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Gene Review

SPI1  -  Spi-1 proto-oncogene

Homo sapiens

Synonyms: 31 kDa-transforming protein, OF, PU.1, SFPI1, SPI-1, ...
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Disease relevance of SPI1

  • To identify a novel protein(s) binding to PU.1, we carried out affinity purification using a column of Glutathione-Sepharose beads bound to GST-PU.1 fusion protein and isolated several individual proteins using murine erythroleukemia (MEL) cell extracts [1].
  • Wild-type Salmonella typhimurium and an isogenic SPI-1 type three secretion system (TTSS) mutant derivative (invA) were used to compare the interactions with 3-D cells and monolayers in adherence/invasion, tissue pathology, and cytokine expression studies [2].
  • Alterations of loci encoding PU.1, BOB1, and OCT2 transcription regulators do not correlate with their suppressed expression in Hodgkin lymphoma [3].
  • 1. In addition, the single-base mutation (C --> T) at position -52 that was identified in a patient with chronic granulomatous disease inhibited the binding of PU.1 to the promoter [4].
  • The myeloid master regulator transcription factor PU.1 is inactivated by AML1-ETO in t(8;21) myeloid leukemia [5].

High impact information on SPI1

  • Using PU.1(-/-) progenitors, we demonstrate that at subthreshold levels, this Ets transcription factor regulates a mixed pattern (macrophage/neutrophil) of gene expression within individual myeloid progenitors [6].
  • Essential role of Jun family transcription factors in PU.1 knockdown-induced leukemic stem cells [7].
  • Examination of human individuals with AML confirmed the correlation between PU.1 and JunB downregulation [7].
  • We examined the transcriptome of preleukemic hematopoietic stem cells (HSCs) in which PU.1 was knocked down (referred to as 'PU.1-knockdown HSCs') to identify transcriptional changes preceding malignant transformation [7].
  • The microA motif was required for microB-dependent enhancer activity, which suggests that a minimal B cell-specific enhancer is composed of both the PU.1 and Ets-1 binding sites [8].

Chemical compound and disease context of SPI1


Biological context of SPI1


Anatomical context of SPI1

  • Our results suggest that interactions between PU.1 and GATA proteins play a critical role in the decision of stem cells to commit to erythroid vs. myeloid lineages [12].
  • Novel combinatorial interactions of GATA-1, PU.1, and C/EBPepsilon isoforms regulate transcription of the gene encoding eosinophil granule major basic protein [15].
  • In Jurkat cells, overexpression of c-Ets-1, c-Ets-2, or PU.1 effectively represses dexamethasone-mediated up-regulation of an hGR 1A promoter-luciferase reporter gene, as do dominant negative c-Myb (c-Myb DNA-binding domain) or Ets proteins (Ets-2 DNA-binding domain) [16].
  • Ectopic expression of Oct-2 was able to fully restore PU.1 promoter activity in the PEL cell line BCBL-1, while PU.1 expression also reconstituted the activity of the lambdaB Ets-IRF site [17].
  • Finally, we showed that the silencer is also active in TAL-1-negative myeloid HL60 cells that express PU.1 at high levels [18].

Associations of SPI1 with chemical compounds


Physical interactions of SPI1

  • We demonstrate further that GATA inhibits binding of PU.1 to c-Jun, a critical coactivator of PU.1 transactivation of myeloid promoters [12].
  • Like E1A, PU.1 binds to the conserved C-terminal domain of TFIID and to the RB "pocket" domain [24].
  • Here we present evidence that the cellular transcription factor PU.1 can bind to both RB and TFIID [24].
  • PU.1/Spi-1 binds to the human TAL-1 silencer to mediate its activity [18].
  • During the onset and normal progression of hematopoiesis, several lineage-specific factors such as C/EBPalpha and PU.1 interact with Runx1 to regulate transcription combinatorially [25].

Regulatory relationships of SPI1


Other interactions of SPI1

  • PU.1 (also known as Spi-1) and GATA-1 are transcription factors essential for the development of myeloid and erythroid lineages, respectively [12].
  • The ability of PU.1 to contact directly both RB and TFIID through the same 75-residue domain prompted us to look for sequence similarity between these two proteins [24].
  • The Ets domain accounted for the bulk of the interaction of PU.1 with Nup153 and RanGMPPNP [26].
  • Our results suggest that MeCP2 acts as a corepressor of PU.1 probably due to facilitating complex formation with mSin3A and HDACs [1].
  • The mechanism of action of VIP on monocyte differentiation may be via inhibition of the transcription factor PU.1 [27].

