||Pin1-mediated Sp1 Highly Phosphorylation by CDK1 Inhibits Sp1 DNA-binding Activity during Mitosis
||Insitute of Bioinformatics and Biosignal Transduction
Our previous study found that Sp1 phosphorylation at Threonine739 decreased DNA-binding activity of Sp1 during mitosis. Here, we demonstrated that Sp1 Thr739 phosphorylation alone is necessary, but not sufficient for the decrease of DNA-binding activity in mitosis stage. Further study showed that Pin1 could be recruited to phospho-Thr739-Pro740 motif of Sp1 and then regulate the interaction between phospho-Thr739-Sp1 and CDK1 during mitosis, thereby Sp1 could be further highly phosphorylated by CDK1 at Ser720, Thr723, and Thr737. The Pin1-mediated Sp1 highly phosphorylation by CDK1 can decrease DNA-binding affinity of Sp1. Loss of C-terminus (amino acid 741-785) significantly increased the phosphorylation by CDK1 without Pin1, suggesting that C-terminus of Sp1 inhibits highly phosphorylation by CDK1. The structure study by X-ray crystallography indicated that Pin1 increased the cis signal and showed that the phospho-Thr739-Sp1 peptide located in the active site of Pin1, suggesting that Pin1 alters the conformation of C-terminal Sp1. During mitosis, Sp1 highly phosphorylation by CDK1 not only stabilized protein level of Sp1 by reducing the interaction between Sp1 and its ubiquitin E3-ligase RNF4 but also made Sp1 completely leave the chromosomes by decreasing the DNA-binding activity of Sp1. This regulation of Sp1 by CDK1 phosphorylation can facilitate the cell cycle progression. Thus, Pin1-mediated conformational alteration of C-terminal Sp1 is critical for the Sp1 highly phosphorylation by CDK1 in mitosis, leading cell cycle progression. In addition to the cell cycle regulation in cancer cells, highly phosphorylation can preserve Sp1 during cell cycle and then Sp1 can rapidly start to regulate gene transcription in cancer cells after cell division. So we investigated the genes Sp1 regulated in cancer cells to clarify the function of preserved Sp1 during cell cycle. Our ChIP-seq and small RNA-seq data suggested that Sp1 can regulate lots of microRNAs in cancer cells and may affect tumor progression via miRNA regulation. Our data showed that Sp1 can exhibit positive and negative control on miRNA, so we chose the Sp1-positive regulated miR-22 and Sp1-negative regulated miR-103 for our study. In this study, we found that Sp1 can activate the promoter of miR-22 by Sp1 binding site, and Sp1 can repress miR-103 through non-canonical intronic microRNA regulation. Instead of regulating miR-103 host gene promoter, Sp1 can directly regulate miR-103 promoter. Although there is not any Sp1 binding site on miR-103 promoter, we found that Sp1 can repress miR-103 transcription by forming a repression complex with YY1 and HADC1. This study showed that Sp1 can exhibit positive and negative control on miRNA transcription in cancer cells, suggesting that Sp1 might play an important role in tumorigenesis by regulating miRNA.
