Identification of novel direct Stat3 target genes for control of growth and differentiation
Open accessAbstract
Signal transducer and activator of transcription 3 (Stat3) is a key regulator of gene expression in response to signaling of the glycoprotein 130 (gp130) family cytokines, including interleukin 6, oncostatin M, and leukemia inhibitory factor. Many efforts have been made to identify Stat3 target genes and to understand the mechanism of how Stat3 regulates gene expression. Using the microarray technique, hundreds of genes have been documented to be potential Stat3 target genes in different cell types. However, only a small fraction of these genes have been proven to be true direct Stat3 target genes. Here we report the identification of novel direct Stat3 target genes using a genome-wide screening procedure based on the chromatin immunoprecipitation method. These novel Stat3 target genes are involved in a diverse array of biological processes such as oncogenesis, cell growth, and differentiation. We show that Stat3 can act as both a repressor and activator on its direct target genes. We further show that most of the novel Stat3 direct target genes are dependent on Stat3 for their transcriptional regulation. In addition, using a physiological cell system, we demonstrate that Stat3 is required for the transcriptional regulation of two of the newly identified direct Stat3 target genes important for muscle differentiation.
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STAT3-dependent repression of genes has been shown to be critical for muscle cell differentiation.
“Similarly, the STAT3-dependent repression of genes has been shown to be critical for muscle cell differentiation [53].”
From Selective STAT3-α or -β expression reveals spliceform-specific phosphorylation kinetics, nuclear retention and distinct gene expression outcomes (2012) · cites this paper as [53]
STAT3 has been demonstrated to activate or repress its direct target genes in NIH 3T3 cells, with OSM treatment increasing six of 18 direct target genes specifically tested, but decreasing expression of ten of these 18 direct target genes.
“Notably, STAT3 has been demonstrated to activate or repress its direct target genes in NIH 3T3 cells, with OSM treatment increasing six of 18 direct target genes specifically tested, but decreasing expression of ten of these 18 direct target genes [53].”
From Selective STAT3-α or -β expression reveals spliceform-specific phosphorylation kinetics, nuclear retention and distinct gene expression outcomes (2012) · cites this paper as [53]
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Cites
Darnell, J. E., Kerr, L. M., & Stark, G. R. (1994) · Science · doi:10.1126/science.8197455 · Cited by 6,080 · see citing works
Haspel, R. L., Salditt‐Georgieff, M., & Darnell, J. E. (1996) · The EMBO Journal · doi:10.1002/j.1460-2075.1996.tb01016.x · Cited by 312 · see citing works
Validating Stat3 in cancer therapy
Darnell, J. E. (2005) · Nature Medicine · doi:10.1038/nm0605-595 · Cited by 307 · see citing works
YU, Z., ZHANG, W., & KONE, B. C. (2002) · Biochemical Journal · doi:10.1042/bj20020588 · Cited by 255 · see citing works
Flagged first, then by citations
Research works printed but not linked: 5
- Seidel, H. M., Milocco, L. H., Lamb, P., Darnell, J. E., Jr., Stein, R. B., and Rosen, J. (1995) Proc. Natl. Acad. Sci. U. S. A. 92, 3041-3045
- Raz, R., Lee, C. K., Cannizzaro, L. A., d'Eustachio, P., and Levy, D. E. (1999) Proc. Natl. Acad. Sci. U. S. A. 96, 2846 -2851
- Dechow, T. N., Pedranzini, L., Leitch, A., Leslie, K., Gerald, W. L., Linkov, I., and Bromberg, J. F. (2004) Proc. Natl. Acad. Sci. U. S. A. 101, 10602-10607
- Kang, J. S., Feinleib, J. L., Knox, S., Ketteringham, M. A., and Krauss, R. S. (2003) Proc. Natl. Acad. Sci. U. S. A. 100, 3989 -3994
- Snyder, M., He, W., and Zhang, J. J. (2005) Proc. Natl. Acad. Sci. U. S. A. 102, 14539 -14544
Cited by
Sorted by citations
Evo-Devo and an Expanding Evolutionary Synthesis: A Genetic Theory of Morphological Evolution
Carroll, S. B. (2008) · Cell · doi:10.1016/j.cell.2008.06.030 · Cited by 2,067 · see citing works
“, 2007) and the number of signal-regulated STAT3 targets in another cell type (~300; Snyder et al., 2008).”
BackgroundBollrath, J., Phesse, T. J., von Burstin, V. A., Putoczki, T., Bennecke, M., Bateman, T., Nebelsiek, T., Lundgren-May, T., Canli, Ö., Schwitalla, S., et al. (2009) · Cancer Cell · doi:10.1016/j.ccr.2009.01.002 · Cited by 946 · see citing works
“However, it remains to be established whether Stat3 can regulate cyclin B1 in IECs directly, as recently suggested in other cell types (Snyder et al., 2008).”
BackgroundMolecular and Therapeutic Potential and Toxicity of Valproic Acid
Chateauvieux, S., Morceau, F., Dicato, M., & Diederich, M. (2010) · Journal of Biomedicine and Biotechnology · doi:10.1155/2010/479364 · Cited by 526 · see citing works
“This inhibition led to a decrease in the dimerisation of STAT3 and its translocation into the nucleus for transcriptional activation of many genes in a wide range of biological processes, including induction of immune response, oncogenesis, cell cycle control, development, cell adhesion, and differentiation [63].”
