SPI1 explained

Transcription factor PU.1 is a protein that in humans is encoded by the SPI1 gene.^[1]

Function

This gene encodes an ETS-domain transcription factor that activates gene expression during myeloid and B-lymphoid cell development.^[2] The nuclear protein binds to a purine-rich sequence known as the PU-box found on enhancers of target genes, and regulates their expression in coordination with other transcription factors and cofactors. The protein can also regulate alternative splicing of target genes. Multiple transcript variants encoding different isoforms have been found for this gene.^[3]

The PU.1 transcription factor is essential for hematopoiesis and cell fate decisions. PU.1 can physically interact with a variety of regulatory factors like SWI/SNF,^[4] TFIID, GATA-2, GATA-1 and c-Jun. The protein-protein interactions between these factors can regulate PU.1-dependent cell fate decisions. PU.1 can modulate the expression of 3000 genes in hematopoietic cells including cytokines. It is expressed in monocytes, granulocytes, B and NK cells but is absent in T cells, reticulocytes and megakaryocytes. Its transcription is regulated by various mechanisms .^[5]

PU.1 is an essential regulator of the pro-fibrotic system. In fibrotic conditions, PU.1 expression is perturbed in fibrotic diseases, resulting in upregulation of fibrosis-associated genes sets in fibroblasts. Disruption of PU.1 in fibrotic fibroblasts leads to them returning into their resting state from pro-fibrotic fibroblasts. PU.1 is seen to be highly expressed in extracellular matrix producing-fibrotic fibroblasts while it is downregulated in inflammatory/ ECM degrading and resting fibroblasts. The majority of the cells expressing PU.1 in fibrotic conditions remain to be fibroblasts with a few infiltrating lymphocytes. PU.1 induces the polarization of resting and inflammatory fibroblasts into fibrotic fibroblasts.^[6]

Structure

The ETS domain is the DNA-binding module of PU.1 and other ETS-family transcription factors.

Interactions

SPI1 has been shown to interact with:

• FUS,^[7]
• GATA2,^[8]
• IRF4,^{[9] [10]} and
• NONO.^[11]

