PU.1 Activates Transcription of SHP-1 Gene in Hematopoietic Cells
Open accessAbstract
Protein-tyrosine phosphatase SHP-1 is the key negative regulator of numerous signaling pathways. SHP-1 is expressed in the hematopietic and epithelial cells as two structurally similar mRNA transcripts controlled by two different promoters designated P2 and P1, respectively. Whereas the transcriptional regulation of the SHP-1 gene P1 promoter has been partially elucidated, the structure and functional control of the P2 promoter remain unknown despite the critical role played by SHP-1 in the normal and malignant lymphoid and other hematopoetic cells. Using luciferase reporter assays with the set of constructs that contained a gradually truncated intron 1 of the SHP-1 gene, we identified the minimal (<120 bp) fragment that is able to fully activate expression of the reporter gene. Furthermore, we found that PU.1 (a member of the Ets transcription factor family that plays a crucial role in differentiation and function of the lymphoid and myeloid cells) binds to the identified P2 promoter both in vitro and in vivo. PU.1 also activates the promoter in the sequence specific manner and is critical for its expression as evidenced by the profound supression of the SHP-1 gene transcription upon the siRNA-mediated depletion of PU.1. These findings provide an insight into the structure of the hematopoietic cell-specific P2 promoter of the SHP-1 gene and identify PU.1 as the transcriptional activator of the P2 promoter.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Cites
Requirement of transcription factor PU.1 in the development of multiple hematopoietic lineages
Scott, E. W., Simon, M. C., Anastasi, J., & Singh, H. (1994) · Science · doi:10.1126/science.8079170 · Cited by 1,532 · see citing works
Targeted disruption of the PU.1 gene results in multiple hematopoietic abnormalities
McKercher, S. R., Torbett, B. E., Anderson, K. L., Henkel, G. W., Vestal, D. J., Baribault, H., Klemsz, M., Feeney, A. J., Wu, G. E., Paige, C. J., et al. (1996) · The EMBO Journal · doi:10.1002/j.1460-2075.1996.tb00949.x · Cited by 1,130 · see citing works
Regulation of B lymphocyte and macrophage development by graded expression of PU.1
DeKoter, R. P., & Singh, H. (2000) · Science · doi:10.1126/science.288.5470.1439 · Cited by 749 · see citing works
Shultz, L. D., Schweitzer, P. A., Rajan, T. V., Yi, T., Ihle, J. N., Matthews, R. J., Thomas, M. L., & Beier, D. R. (1993) · Cell · doi:10.1016/0092-8674(93)90369-2 · Cited by 741 · see citing works
Motheaten and viable motheaten mice have mutations in the haematopoietic cell phosphatase gene
Tsui, H. W., Siminovitch, K. A., de Souza, L., & Tsui, F. W. L. (1993) · Nature Genetics · doi:10.1038/ng0693-124 · Cited by 564 · see citing works
Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1.
Rosenbauer, F., Wagner, K., Kutok, J. L., Iwasaki, H., Le Beau, M. M., Okuno, Y., Akashi, K., Fiering, S., & Tenen, D. G. (2004) · Nature Genetics · doi:10.1038/ng1361 · Cited by 506 · see citing works
Shen, S., Bastien, L., Posner, B. I., et al. (1991) · Nature · doi:10.1038/352736a0 · Cited by 396 · see citing works
Yi, T., Cleveland, J. L., & Ihle, J. N. (1992) · Molecular and Cellular Biology · doi:10.1128/mcb.12.2.836 · Cited by 344 · see citing works
Stebbins, C. C., Watzl, C., Billadeau, D. D., Leibson, P. J., Burshtyn, D. N., & Long, E. O. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.17.6291-6299.2003 · Cited by 296 · see citing works
The function of the protein tyrosine phosphatase SHP-1 in cancer
Wu, C. (2003) · Gene · doi:10.1016/s0378-1119(03)00400-1 · Cited by 273 · see citing works
Chim, C. S., Fung, T.-K., Cheung, W. C., Liang, R. H. S., & Kwong, Y. (2004) · Blood · doi:10.1182/blood-2003-06-2007 · Cited by 246 · see citing works
Heterozygous PU.1 mutations are associated with acute myeloid leukemia
Mueller, B. U., Pabst, T., Osato, M., Asou, N., Johansen, L. M., Minden, M. D., Behre, G., Hiddemann, W., Ito, Y., & Tenen, D. G. (2002) · Blood · doi:10.1182/blood.v100.3.998 · Cited by 243 · see citing works
Rosenbauer, F., Owens, B. M., Yu, L., Tumang, J. R., Steidl, U., Kutok, J. L., Clayton, L. K., Wagner, K., Scheller, M., Iwasaki, H., et al. (2006) · Nature Genetics · doi:10.1038/ng1679 · Cited by 237 · see citing works
Gene silencing of the tyrosine phosphatase SHP1 gene by aberrant methylation in leukemias/lymphomas.