BackgroundROCK and JAK1 Signaling Cooperate to Control Actomyosin Contractility in Tumor Cells and Stroma
Sanz-Moreno, V., Gaggioli, C., Yeo, M., Albrengues, J., Wallberg, F., Viros, A., Hooper, S., Mitter, R., Féral, C. C., Cook, M., et al. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.06.018 · Cited by 409 · see citing works
The myocardial JAK/STAT pathway: from protection to failure.
Boengler, K., Hilfiker-Kleiner, D., Drexler, H., Heusch, G., & Schulz, R. (2008) · Pharmacology and Therapeutics · doi:10.1016/j.pharmthera.2008.08.002 · Cited by 379 · see citing works
Bonetto, A., Aydogdu, T., Kunzevitzky, N., Guttridge, D. C., Khuri, S., Koniaris, L. G., & Zimmers, T. A. (2011) · PLoS ONE · doi:10.1371/journal.pone.0022538 · Cited by 348 · see citing works
“Examination of the literature resulted in identification of 186 validated STAT3 target genes identified in several different species and systems (Table S6) [41,42,43,44,45,46].”
BackgroundSTAT3 in the Systemic Inflammation of Cancer Cachexia
Zimmers, T., Fishel, M., & Bonetto, A. (2016) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2016.02.009 · Cited by 216 · see citing works
Regulation of embryonic stem cell self-renewal and pluripotency by leukaemia inhibitory factor
Hirai, H., Karian, P., & Kikyo, N. (2011) · Biochemical Journal · doi:10.1042/bj20102152 · Cited by 196 · see citing works
IL-22 promotes fibroblast-mediated wound repair in the skin
McGee, H. M., Schmidt, B. A., Booth, C. J., Yancopoulos, G. D., Valenzuela, D. M., Murphy, A. J., Stevens, S., Flavell, R. A., & Horsley, V. (2013) · Journal of Investigative Dermatology · doi:10.1038/jid.2012.463 · Cited by 161 · see citing works
Molecular basis of embryonic stem cell self-renewal: from signaling pathways to pluripotency network
Huang, G., Ye, S.-D., Zhou, X., Liu, D.-H., & Ying, Q. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-1833-2 · Cited by 153 · see citing works
JAK2/STAT2/STAT3 Are Required for Myogenic Differentiation*
Wang, K.-P., Wang, C., Xiao, F., Wang, H.-X., & Wu, Z.-G. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m803012200 · Cited by 153 · see citing works
O'Donoghue, R. J. J., Knight, D. A., Richards, C. D., Prêle, C. M., Lau, H. L., Jarnicki, A. G., Jones, J., Bozinovski, S., Vlahos, R., Thiem, S., et al. (2012) · EMBO Molecular Medicine · doi:10.1002/emmm.201100604 · Cited by 152 · see citing works
“…of our findings in the gp130 757F mouse model to human IPF, we first confirmed that excessive Stat3 activation in fibrotic lungs of bleomycin challenged gp130 757F mice was dependent on IL-6 by monitoring expression of the bona fide Stat3 target gene Socs3 (Kidder et al, 2008; Snyder et al, 2008).”
McKay, B. R., De Lisio, M., Johnston, A. P. W., O'Reilly, C. E., Phillips, S. M., Tarnopolsky, M. A., & Parise, G. (2009) · PLoS ONE · doi:10.1371/journal.pone.0006027 · Cited by 149 · see citing works
“The reduction of nuclear p-STAT3 may be necessary for the induction of differentiation [57] and the timing of withdrawal of SC pSTAT3 observed in the present study (i.”
BackgroundNiederreiter, L., Fritz, T., Adolph, T. E., Krismer, A., Offner, F., Tschurtschenthaler, M., Flak, M. B., Hosomi, S., Tomczak, M. F., Kaneider, N., et al. (2013) · Journal of Experimental Medicine · doi:10.1084/jem.20122341 · Cited by 139 · see citing works
“3 A), which might reflect the known capacity of Stat3 to bind its own promoter and to transactivate its transcription (Narimatsu et al., 2001; Lam et al., 2008; Snyder et al., 2008).”
BackgroundEpstein-Barr Virus LMP1 Activates EGFR, STAT3, and ERK through Effects on PKCδ
Kung, C.-P., Meckes, D., & Raab-Traub, N. (2011) · Journal of Virology · doi:10.1128/jvi.01703-10 · Cited by 136 · see citing works
“of LMP1) and pBabe-HA-LMP1-CTAR1 (1-220) (which contains aa 1 to 220 of”
BackgroundOxidative Stress and Inflammation Caused by Cisplatin Ototoxicity
Ramkumar, V., Mukherjea, D., Dhukhwa, A., & Rybak, L. (2021) · Antioxidants · doi:10.3390/antiox10121919 · Cited by 124 · see citing works
“Additional targets of STAT3 that promote survival are: the anti-apoptotic molecules Bcl-xL and Bcl-2 [79].”