Further reading

• Klemsz MJ, McKercher SR, Celada A, Van Beveren C, Maki RA . The macrophage and B cell-specific transcription factor PU.1 is related to the ets oncogene . Cell . 61 . 1 . 113–124 . April 1990 . 2180582 . 10.1016/0092-8674(90)90219-5 . 27819155 .
• Nguyen VC, Ray D, Gross MS, de Tand MF, Frézal J, Moreau-Gachelin F . Localization of the human oncogene SPI1 on chromosome 11, region p11.22 . Human Genetics . 84 . 6 . 542–546 . May 1990 . 2338340 . 10.1007/bf00210807 . 22337200 .
• Chen H, Ray-Gallet D, Zhang P, Hetherington CJ, Gonzalez DA, Zhang DE, Moreau-Gachelin F, Tenen DG . PU.1 (Spi-1) autoregulates its expression in myeloid cells . Oncogene . 11 . 8 . 1549–1560 . October 1995 . 7478579 .
• Nagulapalli S, Pongubala JM, Atchison ML . Multiple proteins physically interact with PU.1. Transcriptional synergy with NF-IL6 beta (C/EBP delta, CRP3) . Journal of Immunology . 155 . 9 . 4330–4338 . November 1995 . 10.4049/jimmunol.155.9.4330 . 7594592 . free .
• Pongubala JM, Atchison ML . Activating transcription factor 1 and cyclic AMP response element modulator can modulate the activity of the immunoglobulin kappa 3' enhancer . The Journal of Biological Chemistry . 270 . 17 . 10304–10313 . April 1995 . 7730336 . 10.1074/jbc.270.17.10304 . free .
• Hromas R, Orazi A, Neiman RS, Maki R, Van Beveran C, Moore J, Klemsz M . Hematopoietic lineage- and stage-restricted expression of the ETS oncogene family member PU.1 . Blood . 82 . 10 . 2998–3004 . November 1993 . 8219191 . 10.1182/blood.V82.10.2998.2998 . free .
• Hagemeier C, Bannister AJ, Cook A, Kouzarides T . 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 . Proceedings of the National Academy of Sciences of the United States of America . 90 . 4 . 1580–1584 . February 1993 . 8434021 . 45918 . 10.1073/pnas.90.4.1580 . free . 1993PNAS...90.1580H .
• Hallier M, Tavitian A, Moreau-Gachelin F . The transcription factor Spi-1/PU.1 binds RNA and interferes with the RNA-binding protein p54nrb . The Journal of Biological Chemistry . 271 . 19 . 11177–11181 . May 1996 . 8626664 . 10.1074/jbc.271.19.11177 . free .
• Bassuk AG, Anandappa RT, Leiden JM . Physical interactions between Ets and NF-kappaB/NFAT proteins play an important role in their cooperative activation of the human immunodeficiency virus enhancer in T cells . Journal of Virology . 71 . 5 . 3563–3573 . May 1997 . 9094628 . 191503 . 10.1128/JVI.71.5.3563-3573.1997 .
• Li SL, Valente AJ, Zhao SJ, Clark RA . PU.1 is essential for p47(phox) promoter activity in myeloid cells . The Journal of Biological Chemistry . 272 . 28 . 17802–17809 . July 1997 . 9211934 . 10.1074/jbc.272.28.17802 . free .
• Tsukada J, Misago M, Serino Y, Ogawa R, Murakami S, Nakanishi M, Tonai S, Kominato Y, Morimoto I, Auron PE, Eto S . Human T-cell leukemia virus type I Tax transactivates the promoter of human prointerleukin-1beta gene through association with two transcription factors, nuclear factor-interleukin-6 and Spi-1 . Blood . 90 . 8 . 3142–3153 . October 1997 . 9376596 . 10.1182/blood.V90.8.3142 . free .
• Hallier M, Lerga A, Barnache S, Tavitian A, Moreau-Gachelin F . The transcription factor Spi-1/PU.1 interacts with the potential splicing factor TLS . The Journal of Biological Chemistry . 273 . 9 . 4838–4842 . February 1998 . 9478924 . 10.1074/jbc.273.9.4838 . free .
• Suzuki S, Kumatori A, Haagen IA, Fujii Y, Sadat MA, Jun HL, Tsuji Y, Roos D, Nakamura M . PU.1 as an essential activator for the expression of gp91(phox) gene in human peripheral neutrophils, monocytes, and B lymphocytes . Proceedings of the National Academy of Sciences of the United States of America . 95 . 11 . 6085–6090 . May 1998 . 9600921 . 27589 . 10.1073/pnas.95.11.6085 . free . 1998PNAS...95.6085S .
• Carrère S, Verger A, Flourens A, Stehelin D, Duterque-Coquillaud M . Erg proteins, transcription factors of the Ets family, form homo, heterodimers and ternary complexes via two distinct domains . Oncogene . 16 . 25 . 3261–3268 . June 1998 . 9681824 . 10.1038/sj.onc.1201868 . 26807714 .
• Sato M, Morii E, Takebayashi-Suzuki K, Yasui N, Ochi T, Kitamura Y, Nomura S . Microphthalmia-associated transcription factor interacts with PU.1 and c-Fos: determination of their subcellular localization . Biochemical and Biophysical Research Communications . 254 . 2 . 384–387 . January 1999 . 9918847 . 10.1006/bbrc.1998.9918 .
• Brass AL, Zhu AQ, Singh H . Assembly requirements of PU.1-Pip (IRF-4) activator complexes: inhibiting function in vivo using fused dimers . The EMBO Journal . 18 . 4 . 977–991 . February 1999 . 10022840 . 1171190 . 10.1093/emboj/18.4.977 .
• Yamamoto H, Kihara-Negishi F, Yamada T, Hashimoto Y, Oikawa T . Physical and functional interactions between the transcription factor PU.1 and the coactivator CBP . Oncogene . 18 . 7 . 1495–1501 . February 1999 . 10050886 . 10.1038/sj.onc.1202427 . free .
• Rao S, Matsumura A, Yoon J, Simon MC . SPI-B activates transcription via a unique proline, serine, and threonine domain and exhibits DNA binding affinity differences from PU.1 . The Journal of Biological Chemistry . 274 . 16 . 11115–11124 . April 1999 . 10196196 . 10.1074/jbc.274.16.11115 . free .
• Mao S, Frank RC, Zhang J, Miyazaki Y, Nimer SD . Functional and physical interactions between AML1 proteins and an ETS protein, MEF: implications for the pathogenesis of t(8;21)-positive leukemias . Molecular and Cellular Biology . 19 . 5 . 3635–3644 . May 1999 . 10207087 . 84165 . 10.1128/mcb.19.5.3635 .

