tamura T, Ozato K. Transcription factors that regulate growth and differentiation of myeloid cells. Int Rev Immunol 2001;20:83-105.
  10. Tamura T, Nagamura-Inoue T, Shmeltzer Z, Kuwata T, Ozato K. ICSBP directs bipotential myeloid progenitor cells to differentiate into mature macrophages. Immunity 2000;13:155-165.
  11. Ung TL, Cao C, Lu J, Ozato K, Dever TE. Heterologous dimerization domains functionally substitute for the double-stranded RNA binding domains of the kinase PKR. EMBO J 2001;20:3728-3737.
  12. Wang IM, Contursi C, Masumi A, Ma X, Trinchieri G, Ozato K. An IFN-gamma-inducible transcription factor, IFN consensus sequence binding protein (ICSBP), stimulates IL-12 p40 expression in macrophages. J Immunol 2000;165:271-279.
  13. Xu RH, Peng Y, Fan J, Yan D, Yamagoe S, Princler G, Sredni D, Ozato K, Kung HF. Histone acetylation is a checkpoint in FGF-stimulated mesoderm induction. Dev Dyn 2000;218:628-635.
  14. Yamauchi T, Yamauchi J, Kuwata T, Tamura T, Yamashita T, Bae N, Westphal H, Ozato K, Nakatani Y. Distinct but overlapping roles of histone acetylase PCAF and the closely related PCAF-B/GCN5 in mouse embryogenesis. Proc Natl Acad Sci USA 2000;97:11303-11306.
  15. Zhang F, Romano PR, Nagamura-Inoue T, Tian B, Dever TE, Mathews MB, Ozato K, Hinnebusch AG. Binding of double-stranded RNA to protein kinase PKR is required for dimerization and promotes critical autophosphorylation events in the activation loop. J Biol Chem 2001;276:24946-24958.