BackgroundHaghikia, A., Stapel, B., Hoch, M., & Hilfiker-Kleiner, D. (2010) · Heart Failure Reviews · doi:10.1007/s10741-010-9170-x · Cited by 117 · see citing works
IL-6 regulates induction of C-reactive protein gene expression by activating STAT3 isoforms
Ngwa, D. N., Pathak, A., & Agrawal, A. (2022) · Molecular Immunology · doi:10.1016/j.molimm.2022.04.003 · Cited by 114 · see citing works
Combined inhibition of STAT3 and DNA repair in palbociclib-resistant ER-positive breast cancer
Kettner, N., Vijayaraghavan, S., Durak, M., Bui, T., Kohansal, M., Min, J.-Y., Liu, B., Rao, X.-Y., Wang, J., Yi, M., et al. (2019) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-18-3274 · Cited by 103 · see citing works
“the importance of IL6 signaling in driving STAT3 activation, ER has also been identified as a target gene of STAT3 by microarray and ChIP analyses (59), suggesting STAT3 may also regulate ER transcription.”
BackgroundAlrasheed, N., Alrasheed, N., Hasan, I. H., Al-Amin, M., Al-Ajmi, H., & Mahmoud, A. (2016) · Drug Design, Development and Therapy · doi:10.2147/dddt.s109287 · Cited by 101 · see citing works
“In the heart, STATs regulate the expression of gene encoding proteins involved in angiogenesis, extracellular matrix composition, inflammation, apoptosis, and cellular signaling.(13,14) IL-6 and its family-related proteins transduce their signals via glycoprotein 130 (gp130) mostly to STAT3 and play a key role in the…”
BackgroundSmall-molecule inhibition of STAT3 in radioresistant head and neck squamous cell carcinoma
Bharadwaj, U., Eckols, T. K., Xu, X.-J., Kasembeli, M., Chen, Y.-Y., Adachi, M., Song, Y.-C., Mo, Q., Lai, S., & Tweardy, D. (2016) · OncoTarget · doi:10.18632/oncotarget.8368 · Cited by 100 · see citing works
Snyder, M., Huang, X., & Zhang, J. J. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.286245 · Cited by 99 · see citing works
Self-citationInhibition of STAT3 expression and signaling in resveratrol-differentiated medulloblastoma cells.
Yu, L.-J., Wu, M.-L., Li, H., Chen, X.-Y., Wang, Q., Sun, Y., Kong, Q.-Y., & Liu, J. (2008) · Neoplasia · doi:10.1593/neo.08304 · Cited by 91
“Leukemia inhibitory factor belongs to the member of IL-6 family, which acts as a key upstream stimulator of the JAK/STATs signaling [49].”
BackgroundSTAT3: A Novel Molecular Mediator of Resistance to Chemoradiotherapy
Spitzner, M., Ebner, R., Wolff, H. A., Ghadimi, Β. M., Wienands, J., & Grade, M. (2014) · Cancers · doi:10.3390/cancers6041986 · Cited by 91 · see citing works
“STAT3 suppresses apoptosis genes and induces expression of proliferation genes, as well as stemness-promoting or -preserving gene targets and, also, some known oncogenes [20,118–121].”
BackgroundSteyn, P., Dzobo, K., Smith, R. I., & Myburgh, K. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20215273 · Cited by 89 · see citing works
“Other contrasting data having been published with some studies showing that SOCS3 is involved in cell differentiation as we show in this study [101] and others showing that SOCS3 is actually involved cell proliferation [97,100,102].”
ResultJak/Stat3 Signaling Promotes Somatic Cell Reprogramming by Epigenetic Regulation
Tang, Y., Luo, Y., Jiang, Z., Ma, Y., Lin, C., Kim, C. G., Carter, M. G., Amano, T., Park, J., Kish, S. L., et al. (2012) · Stem Cells · doi:10.1002/stem.1225 · Cited by 82 · see citing works
STAT3 in Skeletal Muscle Function and Disorders
Guadagnin, E., Mázala, D., & Chen, Y.-W. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19082265 · Cited by 85 · see citing works
“This table was generated by integrating data from seven genome-wide studies of direct target genes of STAT3 by microarray, ChIP or ChIP-Seq [44, [50] [51] [52] [53] [54] [55] .”
MethodVallania, F., Schiavone, D., Dewilde, S., Pupo, E., Garbay, S., Calogero, R., Pontoglio, M., Provero, P., & Poli, V. (2009) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.0900473106 · Cited by 82 · see citing works
“To assess the validity of our method compared with the more direct ChIP and sequencing approach, we compared the evolutionary conserved BSs identified above with 2 recently reported experimental datasets obtained by measuring Stat3 occupancy in vivo in ES cells and 3T3 fibroblasts, respectively (13, 14).”
MethodPhesse, T. J., Büchert, M., Stuart, E. C., Flanagan, D. J., Faux, M. C., Afshar‐Sterle, S., Walker, F., Zhang, H., Nowell, C. J., Jorissen, R. N., et al. (2014) · Science Signaling · doi:10.1126/scisignal.2005411 · Cited by 76 · see citing works
“Stat3 signaling pathways (30, 31) in human CRC samples when compared to matched normal colons (fig.”