Oka, T., Ouchida, M., Koyama, M., Ogama, Y., Takada, S., Nakatani, Y., Tanaka, T., Yoshino, T., Hayashi, K., Ohara, N., et al. (2002) · PubMed · Cited by 208 · see citing works
Rosmarin, A. G., Yang, Z., & Resendes, K. K. (2005) · Experimental Hematology · doi:10.1016/j.exphem.2004.08.015 · Cited by 142 · see citing works
GA binding protein regulates interleukin 7 receptor α-chain gene expression in T cells
Xue, H., Bollenbacher, J., Rovella, V., Tripuraneni, R., Du, Y., Liu, C., Williams, A., McCoy, J. P., & Leonard, W. J. (2004) · Nature Immunology · doi:10.1038/ni1117 · Cited by 140 · see citing works
Site-specific DNA methylation by a complex of PU.1 and Dnmt3a/b
Suzuki, M., Yamada, T., Kihara-Negishi, F., Sakurai, T., Hara, E., Tenen, D. G., Hozumi, N., & Oikawa, T. (2006) · Oncogene · doi:10.1038/sj.onc.1209272 · Cited by 132 · see citing works
Zhang, Q., Raghunath, P. N., Vonderheid, E. C., et al. (2000) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)64629-9 · Cited by 129 · see citing works
Self-citationEffective Dephosphorylation of Src Substrates by SHP-1
Frank, C., Burkhardt, C., Imhof, D., et al. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m309096200 · Cited by 106 · see citing works
Subversion of host cell signalling by the protozoan parasiteLeishmania
Gregory, D. J., & Olivier, M. (2005) · Parasitology · doi:10.1017/s0031182005008139 · Cited by 105 · see citing works
Transcription factors drive B cell development
Hagman, J. R., & Lukin, K. (2006) · Current Opinion in Immunology · doi:10.1016/j.coi.2006.01.007 · Cited by 98 · see citing works
Inactivation of PU.1 in adult mice leads to the development of myeloid leukemia
Metcalf, D., Dakic, A., Mifsud, S., Di Rago, L., Wu, L., & Nutt, S. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0510616103 · Cited by 95 · see citing works
Myb and Ets Proteins Are Candidate Regulators of c-kit Expression in Human Hematopoietic Cells
Ratajczak, M. Z., Perrotti, D., Melotti, P., Powzaniuk, M., Calabretta, B., Onodera, K., Kregenow, D. A., Machalinski, B., & Gewirtz, A. M. (1998) · Blood · doi:10.1182/blood.v91.6.1934 · Cited by 90 · see citing works
PU.1 but not ets-2 is essential for macrophage development from embryonic stem cells
Henkel, G., McKercher, Sr., Yamamoto, H., Anderson, K., Oshima, R., & Maki, R. (1996) · Blood · doi:10.1182/blood.v88.8.2917.bloodjournal8882917 · Cited by 76 · see citing works
McIvor, Z., Hein, S., Fiegler, H., Schroeder, T., Stocking, C., Just, U., & Cross, M. (2003) · Experimental Hematology · doi:10.1016/s0301-472x(02)01017-2 · Cited by 58 · see citing works
O’Prey, J., Ramsay, S., Chambers, I., & Harrison, P. R. (1993) · Molecular and Cellular Biology · doi:10.1128/mcb.13.10.6290 · Cited by 47 · see citing works
Molecular mechanisms underlying SHP‐1 gene expression
Tsui, H. W., Hasselblatt, K. T., Martín, A., et al. (2002) · European Journal of Biochemistry · doi:10.1046/j.1432-1033.2002.02986.x · Cited by 40 · see citing works
