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Gene Review

Spi1  -  spleen focus forming virus (SFFV) proviral...

Mus musculus

Synonyms: 31 kDa-transforming protein, Dis-1, Dis1, PU.1, SFFV proviral integration 1 protein, ...
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Disease relevance of Sfpi1

  • Insertion of the MAIDS defective provirus into this region led to a two- to threefold increase in the expression of Sfpi1 RNA [1].
  • To determine whether PU.1 and c-Myb are functionally interrelated, murine bone marrow (BM) cells and 32Dcl3 murine myeloid precursor cells were infected with a retrovirus carrying a PU.1 cDNA and assessed for myeloid colony formation and for granulocytic differentiation, respectively [2].
  • The PU.1 gene is identical to the Spi-1 gene isolated from common proviral integration sites in Friend virus-induced murine erythroleukemia (MEL), and deregulated expression of the gene is believed to be an essential step of the disease [3].
  • We speculate that a combinatorial role of PU.1 and C/EBP-beta mediates the robust production of COX-2 products by macrophages which occurs in Gram-negative bacterial sepsis [4].
  • A frequent event in the generation of these malignant cells is deregulation of the hematopoietic-specific transcription factor PU.1 (Spi-1) by retroviral insertion of the spleen-focus-forming virus component of Friend virus [5].

High impact information on Sfpi1


Chemical compound and disease context of Sfpi1

  • We found that over-expression of PU.1, a member of the ets family of transcription factors, induces apoptotic cell death along with differentiation of DMSO stimulation in murine erythroleukemia (MEL) cells [7].
  • Lysine 170 was acetylated in pre-B cells and plasmacytoma cells, but TSA treatment did not stimulate PU.1 acetylation at this residue arguing that a second mechanism can stimulate 3' enhancer activity [8].
  • PU.1 reduced expression of integrin beta(5), a host factor important for endosomal escape of adenovirus, suggesting that PU.1 redirects adenoviral trafficking by modulating integrin signaling [9].

Biological context of Sfpi1


Anatomical context of Sfpi1

  • Constitutive expression of PU.1 in fetal hematopoietic progenitors blocks T cell development at the pro-T cell stage [11].
  • Importantly, retroviral transduction of PU.1 into mutant progenitors restores responsiveness to myeloid-specific cytokines and development of mature granulocytes and macrophages [12].
  • We demonstrate that mutation of the PU.1 gene causes a severe reduction in myeloid (granulocyte/macrophage) progenitors [12].
  • PU.1 is a unique regulatory protein required for the generation of both the innate and the adaptive immune system [12].
  • Furthermore, deletion of PU.1 in B cells did not compromise their ability to establish and maintain an immune response [14].

Associations of Sfpi1 with chemical compounds

  • Taken together, our results demonstrate that IL-3 stimulation of mcl-1 gene transcription through the SIE motif involves phosphorylation of PU.1 at serine 142 by a p38(MAPK)-dependent pathway [15].
  • Similar to the PU.1 null colonies, the GM-CSF-dependent cells also possessed early monocytic characteristics, including the ability to phagocytize latex beads [16].
  • Transient expression of PU.1 in cotransfection assays in different cell lines resulted in inhibition of chloramphenicol acetyl transferase activity driven by different segments of the c-myb promoter [2].
  • We recently demonstrated that overexpression of PU.1 inhibits erythroid differentiation of MEL cells induced with the differentiating agent DMSO [3].
  • Together, these data suggest that PU.1 is activated by phosphorylation of Ser148 in response to lipopolysaccharide treatment and subsequently binds to sequences in the endogenous COX-2p in a time-dependent manner [4].

Physical interactions of Sfpi1


Regulatory relationships of Sfpi1

  • We present evidence that PU.1 inhibits terminal differentiation at an earlier step than c-Myc and c-Myb [5].
  • Microphthalmia transcription factor and PU.1 synergistically induce the leukocyte receptor osteoclast-associated receptor gene expression [20].
  • PU.1(-/-) embryos also lack progenitors capable of differentiating into myeloid DC in response to granulocyte-macrophage colony-stimulating factor plus interleukin-4 [21].
  • Expression of the p53 gene was reduced rather than enhanced, suggesting that PU.1-induced apoptosis in MEL cells is p53-independent [7].
  • Promoter and chromatin crosslinking analyses suggest that PU.1 directly regulates transcription of the IL-7Ralpha gene [22].