BackgroundDorritie, K., McCubrey, J. A., & Johnson, D. E. (2014) · Leukemia · doi:10.1038/leu.2013.192 · Cited by 72 · see citing works
Bui, Q. T., Im, J., Jeong, S. B., Kim, Y.-M., Lim, S.-C., Kim, B., & Kang, K. (2017) · Cancer Letters · doi:10.1016/j.canlet.2017.01.014 · Cited by 71
Protein and glycomic plasma markers for early detection of adenoma and colon cancer
Rho, J.-H., Ladd, J. J., Li, C. I., Potter, J. D., Zhang, Y., Shelley, D., Shibata, D., Coppola, D., Yamada, H., Toyoda, H., et al. (2016) · Gut · doi:10.1136/gutjnl-2016-312794 · Cited by 77 · see citing works
Ng, I. H. W., Ng, D. C. H., Jans, D. A., & Bogoyevitch, M. A. (2012) · Biochemical Journal · doi:10.1042/bj20120941 · Cited by 63 · see citing works
Roles of STATs signaling in cardiovascular diseases
Kishore, R., & Verma, S. (2012) · JAK-STAT · doi:10.4161/jkst.20115 · Cited by 62 · see citing works
“In the heart, STAT proteins regulate the expression of genes encoding proteins mainly involved in inflammation, cellular signaling, apoptosis, angiogenesis and extracellular matrix composition.(17,18) The phosphorylation of an additional specific serine residue in the transactivation domain of STAT proteins (Ser727 fo…”
BackgroundImpact of the N-Terminal Domain of STAT3 in STAT3-Dependent Transcriptional Activity
Hu, T., Yeh, J. E., Pinello, L., Jacob, J., Chakravarthy, S., Yuan, G.-C., Chopra, R., & Frank, D. (2015) · Molecular and Cellular Biology · doi:10.1128/mcb.00060-15 · Cited by 60 · see citing works
Mirzaei, S., Gholami, M., Mahabady, M. K., Nabavi, N., Zabolian, A., Banihashemi, S. M., Haddadi, A., Entezari, M., Hushmandi, K., Makvandi, P., et al. (2021) · Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · doi:10.1016/j.biopha.2020.111077 · Cited by 59 · see citing works
RetractedSnyder, M., Huang, X.-Y., & Zhang, J. J. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.101063 · Cited by 59 · see citing works
Self-citationSchiavone, D., Dewilde, S., Vallania, F., Turkson, J., Cunto, F. D., & Poli, V. (2009) · Biochemical Journal · doi:10.1042/bj20090061 · Cited by 58 · see citing works
Alrasheed, N., Al-Oteibi, M. M., Al-Manee, R. Z., Al-shareef, S. A., Alrasheed, N., Hasan, I. H., Mohamad, R., & Mahmoud, A. (2015) · Drug Design, Development and Therapy · doi:10.2147/dddt.s86431 · Cited by 57 · see citing works
Snyder, M., Huang, J., Huang, X.-Y., & Zhang, J. J. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.591719 · Cited by 57 · see citing works
“Quantitative Real-time Reverse Transcription (RT)-PCR— RT-PCR analyses were performed as described previously (18, 32, 33).”
MethodSelf-citationKurosaka, M., & Machida, S. (2013) · Cell Proliferation · doi:10.1111/cpr.12045 · Cited by 53 · see citing works
Kahweol blocks STAT3 phosphorylation and induces apoptosis in human lung adenocarcinoma A549 cells.
Kim, H. G., Hwang, Y., & Jeong, H. (2009) · Toxicology Letters · doi:10.1016/j.toxlet.2009.01.022 · Cited by 51 · see citing works
Harwardt, T., Lukas, S., Zenger, M., Reitberger, T., Danzer, D., Übner, T., Munday, D. C., Nevels, M., & Paulus, C. (2016) · PLoS Pathogens · doi:10.1371/journal.ppat.1005748 · Cited by 44 · see citing works
Stirm, K., Leary, P. J., Bertram, K., Núñez, N., Wüst, D., Boudesco, C., Verhoeyen, E., Zenz, T., Becher, B., Menter, T., et al. (2021) · Oncoimmunology · doi:10.1080/2162402x.2021.2003533 · Cited by 43 · see citing works
Yogev, O., Almeida, G. S., Barker, K., George, S. L., Kwok, C., Campbell, J. J., Zarowiecki, M., Kleftogiannis, D., Smith, L. M., Hallsworth, A., et al. (2019) · Cancer Research · doi:10.1158/0008-5472.can-18-2759 · Cited by 43
JAK-STAT3 and somatic cell reprogramming
Tang, Y., & Tian, X. (2013) · JAK-STAT · doi:10.4161/jkst.24935 · Cited by 42 · see citing works
Identification of abrogated pathways in fallopian tube epithelium from BRCA1 mutation carriers
George, S., Greenaway, J., Milea, A., Clary, V., Shaw, S., Sharma, M., Virtanen, C., & Shaw, P. (2011) · Journal of Pathology · doi:10.1002/path.2927 · Cited by 42 · see citing works
“many cellular processes, including cell growth, apoptosis, transformation, differentiation, migration and cell survival [28].”
BackgroundRen, H.-X., Li, L.-J., Su, H.-W., Xu, L.-Y., Wei, C.-H., Zhang, L., Li, H.-B., Liu, W., & Du, L. (2011) · BMC Genomics · doi:10.1186/1471-2164-12-411 · Cited by 42 · see citing works
“DE genes involved in muscle and adipose development STAT3, a member of the STAT family and a cooperator in the Janus kinase pathway, plays a dual role in the regulation of myoblast proliferation and differentiation, but is dependent on interactions with various cofactors [58-62].”