Research aims and significance of the current study 8
Materials and methods
Pin1 recruits phospho-Sp1 during mitosis 24
Sp1 can interacts with CDK1 and Pin1 during mitosis 25
Sp1 can be highly phosphorylated Sp1 by CDK1 in the presence of Pin1 26
Pin1 modulates conformational change at the C-terminus of Sp1 27
Pin1-depentent highly phosphorylation of Sp1 by CDK1 is crucial to the inhibition of the DNA-binding activity of Sp1 during mitosis 27
Pin1-mediated highly phosphorylation is important for cell cycle progression and DNA-binding affinity of Sp1 29
C-terminus of Sp1 is involved in the regulation of its stability and DNA-binding activity 30
Pin1 knockout decreases the interaction between CDK1 and its interacted proteins 31
microRNAs are the target of Sp1 32
miR-22 and miR-103 are regulated by Sp1 33
Sp1 can activate miR-22 transcription by the canonical Sp1-binding site 33
Sp1 can indirectly repress miR-103 transcription with YY1 34
Sp1 and YY1 can form a repression complex with HDAC1 35
Figure.1 Pin1 recruits phospho-Sp1 during mitosis 64
Figure.2 Pin1 can interact with phospho-Sp1 and CDK1 in vitro 65
Figure.3 Sp1 can interact with Pin1 and CDK1 during mitosis (1) 66
Figure.4 Sp1 can interact with Pin1 and CDK1 during mitosis (2) 67
Figure.5 Interaction between Sp1 and CDK1 is affected by Pin1 68
Figure.6 The band-shift of Sp1 by CDK1 phosphorylation in presence of Pin1 69
Figure.7 Sp1 can be highly phosphorylated by CDK1 in presence of Pin1 70
Figure.8 The highly phosphorylated sites of Sp1 are located at a.a. 715 to 740 71
Figure.9 Pin1 interacts with C-terminus of Sp1 72
Figure.10 Pin1 modulates conformational change at the C-terminus of Sp1 73
Figure.11 Phosphorylation at Thr739 cannot affect DNA-binding affinity of Sp1 75
Figure.12 The possible highly phosphorylated sites of Sp1 76
Figure.13 The possible highly phosphorylated sites of Sp1 are Ser720, Thr723, and Thr737 77
Figure.14 The highly phosphorylation of Sp1 by CDK1 is Pin1- dependent 79
Figure.15 The DNA-binding affinity of Sp1 mimic phosphorylation and non-phosphorylation mutant are affected 80
Figure.16 The localization of Sp1 and chromosome are affected by Sp1 highly phosphorylation 81
Figure.17 Pin1-mediated highly phosphorylation can affect cell cycle 82
Figure.18 Pin1 can affect cell cycle progress 84
Figure.19 Pin1-mediated highly phosphorylation can affect mitosis progression 85
Figure.20 Loss of C-terminus of Sp1 increases its stability 87
Figure.21 C-terminus of Sp1 and RNF4 are regulated Sp1 stability. 88
Figure.22 C-terminus of Sp1 is involved in the regulation of its DNA-binding activity 89
Figure.23 C-terminus of Sp1 is involved in the regulation of its transcriptional activity 90
Figure.24 Pin1 knockout decreases the interaction between CDK1 and its interacted proteins 91
Figure.25 The Pin1-mediated CDK1-interacting network 92
Figure.26 Working model 93
Figure.27 Sp1 can regulate miR-22 and miR-103 94
Figure.28 Sp1 can activate miR-22 promoter by Sp1-binding motif .95
Figure.29 Sp1 cannot affect the promoter of PANK2 96
Figure.30 Sp1 can repress miR-103 promoter 97
Figure.31 YY1 binding sites are important for miR-103 repression 98
Figure.32 YY1 might participate in miR-103 repression 99
Figure.33 The interaction of YY1 and HDAC1 is affected by Sp1.. 100
Figure.34 Current working model of regulation of Sp1-related miRNAs 101
Appendix 1. Data collection statistics of the Pin1 crystals 102
Appendix 2. Electron density map around the active site of Pin1 bound the Thr739(p)-Sp1 peptide 103
Appendix 3. Positive regulation of miRNAs expression by Sp1 104
Appendix 4. Negative regulation of miRNAs expression by Sp1 106
Appendix 5. Regulatory networks among Sp1, miRNAs, and miRNAs target genes 107
Appendix 6. Model of CDK1 and PP2A regulating the phosphorylation of Sp1 108
Appendix 7. CDK1/cyclin B1 interacts with Sp1 and phosphorylates Sp1 at Thr739 during mitosis 109
Appendix 8. Sp1 phosphorylation during mitosis is required for chromatin condensation 110
Appendix 9. RNA4 is the E3 ubiquitin ligase of Sp1 111
Appendix 10. The different model of intronic miRNA biogenesis 112
Abbas, T., and Dutta, A. (2009). p21 in cancer: intricate networks and multiple activities. Nat. Rev. Cancer 9, 400–414.
Abdelrahim, M., and Safe, S. (2005). Cyclooxygenase-2 inhibitors decrease vascular endothelial growth factor expression in colon cancer cells by enhanced degradation of Sp1 and Sp4 proteins. Mol. Pharmacol 68, 317–329.
Abdelrahim, M., Smith, R., 3rd, Burghardt, R., and Safe, S. (2004). Role of Sp proteins in regulation of vascular endothelial growth factor expression and proliferation of pancreatic cancer cells. Cancer Res. 64, 6740–6749.