Other interactions of Sfpi1


Analytical, diagnostic and therapeutic context of Sfpi1

  • The significance of PU.1 downregulation was tested using retroviral vectors to force hematopoietic precursors to maintain PU.1 expression during differentiation in fetal thymic organ culture [11].
  • A chromatin immunoprecipitation assay further confirmed that PU.1 binds to the mcl-1 promoter region containing the SIE motif in vivo [15].
  • Endotoxemia in animals caused the similar inducible interaction between PU.1 and IRF4 and the TLR4 promoter in lung tissue of mice that was treated with a single intraperitoneal injection of endotoxin [18].
  • These animals were rescued by marrow transplantation, with complete restoration of osteoclast and macrophage differentiation, verifying that the PU.1 lesion is intrinsic to haematopoietic cells [24].
  • No identifiable common lymphoid or myeloid progenitor populations were discernable by flow cytometry; however, clonogenic assays suggested an overall increased frequency of blast colony-forming cells and BM chimeras revealed existence of long-term self-renewing PU.1-deficient cells that required PU.1 for lymphoid, but not granulocyte, generation [25].


  1. The murine AIDS defective provirus acts as an insertional mutagen in its infected target B cells. Huang, M., Takac, M., Kozak, C.A., Jolicoeur, P. J. Virol. (1995) [Pubmed]
  2. Granulocytic differentiation of normal hematopoietic precursor cells induced by transcription factor PU.1 correlates with negative regulation of the c-myb promoter. Bellon, T., Perrotti, D., Calabretta, B. Blood (1997) [Pubmed]
  3. The role of Ets family transcription factor PU.1 in hematopoietic cell differentiation, proliferation and apoptosis. Oikawa, T., Yamada, T., Kihara-Negishi, F., Yamamoto, H., Kondoh, N., Hitomi, Y., Hashimoto, Y. Cell Death Differ. (1999) [Pubmed]
  4. Transcriptional regulation of the cyclooxygenase-2 gene in macrophages by PU.1. Joo, M., Park, G.Y., Wright, J.G., Blackwell, T.S., Atchison, M.L., Christman, J.W. J. Biol. Chem. (2004) [Pubmed]
  5. Deregulated expression of the PU.1 transcription factor blocks murine erythroleukemia cell terminal differentiation. Rao, G., Rekhtman, N., Cheng, G., Krasikov, T., Skoultchi, A.I. Oncogene (1997) [Pubmed]
  6. Lymphoid cell growth and transformation are suppressed by a key regulatory element of the gene encoding PU.1. Rosenbauer, F., Owens, B.M., Yu, L., Tumang, J.R., Steidl, U., Kutok, J.L., Clayton, L.K., Wagner, K., Scheller, M., Iwasaki, H., Liu, C., Hackanson, B., Akashi, K., Leutz, A., Rothstein, T.L., Plass, C., Tenen, D.G. Nat. Genet. (2006) [Pubmed]
  7. Down-regulation of c-myc and bcl-2 gene expression in PU.1-induced apoptosis in murine erythroleukemia cells. Kihara-Negishi, F., Yamada, T., Kubota, Y., Kondoh, N., Yamamoto, H., Abe, M., Shirai, T., Hashimoto, Y., Oikawa, T. Int. J. Cancer (1998) [Pubmed]
  8. Protein acetylation regulates both PU.1 transactivation and Ig kappa 3' enhancer activity. Bai, Y., Srinivasan, L., Perkins, L., Atchison, M.L. J. Immunol. (2005) [Pubmed]
  9. 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]