BackgroundMartorelli, D., Muraro, E., Mastorci, K., Col, J. D., Faè, D. A., Furlan, C., Giagulli, C., Caccuri, F., Rusnati, M., Fiorentini, S., et al. (2015) · International Journal of Cancer · doi:10.1002/ijc.29494 · Cited by 41 · see citing works
“The increased levels of cyclin D2 and D3 mRNA observed in p17- and S75X-treated EBV(1) Blymphocytes may be related to p17 proteins-induced activation of STAT3, which regulates cyclin D transcription in B-cells directly or through the up-regulation of c-myc.(34,35) On the other hand, S75X-induced Akt activation may con…”
BackgroundSugase, T., Takahashi, T., Serada, S., Fujimoto, M., Hiramatsu, K., Ohkawara, T., Tanaka, K., Miyazaki, Y., Makino, T., Kurokawa, Y., et al. (2017) · Cancer Research · doi:10.1158/0008-5472.can-17-1525 · Cited by 47 · see citing works
“and induces the expression of proliferative genes (30), in addition to stemness-promoting or stemness-preserving genes (31).”
FK506 causes cellular and functional defects in human natural killer cells
Kim, T.-J., Kim, N., Kang, H., Kim, E.-O., Kim, S. T., Ahn, H., Bluestone, J. A., & Lee, K.-M. (2010) · Journal of Leukocyte Biology · doi:10.1189/jlb.0310148 · Cited by 34
“Upon IL-2 stimulation, STAT3 becomes activated, phosphorylated by a Janus kinase 1 (JAK1), and then translocated to the nucleus to induce transcription of multiple genes, including Cyclin D1, TNFR, and FasL [21, 22].”
BackgroundSnyder, M., Huang, X.-Y., & Zhang, J. J. (2010) · FEBS Letters · doi:10.1016/j.febslet.2010.11.030 · Cited by 33
“RNAi was performed as described previously [8,11].”
BackgroundMethodInfluentialSelf-citationPrediction and Experimental Validation of Novel STAT3 Target Genes in Human Cancer Cells
Oh, Y., Kim, J. K., Choi, Y., Choi, S.-J., & Yoo, J.-Y. (2009) · PLoS ONE · doi:10.1371/journal.pone.0006911 · Cited by 31 · see citing works
“05E-12 + [76]”
Abyaneh, H. S., Gupta, N., Alshareef, A., Gopal, K., Lavasanifar, A., & Lai, R. (2018) · Cancer Microenvironment · doi:10.1007/s12307-018-0218-0 · Cited by 29 · see citing works
Impaired JAK2-induced activation of STAT3 in failing human myocytes.
Cambi, G., Lucchese, G., Djeokeng, M. M. H., Modesti, A., Fiaschi, T., Faggian, G., Sani, G., & Modesti, P. (2012) · Molecular Biosystems · doi:10.1039/c2mb25120e · Cited by 27 · see citing works
Linton, K., Howarth, C., Wappett, M., Newton, G., Lachel, C. M., Iqbal, J., Pepper, S., Byers, R., Chan, W., & Radford, J. (2012) · Journal of Molecular Diagnostics · doi:10.1016/j.jmoldx.2012.01.008 · Cited by 26
Constitutive STAT3 serine phosphorylation promotes Helicobacter-mediated gastric disease.
Balic, J., Saad, M., Dawson, R. E., West, A. J., McLeod, L., West, A., D'Costa, K., Deswaerte, V., Dev, A., Sievert, W., et al. (2020) · American Journal of Pathology · doi:10.1016/j.ajpath.2020.01.021 · Cited by 25 · see citing works
RETRACTED: Death-Associated Protein Kinase Controls STAT3 Activity in Intestinal Epithelial Cells
Chakilam, S., Gandesiri, M., Rau, T. T., Agaimy, A., Mahadevan, V., Ivanovska, J., Wirtz, R. M., Schulze‐Luehrmann, J., Benderska, N., Wittkopf, N., et al. (2013) · American Journal Of Pathology · doi:10.1016/j.ajpath.2012.11.026 · Cited by 24 · see citing works
“Previous studies have shown that STAT3 could either promote or suppress the expression of its target genes.(40,48) To further evaluate STAT3 transcriptional regulation of DAPK expression, HCEC cells were stimulated with TNF in the presence or absence of AG490 (Janus kinase inhibitor) or Stattic (inhibits STAT3 phospho…”
RetractedHan, X., Qi, J., Yang, Y.-K., Zheng, B., Liu, M.-M., Liu, Y., Li, L., Guan, S.-J., Jia, Q.-Z., & Chu, L. (2022) · Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · doi:10.1016/j.biopha.2022.113082 · Cited by 23 · see citing works
Ivanov, V., Ghandhi, S., Zhou, H.-N., Huang, S. X., Chai, Y., Amundson, S., & Hei, T. (2011) · Experimental Cell Research · doi:10.1016/j.yexcr.2011.03.012 · Cited by 23 · see citing works
“general cell survival andproliferation [33,34].”