Zou, G.-M., Chen, J., Yöder, M. C., Wu, W., & Rowley, J. D. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506218102 · Cited by 39 · see citing works
ets-2 Regulates cdc2 Kinase Activity in Mammalian Cells: Coordinated Expression of cdc2 and Cyclin A
Wen, S.-C., Ku, D.-H., Luca, A. D., et al. (1995) · Experimental Cell Research · doi:10.1006/excr.1995.1057 · Cited by 31 · see citing works
Mena-Durán, A. V., Togo, S. H., Bazhenova, L. A., et al. (2005) · British Journal of Haematology · doi:10.1111/j.1365-2141.2005.05516.x · Cited by 24 · see citing works
Oh, I., & Reddy, E. P. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.34.21432 · Cited by 19 · see citing works
Nishigaki, K., Hanson, C. A., Ohashi, T., Spadaccini, A., & Ruscetti, S. K. (2006) · Journal of Virology · doi:10.1128/jvi.02651-05 · Cited by 15 · see citing works
Flagged first, then by citations
Research works printed but not linked: 3
- Yi, 1992, Mol. Cell. Biol., 12, 836
- Oka, 2002, Cancer Res., 62, 6390
- O'Prey, 1993, Mol. Cell. Biol., 13, 6290
Cited by
Sorted by citations
Master Transcription Factors and Mediator Establish Super-Enhancers at Key Cell Identity Genes
Whyte, W. A., Orlando, D. A., Hnisz, D., Abraham, B. J., Lin, C. Y., Kagey, M. H., Rahl, P. B., Lee, T. I., & Young, R. A. (2013) · Cell · doi:10.1016/j.cell.2013.03.035 · Cited by 4,143 · see citing works
“Previous studies have shown that occupancy of pro-B genomic sites by PU.1 is predictive of enhancer activity (Abujarour et al., 2010; Wlodarski et al., 2007).”
Macrophage-specific gene functions in Spi1-directed innate immunity
Zakrzewska, A., Cui, C., Stockhammer, O. W., Benard, E. L., Spaink, H. P., & Meijer, A. H. (2010) · Blood · doi:10.1182/blood-2010-01-262873 · Cited by 199 · see citing works
Nesterovitch, A. B., Györfy, Z., Hoffman, M. D., et al. (2011) · American Journal Of Pathology · doi:10.1016/j.ajpath.2010.12.035 · Cited by 84 · see citing works
IRF8 and IRF3 cooperatively regulate rapid interferon-β induction in human blood monocytes
Li, P., Wong, J. J.-Y., Sum, C., Sin, W., Ng, K.-Q., Koh, M., & Chin, K.-C. (2011) · Blood · doi:10.1182/blood-2010-07-294272 · Cited by 75 · see citing works
“Similarly, IRF8 mutants with a major deletion in the IAD, designated IRF8(1-390), IRF8(1-305), and IRF8(1-253) (Figure 5G lanes 7, 9, and 11), as well as the DBD-deletion mutant IRF8( 1-122), were able to interact with IRF3 (Figure 5G lane 15).”
BackgroundInfluentialKumagai, C., Kálmán, B., Middleton, F. A., Vyshkina, T., & Massa, P. T. (2012) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2012.03.003 · Cited by 68 · see citing works
“…seen in MS subjects includes substantialmethylationwithin the critical CpG 13–25 region containing the binding sites for various transcription factors, such as Sp1, Oct-1, NF-κB, PU.1 and CREB-1 important for the expression of SHP-1 (Cheng et al., 2007; Wlodarski et al., 2007; Nakase et al., 2009).”
