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Blood, 1 June 2004, Vol. 103, No. 11, pp. 4142-4149. Prepublished online as a Blood First Edition Paper on February 19, 2004; DOI 10.1182/blood-2003-01-0285. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-01-0285v1 103/11/4142    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Schmidt, M. Articles by Wolff, L. Search for Related Content PubMed PubMed Citation Articles by Schmidt, M. Articles by Wolff, L. Related Collections Oncogenes and Tumor Suppressors Hematopoiesis Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS The interferon regulatory factor ICSBP/IRF-8 in combination with PU.1 up-regulates expression of tumor suppressor p15Ink4b in murine myeloid cells Martina Schmidt, Juraj Bies, Tomohiko Tamura, Keiko Ozato, and Linda Wolff From the Laboratory of Cellular Oncology, National Cancer Institute, Bethesda, MD; and Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, Bethesda, MD. CDKN2B (INK4B), which encodes the cyclin-dependent kinase inhibitor p15INK4b, is up-regulated by many cytokines found in hematopoietic environments in vivo. In human acute myeloid leukemias (AMLs), it is inactivated with high frequency. To gain insight into the regulatory pathways leading to the normal activation of p15Ink4b expression, we examined interferon (IFN)–induced transcription. Using reporter gene assays in murine myeloid cells M1, we determined that a 328-bp fragment, located 117 to 443 bp upstream of the translation initiation site, was sufficient to activate transcription. Both the interferon consensus sequence-binding protein/interferon regulatory factor 8 (ICSBP/IRF-8) and PU.1 were able to increase transcription from this region. It was determined that both ICSBP and PU.1 must bind to DNA to form a stable PU.1/ICSBP binding complex. Interestingly, introduction of the ICSBP into ICSBP-null Tot2 cells led to a significant increase in p15Ink4b RNA expression. This regulation of the Ink4b promoter is apparently myeloid specific because both ICSBP and PU.1 are myeloid commitment factors. Importantly, this provides a mechanism to explain in part the tumor suppressor activity of ICSBP, since ICSBP-deficient mice develop a chronic myelogenous leukemia (CML)–like disease and a high percentage of human AML and CML lack ICSBP transcripts. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: D. Yang, M. Thangaraju, D. D. Browning, Z. Dong, B. Korchin, D. C. Lev, V. Ganapathy, and K. Liu IFN Regulatory Factor 8 Mediates Apoptosis in Nonhemopoietic Tumor Cells via Regulation of Fas Expression J. Immunol., October 1, 2007; 179(7): 4775 - 4782. [Abstract] [Full Text] [PDF] C. Munoz-Fontela, M. A. Garcia, M. Collado, L. Marcos-Villar, P. Gallego, M. Esteban, and C. Rivas Control of virus infection by tumour suppressors Carcinogenesis, June 1, 2007; 28(6): 1140 - 1144. [Abstract] [Full Text] [PDF] J. Markus, M. T. Garin, J. Bies, N. Galili, A. Raza, M. J. Thirman, M. M. Le Beau, J. D. Rowley, P. P. Liu, and L. Wolff Methylation-Independent Silencing of the Tumor Suppressor INK4b (p15) by CBF{beta}-SMMHC in Acute Myelogenous Leukemia with inv(16) Cancer Res., February 1, 2007; 67(3): 992 - 1000. [Abstract] [Full Text] [PDF] J. Liu and X. Ma Interferon Regulatory Factor 8 Regulates RANTES Gene Transcription in Cooperation with Interferon Regulatory Factor-1, NF-{kappa}B, and PU.1 J. Biol. Chem., July 14, 2006; 281(28): 19188 - 19195. [Abstract] [Full Text] [PDF] Y. Wang, R. M. Baron, G. Zhu, M. Joo, J. W. Christman, E. S. Silverman, M. A. Perrella, R. J. Riese, and M. Cernadas PU.1 Regulates Cathepsin S Expression in Professional APCs J. Immunol., January 1, 2006; 176(1): 275 - 283. [Abstract] [Full Text] [PDF] T. Tamura, P. Thotakura, T. S. Tanaka, M. S. H. Ko, and K. Ozato Identification of target genes and a unique cis element regulated by IRF-8 in developing macrophages Blood, September 15, 2005; 106(6): 1938 - 1947. [Abstract] [Full Text] [PDF] T. V. Pedchenko, G. Y. Park, M. Joo, T. S. Blackwell, and J. W. Christman Inducible binding of PU.1 and interacting proteins to the Toll-like receptor 4 promoter during endotoxemia Am J Physiol Lung Cell Mol Physiol, September 1, 2005; 289(3): L429 - L437. [Abstract] [Full Text] [PDF] W. D. Cook, B. J. McCaw, C. Herring, D. L. John, S. J. Foote, S. L. Nutt, and J. M. Adams PU.1 is a suppressor of myeloid leukemia, inactivated in mice by gene deletion and mutation of its DNA binding domain Blood, December 1, 2004; 104(12): 3437 - 3444. [Abstract] [Full Text] [PDF]

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