Li, P., Li, Q., Biswas, N., Xin, H., Diemer, T., Liu, L., Pérez-Gutiérrez, L., Paternostro, G., Piermarocchi, C., Domanskyi, S., et al. (2021) · EMBO Molecular Medicine · doi:10.15252/emmm.202114511 · Cited by 21 · see citing works
“It has been reported that cyclin A1 and cyclin B1 are direct STAT3 targets (Snyder et al , 2008).”
Jung, K. B., Kwon, O., Lee, M.-O., Lee, H., Son, Y. S., Habib, O., Oh, J.-H., Cho, H.-S., Jung, C.-R., Kim, J., et al. (2019) · Journal of Clinical Medicine · doi:10.3390/jcm8070976 · Cited by 20 · see citing works
Chang, Y.-J., Chen, K.-W., Chen, C.-J., Lin, M.-H., Sun, Y.-J., Lee, J.-L., Chiu, I.-M., & Chen, L.-Y. (2014) · Molecular and Cellular Biology · doi:10.1128/mcb.00940-13 · Cited by 20 · see citing works
“Cdh2 is a direct target of STAT3 in response to oncostatin M (43), and expression of N-cadherin is required for neuronal differentiation (44, 45).”
BackgroundInfluentialTeratogenicity of valproic acid and its constitutional isomer, amide derivative valnoctamide in mice
Lin, Y., Bialer, M., Cabrera, R. M., Finnell, R., & Wlodarczyk, B. (2018) · Birth Defects Research · doi:10.1002/bdr2.1406 · Cited by 19
Yang, Y., Hu, W., Di, S., Ma, Z.-Q., Fan, C., Wang, D., Jiang, S., Li, Y., Zhou, Q., Li, T., et al. (2017) · Expert opinion on therapeutic targets · doi:10.1080/14728222.2017.1275566 · Cited by 19 · see citing works
“The specific regulatory mechanisms of STAT3 have been investigated in previous studies [39,40].”
BackgroundNecdin, a negative growth regulator, is a novel STAT3 target gene down-regulated in human cancer
Haviland, R., Eschrich, S., Bloom, G., Ma, Y., Minton, S., Jove, R., & Cress, W. D. (2011) · PLoS ONE · doi:10.1371/journal.pone.0024923 · Cited by 19 · see citing works
“. These STAT3 target genes have generally been identified on an individual basis, while few studies have attempted to identify large numbers of STAT3 regulated genes”
BackgroundMalemud, C. (2010) · International Journal of Interferon Cytokine and Mediator Research · doi:10.2147/ijicmr.s9470 · Cited by 19 · see citing works
Lin, M.-H., Chang, K.-W., Lin, S.-C., & Miner, J. (2010) · Developmental Biology · doi:10.1016/j.ydbio.2010.05.503 · Cited by 19 · see citing works
“Along with ectopic activation of STAT3 in suprabasal keratinocytes, Fatp4 mutant skin exhibited upregulation of Icam1, Myc, Socs3, Adam8 (Table 1), and Bcl3 (data not shown), five direct targets of STAT3 (Caldenhoven et al., 1995; Kiuchi et al., 1999; Snyder et al., 2008).”
BackgroundPérez-Baos, S., Gratal, P., Barrasa, J. I., Lamuedra, A., Sánchez-Pernaute, O., Herrero-Beaumont, G., & Largo, R. (2019) · Journal of Inflammation · doi:10.1186/s12950-019-0206-2 · Cited by 17 · see citing works
Rac1 promotes chondrogenesis by regulating STAT3 signaling pathway
Kim, H., & Sonn, J. (2016) · Cell Biology International · doi:10.1002/cbin.10635 · Cited by 17 · see citing works
“STAT3 plays essential roles in a diverse array of cellular processes including the cell cycle, development, and differentiation by interaction with its target genes including BMP4 (Snyder et al., 2008).”
BackgroundGrillo, M., Palmer, C., Holmes, N., Sang, F., Larner, A., Bhosale, R., & Shaw, P. (2020) · PLoS ONE · doi:10.1371/journal.pone.0244255 · Cited by 16 · see citing works
STAT3 enhances the constitutive activity of AGC kinases in melanoma by transactivating PDK1
Picco, M. E., Castro, M. V., Quezada, M. J., Barbero, G., Villanueva, M. B., Fernández, N. B., Kim, H., & Lopez-Bergami, P. (2019) · Cell & Bioscience · doi:10.1186/s13578-018-0265-8 · Cited by 16 · see citing works
Tyrosine 705 Phosphorylation of STAT3 Is Associated with Phenotype Severity in TGFβ1 Transgenic Mice
Guadagnin, E., Narola, J., Bonnemann, C., & Chen, Y.-W. (2015) · BioMed Research International · doi:10.1155/2015/843743 · Cited by 16 · see citing works
“It is expressed in a large number of tissues and its activation drives the transcription of genes encoding proteins involved in angiogenesis, inflammation, apoptosis, extracellular matrix deposition, and cellular signaling [32].”
BackgroundSuppression of Pro-Inflammatory Cytokines via Targeting of STAT-Responsive Genes
Malemud, C. (2013) · InTech eBooks · doi:10.5772/52506 · Cited by 16 · see citing works
“Electrophoretic mobility shift analysis of the nuclear extracts from synoviocytes from the STAT1 decoy ODN-treated animals incubated with the STAT-1 decoy ODN inhibited STAT-1 binding to DNA.”