Analytical, diagnostic and therapeutic context of SPI1


  1. Direct association between PU.1 and MeCP2 that recruits mSin3A-HDAC complex for PU.1-mediated transcriptional repression. Suzuki, M., Yamada, T., Kihara-Negishi, F., Sakurai, T., Oikawa, T. Oncogene (2003) [Pubmed]
  2. Three-dimensional organotypic models of human colonic epithelium to study the early stages of enteric salmonellosis. zu Bentrup, K.H., Ramamurthy, R., Ott, C.M., Emami, K., Nelman-Gonzalez, M., Wilson, J.W., Richter, E.G., Goodwin, T.J., Alexander, J.S., Pierson, D.L., Pellis, N., Buchanan, K.L., Nickerson, C.A. Microbes Infect. (2006) [Pubmed]
  3. Alterations of loci encoding PU.1, BOB1, and OCT2 transcription regulators do not correlate with their suppressed expression in Hodgkin lymphoma. Cavazzini, F., De Wolf-Peeters, C., Wlodarska, I. Cancer Genet. Cytogenet. (2005) [Pubmed]
  4. PU.1 as an essential activator for the expression of gp91(phox) gene in human peripheral neutrophils, monocytes, and B lymphocytes. Suzuki, S., Kumatori, A., Haagen, I.A., Fujii, Y., Sadat, M.A., Jun, H.L., Tsuji, Y., Roos, D., Nakamura, M. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  5. The myeloid master regulator transcription factor PU.1 is inactivated by AML1-ETO in t(8;21) myeloid leukemia. Vangala, R.K., Heiss-Neumann, M.S., Rangatia, J.S., Singh, S.M., Schoch, C., Tenen, D.G., Hiddemann, W., Behre, G. Blood (2003) [Pubmed]
  6. Multilineage transcriptional priming and determination of alternate hematopoietic cell fates. Laslo, P., Spooner, C.J., Warmflash, A., Lancki, D.W., Lee, H.J., Sciammas, R., Gantner, B.N., Dinner, A.R., Singh, H. Cell (2006) [Pubmed]
  7. Essential role of Jun family transcription factors in PU.1 knockdown-induced leukemic stem cells. Steidl, U., Rosenbauer, F., Verhaak, R.G., Gu, X., Ebralidze, A., Otu, H.H., Klippel, S., Steidl, C., Bruns, I., Costa, D.B., Wagner, K., Aivado, M., Kobbe, G., Valk, P.J., Passegu??, E., Libermann, T.A., Delwel, R., Tenen, D.G. Nat. Genet. (2006) [Pubmed]
  8. Regulation of lymphoid-specific immunoglobulin mu heavy chain gene enhancer by ETS-domain proteins. Nelsen, B., Tian, G., Erman, B., Gregoire, J., Maki, R., Graves, B., Sen, R. Science (1993) [Pubmed]
  9. Both PU.1 and nuclear factor-kappa B mediate lipopolysaccharide- induced HIV-1 long terminal repeat transcription in macrophages. Lodie, T.A., Reiner, M., Coniglio, S., Viglianti, G., Fenton, M.J. J. Immunol. (1998) [Pubmed]
  10. PU.1 Redirects Adenovirus to Lysosomes in Alveolar Macrophages, Uncoupling Internalization from Infection. Carey, B., Staudt, M.K., Bonaminio, D., van der Loo, J.C., Trapnell, B.C. J. Immunol. (2007) [Pubmed]
  11. Localization of the human oncogene SPI1 on chromosome 11, region p11.22. Nguyen, V.C., Ray, D., Gross, M.S., de Tand, M.F., Frézal, J., Moreau-Gachelin, F. Hum. Genet. (1990) [Pubmed]
  12. Negative cross-talk between hematopoietic regulators: GATA proteins repress PU.1. Zhang, P., Behre, G., Pan, J., Iwama, A., Wara-Aswapati, N., Radomska, H.S., Auron, P.E., Tenen, D.G., Sun, Z. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  13. Functional characterization of ETV6 and ETV6/CBFA2 in the regulation of the MCSFR proximal promoter. Fears, S., Gavin, M., Zhang, D.E., Hetherington, C., Ben-David, Y., Rowley, J.D., Nucifora, G. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  14. E47, IRF-4, and PU.1 synergize to induce B-cell-specific activation of the class II transactivator promoter III (CIITA-PIII). van der Stoep, N., Quinten, E., Marcondes Rezende, M., van den Elsen, P.J. Blood (2004) [Pubmed]