Notes and References

1. Ray D, Culine S, Tavitain A, Moreau-Gachelin F . The human homologue of the putative proto-oncogene Spi-1: characterization and expression in tumors . Oncogene . 5 . 5 . 663–668 . May 1990 . 1693183 .
2. Oikawa T, Yamada T, Kihara-Negishi F, Yamamoto H, Kondoh N, Hitomi Y, Hashimoto Y . The role of Ets family transcription factor PU.1 in hematopoietic cell differentiation, proliferation and apoptosis . Cell Death and Differentiation . 6 . 7 . 599–608 . July 1999 . 10453070 . 10.1038/sj.cdd.4400534 . free .
3. Web site: Entrez Gene: SPI1 spleen focus forming virus (SFFV) proviral integration oncogene spi1.
4. Chambers C, Cermakova K, Chan YS, Kurtz K, Wohlan K, Lewis AH, Wang C, Pham A, Dejmek M, Sala M, Loeza Cabrera M, Aguilar R, Nencka R, Lacorazza HD, Rau RE, Hodges HC . SWI/SNF Blockade Disrupts PU.1-Directed Enhancer Programs in Normal Hematopoietic Cells and Acute Myeloid Leukemia . Cancer Research . 83 . 7 . 983–996 . April 2023 . 36662812 . 10071820 . 10.1158/0008-5472.CAN-22-2129 .
5. Burda P, Laslo P, Stopka T . The role of PU.1 and GATA-1 transcription factors during normal and leukemogenic hematopoiesis . Leukemia . 24 . 7 . 1249–1257 . July 2010 . 20520638 . 10.1038/leu.2010.104 . 1941766 .
6. Wohlfahrt T, Rauber S, Uebe S, Luber M, Soare A, Ekici A, Weber S, Matei AE, Chen CW, Maier C, Karouzakis E, Kiener HP, Pachera E, Dees C, Beyer C, Daniel C, Gelse K, Kremer AE, Naschberger E, Stürzl M, Butter F, Sticherling M, Finotto S, Kreuter A, Kaplan MH, Jüngel A, Gay S, Nutt SL, Boykin DW, Poon GM, Distler O, Schett G, Distler JH, Ramming A . PU.1 controls fibroblast polarization and tissue fibrosis . Nature . 566 . 7744 . 344–349 . February 2019 . 30700907 . 6526281 . 10.1038/s41586-019-0896-x .
7. Hallier M, Lerga A, Barnache S, Tavitian A, Moreau-Gachelin F . The transcription factor Spi-1/PU.1 interacts with the potential splicing factor TLS . The Journal of Biological Chemistry . 273 . 9 . 4838–4842 . February 1998 . 9478924 . 10.1074/jbc.273.9.4838 . free .
8. Zhang P, Behre G, Pan J, Iwama A, Wara-Aswapati N, Radomska HS, Auron PE, Tenen DG, Sun Z . Negative cross-talk between hematopoietic regulators: GATA proteins repress PU.1 . Proceedings of the National Academy of Sciences of the United States of America . 96 . 15 . 8705–8710 . July 1999 . 10411939 . 17580 . 10.1073/pnas.96.15.8705 . free . 1999PNAS...96.8705Z .
9. Brass AL, Zhu AQ, Singh H . Assembly requirements of PU.1-Pip (IRF-4) activator complexes: inhibiting function in vivo using fused dimers . The EMBO Journal . 18 . 4 . 977–991 . February 1999 . 10022840 . 1171190 . 10.1093/emboj/18.4.977 .
10. Escalante CR, Shen L, Escalante MC, Brass AL, Edwards TA, Singh H, Aggarwal AK . Crystallization and characterization of PU.1/IRF-4/DNA ternary complex . Journal of Structural Biology . 139 . 1 . 55–59 . July 2002 . 12372320 . 10.1016/s1047-8477(02)00514-2 .
11. Hallier M, Tavitian A, Moreau-Gachelin F . The transcription factor Spi-1/PU.1 binds RNA and interferes with the RNA-binding protein p54nrb . The Journal of Biological Chemistry . 271 . 19 . 11177–11181 . May 1996 . 8626664 . 10.1074/jbc.271.19.11177 . free .