Ai, W., Liu, Y., and Wang, T.C. (2006). Yin yang 1 (YY1) represses histidine decarboxylase gene expression with SREBP-1a in part through an upstream Sp1 site. Am. J. Physiol. Gastrointest. Liver Physiol. 290, G1096-1104.
Allegra, D., Bilan, V., Garding, A., Döhner, H., Stilgenbauer, S., Kuchenbauer, F., and Mertens, D. (2014). Defective DROSHA processing contributes to downregulation of MiR-15/-16 in chronic lymphocytic leukemia. Leukemia 28, 98–107.
Armstrong, S.A., Barry, D.A., Leggett, R.W., and Mueller, C.R. (1997). Casein kinase II-mediated phosphorylation of the C terminus of Sp1 decreases its DNA-binding activity. J. Biol. Chem 272, 13489–13495.
Atchison, M., Basu, A., Zaprazna, K., and Papasani, M. (2011). Mechanisms of Yin Yang 1 in Oncogenesis: The Importance of Indirect Effects. Crit Rev Oncog 16, 143–161.
Bar, N., and Dikstein, R. (2010). miR-22 forms a regulatory loop in PTEN/AKT pathway and modulates signaling kinetics. PLoS ONE 5, e10859.
Beishline, K., and Azizkhan-Clifford, J. (2015). Sp1 and the “hallmarks of cancer.” FEBS J. 282, 224–258.
Biggs, J.R., Kudlow, J.E., and Kraft, A.S. (1996). The role of the transcription factor Sp1 in regulating the expression of the WAF1/CIP1 gene in U937 leukemic cells. J. Biol. Chem. 271, 901–906.
Bond, G.L., Hu, W., Bond, E.E., Robins, H., Lutzker, S.G., Arva, N.C., Bargonetti, J., Bartel, F., Taubert, H., Wuerl, P., et al. (2004). A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell 119, 591–602.
Bonello, M.R., and Khachigian, L.M. (2004). Fibroblast Growth Factor-2 Represses Platelet-derived Growth Factor Receptor-α (PDGFR-α) Transcription via ERK1/2-dependent Sp1 Phosphorylation and an Atypical cis-Acting Element in the Proximal PDGFR-α Promoter. Journal of Biological Chemistry 279, 2377–2382.
Carpentier, C., Laigle-Donadey, F., Marie, Y., Auger, N., Benouaich-Amiel, A., Lejeune, J., Kaloshi, G., Delattre, J.-Y., Thillet, J., and Sanson, M. (2006). Polymorphism in Sp1 recognition site of the EGF receptor gene promoter and risk of glioblastoma. Neurology 67, 872–874.
Chen, H.-Y., Lin, Y.-M., Chung, H.-C., Lang, Y.-D., Lin, C.-J., Huang, J., Wang, W.-C., Lin, F.-M., Chen, Z., Huang, H.-D., et al. (2012). miR-103/107 promote metastasis of colorectal cancer by targeting the metastasis suppressors DAPK and KLF4. Cancer Res. 72, 3631–3641.
Chu, S., and Ferro, T.J. (2005). Sp1: Regulation of gene expression by phosphorylation. Gene 348, 1–11.
Chuang, J.-Y., Wang, Y.-T., Yeh, S.-H., Liu, Y.-W., Chang, W.-C., and Hung, J.-J. (2008). Phosphorylation by c-Jun NH2-terminal kinase 1 regulates the stability of transcription factor Sp1 during mitosis. Mol. Biol. Cell 19, 1139–1151.
Chuang, J.-Y., Wu, C.-H., Lai, M.-D., Chang, W.-C., and Hung, J.-J. (2009). Overexpression of Sp1 leads to p53-dependent apoptosis in cancer cells. Int. J. Cancer 125, 2066–2076.
Chuang, J.-Y., Wang, S.-A., Yang, W.-B., Yang, H.-C., Hung, C.-Y., Su, T.-P., Chang, W.-C., and Hung, J.-J. (2012). Sp1 phosphorylation by cyclin-dependent kinase 1/cyclin B1 represses its DNA-binding activity during mitosis in cancer cells. Oncogene.