  15. Novel combinatorial interactions of GATA-1, PU.1, and C/EBPepsilon isoforms regulate transcription of the gene encoding eosinophil granule major basic protein. Du, J., Stankiewicz, M.J., Liu, Y., Xi, Q., Schmitz, J.E., Lekstrom-Himes, J.A., Ackerman, S.J. J. Biol. Chem. (2002) [Pubmed]
  16. c-Myb and members of the c-Ets family of transcription factors act as molecular switches to mediate opposite steroid regulation of the human glucocorticoid receptor 1A promoter. Geng, C.D., Vedeckis, W.V. J. Biol. Chem. (2005) [Pubmed]
  17. Disruption of the B-cell specific transcriptional program in HHV-8 associated primary effusion lymphoma cell lines. Arguello, M., Sgarbanti, M., Hernandez, E., Mamane, Y., Sharma, S., Servant, M., Lin, R., Hiscott, J. Oncogene (2003) [Pubmed]
  18. PU.1/Spi-1 binds to the human TAL-1 silencer to mediate its activity. Le Clech, M., Chalhoub, E., Dohet, C., Roure, V., Fichelson, S., Moreau-Gachelin, F., Mathieu, D. J. Mol. Biol. (2006) [Pubmed]
  19. PU.1 regulates glutathione peroxidase expression in neutrophils. Throm, S.L., Klemsz, M.J. J. Leukoc. Biol. (2003) [Pubmed]
  20. Indirubin, a Chinese anti-leukaemia drug, promotes neutrophilic differentiation of human myelocytic leukaemia HL-60 cells. Suzuki, K., Adachi, R., Hirayama, A., Watanabe, H., Otani, S., Watanabe, Y., Kasahara, T. Br. J. Haematol. (2005) [Pubmed]
  21. Hematopoietic lineage- and stage-restricted expression of the ETS oncogene family member PU.1. Hromas, R., Orazi, A., Neiman, R.S., Maki, R., Van Beveran, C., Moore, J., Klemsz, M. Blood (1993) [Pubmed]
  22. Multiple PU.1 sites cooperate in the regulation of p40(phox) transcription during granulocytic differentiation of myeloid cells. Li, S.L., Valente, A.J., Qiang, M., Schlegel, W., Gamez, M., Clark, R.A. Blood (2002) [Pubmed]
  23. Functional interference between the Spi-1/PU.1 oncoprotein and steroid hormone or vitamin receptors. Gauthier, J.M., Bourachot, B., Doucas, V., Yaniv, M., Moreau-Gachelin, F. EMBO J. (1993) [Pubmed]
  24. The activation domain of transcription factor PU.1 binds the retinoblastoma (RB) protein and the transcription factor TFIID in vitro: RB shows sequence similarity to TFIID and TFIIB. Hagemeier, C., Bannister, A.J., Cook, A., Kouzarides, T. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  25. Subnuclear targeting of Runx1 is required for synergistic activation of the myeloid specific M-CSF receptor promoter by PU.1. Li, X., Vradii, D., Gutierrez, S., Lian, J.B., van Wijnen, A.J., Stein, J.L., Stein, G.S., Javed, A. J. Cell. Biochem. (2005) [Pubmed]
  26. Carrier-independent nuclear import of the transcription factor PU.1 via RanGTP-stimulated binding to Nup153. Zhong, H., Takeda, A., Nazari, R., Shio, H., Blobel, G., Yaseen, N.R. J. Biol. Chem. (2005) [Pubmed]
  27. Pivotal Advance: Vasoactive intestinal peptide inhibits up-regulation of human monocyte TLR2 and TLR4 by LPS and differentiation of monocytes to macrophages. Foster, N., Lea, S.R., Preshaw, P.M., Taylor, J.J. J. Leukoc. Biol. (2007) [Pubmed]
  28. Ehrlichia chaffeensis downregulates surface Toll-like receptors 2/4, CD14 and transcription factors PU.1 and inhibits lipopolysaccharide activation of NF-kappa B, ERK 1/2 and p38 MAPK in host monocytes. Lin, M., Rikihisa, Y. Cell. Microbiol. (2004) [Pubmed]
  29. PU.1 regulation of human alveolar macrophage differentiation requires granulocyte-macrophage colony-stimulating factor. Bonfield, T.L., Raychaudhuri, B., Malur, A., Abraham, S., Trapnell, B.C., Kavuru, M.S., Thomassen, M.J. Am. J. Physiol. Lung Cell Mol. Physiol. (2003) [Pubmed]
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