  10. Molecular mapping of chromosome 2 deletions in murine radiation-induced AML localizes a putative tumor suppressor gene to a 1.0 cM region homologous to human chromosome segment 11p11-12. Silver, A., Moody, J., Dunford, R., Clark, D., Ganz, S., Bulman, R., Bouffler, S., Finnon, P., Meijne, E., Huiskamp, R., Cox, R. Genes Chromosomes Cancer (1999) [Pubmed]
  11. Constitutive expression of PU.1 in fetal hematopoietic progenitors blocks T cell development at the pro-T cell stage. Anderson, M.K., Weiss, A.H., Hernandez-Hoyos, G., Dionne, C.J., Rothenberg, E.V. Immunity (2002) [Pubmed]
  12. PU.1 regulates both cytokine-dependent proliferation and differentiation of granulocyte/macrophage progenitors. DeKoter, R.P., Walsh, J.C., Singh, H. EMBO J. (1998) [Pubmed]
  13. PU.1 and GATA: components of a mast cell-specific interleukin 4 intronic enhancer. Henkel, G., Brown, M.A. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  14. The development of functional B lymphocytes in conditional PU.1 knock-out mice. Polli, M., Dakic, A., Light, A., Wu, L., Tarlinton, D.M., Nutt, S.L. Blood (2005) [Pubmed]
  15. Interleukin-3 stimulation of mcl-1 gene transcription involves activation of the PU.1 transcription factor through a p38 mitogen-activated protein kinase-dependent pathway. Wang, J.M., Lai, M.Z., Yang-Yen, H.F. Mol. Cell. Biol. (2003) [Pubmed]
  16. Commitment to the monocytic lineage occurs in the absence of the transcription factor PU.1. Henkel, G.W., McKercher, S.R., Leenen, P.J., Maki, R.A. Blood (1999) [Pubmed]
  17. Crystal structure of PU.1/IRF-4/DNA ternary complex. Escalante, C.R., Brass, A.L., Pongubala, J.M., Shatova, E., Shen, L., Singh, H., Aggarwal, A.K. Mol. Cell (2002) [Pubmed]
  18. Inducible binding of PU.1 and interacting proteins to the Toll-like receptor 4 promoter during endotoxemia. Pedchenko, T.V., Park, G.Y., Joo, M., Blackwell, T.S., Christman, J.W. Am. J. Physiol. Lung Cell Mol. Physiol. (2005) [Pubmed]
  19. Prevention of PU.1-induced growth inhibition and apoptosis but not differentiation block in murine erythroleukemia cells by overexpression of CBP. Manabe, N., Yamamoto, H., Yamada, T., Kihara-Negishi, F., Hashimoto, Y., Mochizuki, M., Oikawa, T. Int. J. Oncol. (2003) [Pubmed]
  20. Microphthalmia transcription factor and PU.1 synergistically induce the leukocyte receptor osteoclast-associated receptor gene expression. So, H., Rho, J., Jeong, D., Park, R., Fisher, D.E., Ostrowski, M.C., Choi, Y., Kim, N. J. Biol. Chem. (2003) [Pubmed]
  21. PU.1 is required for myeloid-derived but not lymphoid-derived dendritic cells. Guerriero, A., Langmuir, P.B., Spain, L.M., Scott, E.W. Blood (2000) [Pubmed]
  22. PU.1 regulates expression of the interleukin-7 receptor in lymphoid progenitors. DeKoter, R.P., Lee, H.J., Singh, H. Immunity (2002) [Pubmed]
  23. Physical and functional interactions between the transcription factor PU.1 and the coactivator CBP. Yamamoto, H., Kihara-Negishi, F., Yamada, T., Hashimoto, Y., Oikawa, T. Oncogene (1999) [Pubmed]
  24. Osteopetrosis in mice lacking haematopoietic transcription factor PU.1. Tondravi, M.M., McKercher, S.R., Anderson, K., Erdmann, J.M., Quiroz, M., Maki, R., Teitelbaum, S.L. Nature (1997) [Pubmed]
  25. PU.1 regulates the commitment of adult hematopoietic progenitors and restricts granulopoiesis. Dakic, A., Metcalf, D., Di Rago, L., Mifsud, S., Wu, L., Nutt, S.L. J. Exp. Med. (2005) [Pubmed]
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