Chun, R.F., Semmes, O.J., Neuveut, C., and Jeang, K.T. (1998). Modulation of Sp1 phosphorylation by human immunodeficiency virus type 1 Tat. J. Virol 72, 2615–2629.
Chung, S.S., Choi, H.H., Cho, Y.M., Lee, H.K., and Park, K.S. (2006). Sp1 mediates repression of the resistin gene by PPARγ agonists in 3T3-L1 adipocytes. Biochemical and Biophysical Research Communications 348, 253–258.
Chupreta, S., Du, M., Todisco, A., and Merchant, J.L. (2000). EGF stimulates gastrin promoter through activation of Sp1 kinase activity. American Journal of Physiology - Cell Physiology 278, C697–C708.
Colgan, D.F., Murthy, K.G., Prives, C., and Manley, J.L. (1996). Cell-cycle related regulation of poly(A) polymerase by phosphorylation. Nature 384, 282–285.
Darieva, Z., Pic-Taylor, A., Boros, J., Spanos, A., Geymonat, M., Reece, R.J., Sedgwick, S.G., Sharrocks, A.D., and Morgan, B.A. (2003). Cell cycle-regulated transcription through the FHA domain of Fkh2p and the coactivator Ndd1p. Curr. Biol. 13, 1740–1745.
Davie, J.R., He, S., Li, L., Sekhavat, A., Espino, P., Drobic, B., Dunn, K.L., Sun, J.-M., Chen, H.Y., Yu, J., et al. (2008). Nuclear organization and chromatin dynamics--Sp1, Sp3 and histone deacetylases. Adv. Enzyme Regul. 48, 189–208.
Dedes, K.J., Natrajan, R., Lambros, M.B., Geyer, F.C., Lopez-Garcia, M.A., Savage, K., Jones, R.L., and Reis-Filho, J.S. (2011). Down-regulation of the miRNA master regulators Drosha and Dicer is associated with specific subgroups of breast cancer. European Journal of Cancer 47, 138–150.
Deng, Z., Cao, P., Wan, M., and Sui, G. (2010). Yin Yang 1. Transcription 1, 81–84.
Deniaud, E., Baguet, J., Mathieu, A.-L., Pagès, G., Marvel, J., and Leverrier, Y. (2006). Overexpression of Sp1 transcription factor induces apoptosis. Oncogene 25, 7096–7105.
Dirick, L., Böhm, T., and Nasmyth, K. (1995). Roles and regulation of Cln-Cdc28 kinases at the start of the cell cycle of Saccharomyces cerevisiae. EMBO J. 14, 4803–4813.
Eiring, A.M., Harb, J.G., Neviani, P., Garton, C., Oaks, J.J., Spizzo, R., Liu, S., Schwind, S., Santhanam, R., Hickey, C.J., et al. (2010). miR-328 Functions as an RNA Decoy to Modulate hnRNP E2 Regulation of mRNA Translation in Leukemic Blasts. Cell 140, 652–665.
Eisermann, K., Broderick, C.J., Bazarov, A., Moazam, M.M., and Fraizer, G.C. (2013). Androgen up-regulates vascular endothelial growth factor expression in prostate cancer cells via an Sp1 binding site. Mol. Cancer 12, 7.
Elliott, D.J. (2004). The role of potential splicing factors including RBMY, RBMX, hnRNPG-T and STAR proteins in spermatogenesis. Int. J. Androl. 27, 328–334.
Emsley, P., and Cowtan, K. (2004). Coot: model-building tools for molecular graphics. Acta Crystallogr. D Biol. Crystallogr. 60, 2126–2132.
Enserink, J.M., and Kolodner, R.D. (2010). An overview of Cdk1-controlled targets and processes. Cell Div 5, 11.
Finkenzeller, G., Sparacio, A., Technau, A., Marmé, D., and Siemeister, G. (1997). Sp1 recognition sites in the proximal promoter of the human vascular endothelial growth factor gene are essential for platelet-derived growth factor-induced gene expression. Oncogene 15, 669–676.
Firestone, G.L., and Bjeldanes, L.F. (2003). Indole-3-Carbinol and 3-3’-Diindolylmethane Antiproliferative Signaling Pathways Control Cell-Cycle Gene Transcription in Human Breast Cancer Cells by Regulating Promoter–Sp1 Transcription Factor Interactions. The Journal of Nutrition 133, 2448S–2455S.