SHP-1 deficiency and increased inflammatory gene expression in PBMCs of multiple sclerosis patients
Christophi, G. P., Hudson, C. A., Gruber, R. C., Christophi, C. P., Mihai, C., Mejico, L. J., Jubelt, B., & Massa, P. T. (2008) · Laboratory Investigation · doi:10.1038/labinvest.3700720 · Cited by 67 · see citing works
Nesterovitch, A. B., Szántó, S., Gonda, A., Bárdos, T., Kis‐Tóth, K., Adarichev, V. A., Olasz, K., Ghassemi-Nejad, S., Hoffman, M. D., Tharp, M. D., et al. (2011) · American Journal Of Pathology · doi:10.1016/j.ajpath.2010.12.053 · Cited by 54 · see citing works
Kanwal, Z., Zakrzewska, A., den Hertog, J., Spaink, H. P., Schaaf, M. J. M., & Meijer, A. H. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1200551 · Cited by 51 · see citing works
“1 (Spi1), like its human counterpart (31, 32).”
BackgroundSu, J., Tseng, P., Wu, S., Hsu, C.-Y., Tai, W., Li, Y.-S., Chen, I., Liu, C., Chen, K., & Shiau, C. (2014) · Neoplasia · doi:10.1016/j.neo.2014.06.005 · Cited by 46 · see citing works
“In addition, SHP-1 is a negative regulator of several signaling pathways involved in cancers [23,24], and it can be regulated by several transcription factors [25,26].”
BackgroundSHP-1/STAT3 Interaction Is Related to Luteolin-Induced Myocardial Ischemia Protection
Liu, D., Luo, H., & Qiao, C. (2021) · Inflammation · doi:10.1007/s10753-021-01530-y · Cited by 34 · see citing works
“Src homology region 2 domain-containing phosphatase-1 (SHP-1) contains an SH region 2 domain and is the non-transmembrane protein tyrosine phosphatase (PTP) primarily produced in hematopoietic progenitor cells (HPC) [16].”
BackgroundNakase, K., Cheng, J., Zhu, Q. K., & Marasco, W. A. (2008) · Journal of Leukocyte Biology · doi:10.1189/jlb.0608383 · Cited by 33 · see citing works
“1 [8] were shown to activate transcription of the SHP-1 gene in hematopoietic cells.”
BackgroundMulti-stage Friend murine erythroleukemia: molecular insights into oncogenic cooperation
Moreau-Gachelin, F. (2008) · Retrovirology · doi:10.1186/1742-4690-5-99 · Cited by 31 · see citing works
“Another mechanism may involve the phosphatase SHP-1 [105] that is transcriptionally up regulated by Spi-1 [106].”
BackgroundBi, L., Yu, Z., Wu, J., et al. (2015) · The Tohoku Journal of Experimental Medicine · doi:10.1620/tjem.237.163 · Cited by 29 · see citing works
“PU.1, which plays a crucial role in differentiation and function of the lymphoid and myeloid cells, activated SHP1 expression via binding SHP1 p2 promote region in malignancy hematopoetic cells (Wlodarski et al. 2007).”
InfluentialChristophi, G. P., Panos, M., Hudson, C. A., Tsikkou, C., Mihai, C., Mejico, L. J., Jubelt, B., & Massa, P. T. (2009) · Clinical Immunology · doi:10.1016/j.clim.2009.05.019 · Cited by 24 · see citing works
Cheng, J., Kydd, A. R., Nakase, K., et al. (2007) · Blood · doi:10.1182/blood-2006-11-058388 · Cited by 23 · see citing works
RFX-1-dependent activation of SHP-1 inhibits STAT3 signaling in hepatocellular carcinoma cells
Su, J.-C., Chiang, H.-C., Tseng, P., et al. (2014) · Carcinogenesis · doi:10.1093/carcin/bgu210 · Cited by 22 · see citing works
Alzheimer’s Disease Genetics: A Dampened Microglial Response?