BackgroundInfluentialNeuronal Agrin Promotes Proliferation of Primary Human Myoblasts in an Age-Dependent Manner
Gros, K., Matkovič, U., Parato, G., Miš, K., Luin, E., Bernareggi, A., Sciancalepore, M., Mars, T., Lorenzon, P., & Pirkmajer, S. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231911784 · Cited by 15 · see citing works
“Interestingly, AgFL did not alter the phosphorylation of STAT3 (at Tyr705) (Figure 2D), a transcription factor that plays an important role in myoblast proliferation [71,72] and differentiation [73,74], neither the phosphorylation of focal adhesion kinase (FAK; at Tyr397) (Figure 2E), which participates in the Lrp4-Mu…”
BackgroundModeling the Intra- and Extracellular Cytokine Signaling Pathway under Heat Stroke in the Liver
Rodriguez-Fernandez, M., Grosman, B., Yuraszeck, T., Helwig, B., Leon, L., & Doyle, F. (2013) · PLoS ONE · doi:10.1371/journal.pone.0073393 · Cited by 15 · see citing works
“specific DNA sequences in the promoter regions of target genes [80].”
BackgroundZimmerman, S. M., Nixon, S., Chen, P.-Y., Raj, L., Smith, S. R., Paolini, R., Lin, P. N., & Souroullas, G. (2022) · Oncogene · doi:10.1038/s41388-022-02492-7 · Cited by 14 · see citing works
“In addition to being a transcriptional activator, Stat3 can also repress its target genes [21, 22]; however, the mechanism of how Stat3 represses gene expression is not clear.”
BackgroundEfficacy of niclosamide on the intra-abdominal inflammatory environment in endometriosis
Shi, M.-X., Sekulovski, N., Whorton, A. E., MacLean, J., Greaves, E., & Hayashi, K. (2021) · The FASEB Journal · doi:10.1096/fj.202002541rrr · Cited by 13 · see citing works
Ignatovich, I. V., & Hobbs, J. A. (2013) · Virology · doi:10.1016/j.virol.2013.06.022 · Cited by 11
Muscular Dystrophy: Disease Mechanisms and Therapies
Pandey, S., Kesari, A., Yokota, T., & Pandey, G. (2015) · BioMed Research International · doi:10.1155/2015/456348 · Cited by 10
Park, C., Choi, S. H., Lee, S.-Y., Eun, K., Park, M., Jang, J., Jeong, H. J., Kim, S.-J., Jeong, S., Lee, K., et al. (2022) · Cells · doi:10.3390/cells11132031 · Cited by 9
“TCGA data were obtained from the Firebrowse data portal (http: //firebrowse.org, accessed on 20 June 2022).”
MethodInfluentialKaipa, J. M., Starkuviene, V., Erfle, H., Eils, R., & Gladilin, E. (2020) · PeerJ · doi:10.7717/peerj.10373 · Cited by 9 · see citing works
Fan, C., Chen, H., Liu, K., & Wang, Z.-H. (2021) · Experimental Physiology · doi:10.1113/ep089450 · Cited by 8 · see citing works
“In addition, the regulation of STAT3 suggests an epigenetic mechanism of FGL2 since Snyder et al. (2008 ) performed gene-specific chromatin immunoprecipitation (ChIP) and found an increase in the amount of STAT3 bound to Fgl2 promoter in response to oncostatinM treatment.”
BackgroundTranscriptional regulation of the hypocretin/orexin gene.
Tanaka, S. (2012) · Vitamins and hormones · doi:10.1016/b978-0-12-394623-2.00005-6 · Cited by 8 · see citing works
Tang, Y., Zhong, M., Pan, G., Tan, J.-S., Xie, C., Jiang, Y., Yao, J.-W., Shan, W., Lin, J.-Q., Huang, J.-W., et al. (2022) · Pharmaceuticals · doi:10.3390/ph16010015 · Cited by 7 · see citing works
“Numerous significant genes, including those involved in angiogenesis, cell migration, and cell survival, are regulated by STAT3 [18,19].”
BackgroundProteasome gene expression is controlled by coordinated functions of multiple transcription factors
Gilda, J. E., Nahar, A., Kasiviswanathan, D., Tropp, N., Gilinski, T., Lahav, T., Alexandrovich, D., Mandel-Gutfreund, Y., Park, S., & Shemer, S. (2024) · Journal of Cell Biology · doi:10.1083/jcb.202402046 · Cited by 6 · see citing works
“STAT3, which is activated after denervation (Madaro et al., 2018), may play a role in PAX4 induction, as suggested by previous microarray and ChIP studies in cultured NIH3T3 cells, identifying PAX4 as STAT3 target gene (Snyder et al., 2008).”
Osuala, K. O., Chalasani, A., Aggarwal, N., Ji, K., & Moin, K. (2024) · Cancers · doi:10.3390/cancers16162910 · Cited by 4 · see citing works
“DCIS cells. transcriptional expression of various cytokines and growth factors including GM-CSF [53,54].”
BackgroundGoto, H., Ohtsu, T., Ito, M., Sagisaka, M., Naruto, T., Nagai, J., Kitagawa, N., Tanaka, M., Yanagimachi, M., Hiroshima, Y., et al. (2023) · Human Cell · doi:10.1007/s13577-023-00982-8 · Cited by 3 · see citing works
“…pathogenic mutations; however, these variants were not likely to be targetable by drugs used in the DST. Values of TPM in 44 STAT3 -targeted genes [14] on the RNA-seq panel used in this study were not significantly different in KCS8 compared to KCS9, in which the STAT3 mutation was not detected (…”
MethodTargeting the transcriptional activity of STAT3 by a novel fusion protein
Chen, Y.-Q., Zhang, W.-T., Bai, X., & Liu, Y. (2022) · BMC Cancer · doi:10.1186/s12885-022-09837-1 · Cited by 3 · see citing works
“D, Survival of nude mice after the injection of A375 cells via the caudal vein over-activated STAT3 signaling in cancer cells induces target gene expression; these genes include cyclinD1 (promotes cell growth) and the BCL2 family member MCL-1 (reduces apoptosis).”
BackgroundThe Role of STAT3 in Cancer: From Metabolic Regulation to Therapeutic Targeting
Ashourpour, M., Mohammadian, J., Mehdizadeh, A., Nour, M. A., & Ghorbanihaghjo, A. (2025) · Biofactors · doi:10.1002/biof.70045 · Cited by 2 · see citing works
“Among these, STAT3 plays a role in various biological processes, including early embryogenesis, postnatal survival, wound healing, and lymphocyte proliferation [7, 8].”
Review of Ototoxic Drugs and Treatment Strategies for Reducing Hearing Loss
Mamillapalli, C., Dhukhwa, A., Sheth, S., Mukherjea, D., Rybak, L., & Ramkumar, V. (2020) · Springer eBooks · doi:10.1007/978-3-030-40413-0_3 · Cited by 1 · see citing works
Inhibition of STAT3 decreases OSM induced EDA-FN expression in human lung fibroblasts
Tse, J. (2011) · cIRcle (University of British Columbia) · doi:10.14288/1.0071755 · Cited by 1 · see citing works
“…STAT3 binding sites in the promoter of genes that include c-fos (involved in cell proliferation and differentiation to defense against invasion and cell damage), fgl2 (involved in fibrin deposition in blood coagulation) and SMAD9 (a downstream signalling molecule of TGF) 17 (Snyder et al. 2007).”
BackgroundAranda-Chan, V., Ortega-López, G. I., López-Díaz, P. E., Hernández-Nava, A. M., Gutiérrez-Soto, M., Trigueros, J. L. R., Orozco, R. P., Carrillo, A. Z., & Benítez-Cardoza, C. G. (2026) · Hearing Research · doi:10.1016/j.heares.2026.109811
Antimetastatic activity of seongsanamide B in γ-irradiated human lung cancer
Ryoo, G.-H., Kim, G., Han, A.-R., Jin, C., Lee, H., Nam, J.-W., Choi, H., & Jung, C.-H. (2023) · Heliyon · doi:10.1016/j.heliyon.2023.e20179
Zimmerman, S. M., Nixon, S., Chen, P.-Y., Raj, L., Smith, S. R., Paolini, R., Lin, P. N., & Souroullas, G. (2021) · bioRxiv · doi:10.1101/2021.06.01.446580
“In addition to being a transcriptional activator, Stat3 can also repress its target genes (24,25); however, the mechanism of how Stat3 represses gene expression is not clear.”
BackgroundInfluentialEpstein Barr virus EBNA2 : interactions of intrinsically disordered proteins with host cell factors.
Geenen, E. (2013) · doi:10.70675/100f530ezfbe0z45dfzbc07za98f56e10d5a
“Based upon our preliminary data, we would expect that EBNA2 point mutants would affect the expression of a number of STAT3-dependent host genes that could then be compared to those identified via chromatin precipitation studies (Snyder et al., 2008; Vallania et al., 2009).”
- Authors
- Snyder, M., Huang, X.-Y., & Zhang, J. J.
- Affiliations
- Cornell University (US)
- Corresponding author
- Zhang, J. Jillian
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2008-02
- Volume
- 283
- Issue
- 7
- Pages
- 3791-3798
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2009177754
- Cited by
- 108
- References
- 43
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 3 · 2023: 4 · 2022: 9 · 2021: 6 · 2020: 5 · 2019: 7 · 2018: 3 · 2017: 2 · 2016: 7 · 2015: 6 · 2014: 4 · 2013: 8 · 2012: 10
- FWCI
- 3.54
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- National Institutes of Health
- National Institute on Aging (AG023202, R01AG023202)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Keywords
- STAT3, direct target genes, transcriptional regulation, interleukin-6, oncostatin M, leukemia inhibitory factor, myogenesis, cell growth, carcinogenesis, transcriptional repression, transcriptional activation, chromatin immunoprecipitation
- MeSH terms
- Animals, Base Sequence, Cell Differentiation, Cell Division, Transcription, Genetic, 3T3 Cells, DNA Primers, Reverse Transcriptase Polymerase Chain Reaction, RNA, Small Interfering, Chromatin Immunoprecipitation, STAT3 Transcription Factor, Mice
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