Chatila, Z. K., & Bradshaw, E. M. (2021) · The Neuroscientist · doi:10.1177/10738584211024531 · Cited by 20 · see citing works
Consideration of SHP-1 as a Molecular Target for Tumor Therapy
Lim, S., Lee, K. W., Kim, J. Y., & Kim, K. D. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms25010331 · Cited by 18 · see citing works
“Promoter 1 is activated by various transcription factors, including NF κ B, upstream stimulatory factor 1 (USF-1), or NF-Y [11,13]; promoter 2 can be activated by NF κ B p65 and PU.1 in hematopoietic cells (Figure 1A) [14,15].”
BackgroundCao, X., Zhu, N., Zhang, Y., Chen, Y., Zhang, J., Li, J., Hao, P., Gao, C., & Li, L. (2020) · Journal of Cellular Physiology · doi:10.1002/jcp.29474 · Cited by 19 · see citing works
“Src homology region 2 domain‐containing phosphatase 1 (SHP‐1), a nontransmembrane protein tyrosine phosphatase, is expressed primarily in hematopoietic cells (Wlodarski et al., 2007).”
BackgroundPromoter‐specific induction of the phosphatase SHP‐1 by viral infection and cytokines in CNS glia
Christophi, G. P., Hudson, C. A., Gruber, R. C., Christophi, C. P., & Massa, P. T. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2008.05337.x · Cited by 18 · see citing works
Identification of annexin 1 as a PU.1 target gene in leukemia cells
Iseki, Y., Imoto, A., Okazaki, T., Harigae, H., & Takahashi, S. (2009) · Leukemia Research · doi:10.1016/j.leukres.2009.04.010 · Cited by 17 · see citing works
Yang, J., Chen, H., Zheng, X., Li, H., Wu, J., Tang, L., & Gao, S. (2015) · Asian Pacific Journal of Cancer Prevention · doi:10.7314/apjcp.2015.16.6.2219 · Cited by 12 · see citing works
Non-transmembrane PTPs in Cancer
Hendriks, W. J. A. J., & Böhmer, F. (2016) · Springer eBooks · doi:10.1007/978-1-4939-3649-6_3 · Cited by 8 · see citing works
Devi, P., Ota, S., Punga, T., & Bergqvist, A. (2021) · Viruses · doi:10.3390/v13122514 · Cited by 9 · see citing works
Gu, Y., Liu, X., Zhang, X., et al. (2025) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2025.110669 · Cited by 6 · see citing works
Self-citationCorrelation of PU.1 and signal regulatory protein α1 expression in PU.1 transgenic K562 cells
Takahashi, S. (2011) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2011.827 · Cited by 5 · see citing works
SHP-1 alleviates atrial fibrosis in atrial fibrillation by modulating STAT3 activation
Zang, X., Zhao, Z., Chen, K., et al. (2023) · Experimental Biology and Medicine · doi:10.1177/15353702231165717 · Cited by 5 · see citing works
Kamath, M. B. (2009) · OhioLink ETD Center (Ohio Library and Information Network)
Xu, E. (2012) · Corpus Université Laval (Université Laval)
- Authors
- Wlodarski, P., Zhang, Q., Liu, X., Kasprzycka, M., Marzec, M., & Wasik, M. A.
- Affiliations
- Department of Embryology (US)
- University of Pennsylvania (US)
- Medical University of Warsaw (PL)
- Corresponding author
- Wasik, Mariusz A.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2007-03
- Volume
- 282
- Issue
- 9
- Pages
- 6316-6323
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2089766428
- Semantic Scholar
- 28855f6528ecee87fe9593cfdb7424c5d5ecb4fb
- Cited by
- 29
- References
- 32
- Citations by year
- 2025: 1 · 2023: 2 · 2021: 3 · 2020: 1 · 2016: 1 · 2015: 2 · 2014: 2 · 2013: 2 · 2012: 2
- FWCI
- 1.09
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Keywords
- PU.1, SHP-1, protein tyrosine phosphatase, P2 promoter, transcriptional regulation, ETS transcription factors, hematopoietic cells, promoter structure
- MeSH terms
- Proto-Oncogene Protein Spi-1, Blood Cells, Humans, Luciferases, Lymphocytes, Promoter Regions, Genetic, Proto-Oncogene Proteins, Transfection, Transcriptional Activation
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