Fojas de Borja, P., Collins, N.K., Du, P., Azizkhan-Clifford, J., and Mudryj, M. (2001). Cyclin A-CDK phosphorylates Sp1 and enhances Sp1-mediated transcription. EMBO J 20, 5737–5747.
Fu, X., Zhang, W., Su, Y., Lu, L., Wang, D., and Wang, H. (2016). MicroRNA-103 suppresses tumor cell proliferation by targeting PDCD10 in prostate cancer. Prostate.
Gaglio, T., Saredi, A., and Compton, D.A. (1995). NuMA is required for the organization of microtubules into aster-like mitotic arrays. J. Cell Biol. 131, 693–708.
Garzon, R., Calin, G.A., and Croce, C.M. (2009). MicroRNAs in Cancer. Annual Review of Medicine 60, 167–179.
Gebara, M.M., Sayre, M.H., and Corden, J.L. (1997). Phosphorylation of the carboxy-terminal repeat domain in RNA polymerase II by cyclin-dependent kinases is sufficient to inhibit transcription. J. Cell. Biochem 64, 390–402.
Geng, L., Sun, B., Gao, B., Wang, Z., Quan, C., Wei, F., and Fang, X.-D. (2014). MicroRNA-103 promotes colorectal cancer by targeting tumor suppressor DICER and PTEN. Int J Mol Sci 15, 8458–8472.
Grinnell, F. (1984). Fibronectin and wound healing. J. Cell. Biochem. 26, 107–116.
Grinstein, E., Jundt, F., Weinert, I., Wernet, P., and Royer, H.-D. (2002). Sp1 as G1 cell cycle phase specific transcription factor in epithelial cells. Oncogene 21, 1485–1492.
Haidweger, E., Novy, M., and Rotheneder, H. (2001). Modulation of Sp1 activity by a cyclin A/CDK complex. Journal of Molecular Biology 306, 201–212.
Haley, J., Whittle, N., Bennet, P., Kinchington, D., Ullrich, A., and Waterfield, M. (1987). The human EGF receptor gene: structure of the 110 kb locus and identification of sequences regulating its transcription. Oncogene Res. 1, 375–396.
Han, I., and Kudlow, J.E. (1997). Reduced O glycosylation of Sp1 is associated with increased proteasome susceptibility. Mol. Cell. Biol 17, 2550–2558.
Hanahan, D., and Weinberg, R.A. (2000). The Hallmarks of Cancer. Cell 100, 57–70.
Heinrich, B., Zhang, Z., Raitskin, O., Hiller, M., Benderska, N., Hartmann, A.M., Bracco, L., Elliott, D., Ben-Ari, S., Soreq, H., et al. (2009). Heterogeneous nuclear ribonucleoprotein G regulates splice site selection by binding to CC(A/C)-rich regions in pre-mRNA. J. Biol. Chem. 284, 14303–14315.
Hsu, T.-I., Wang, M.-C., Chen, S.-Y., Yeh, Y.-M., Su, W.-C., Chang, W.-C., and Hung, J.-J. (2012). Sp1 expression regulates lung tumor progression. Oncogene 31, 3973–3988.
Hu, X., and Moscinski, L.C. (2011). Cdc2: a monopotent or pluripotent CDK? Cell Proliferation 44, 205–211.
Hung, J.-J., Wang, Y.-T., and Chang, W.-C. (2006). Sp1 deacetylation induced by phorbol ester recruits p300 to activate 12(S)-lipoxygenase gene transcription. Mol. Cell. Biol 26, 1770–1785.
Hung, W.-C., Tseng, W.-L., Shiea, J., and Chang, H.-C. (2010). Skp2 overexpression increases the expression of MMP-2 and MMP-9 and invasion of lung cancer cells. Cancer Lett. 288, 156–161.
Iraci, N., Diolaiti, D., Papa, A., Porro, A., Valli, E., Gherardi, S., Herold, S., Eilers, M., Bernardoni, R., Valle, G.D., et al. (2011). A SP1/MIZ1/MYCN Repression Complex Recruits HDAC1 at the TRKA and p75NTR Promoters and Affects Neuroblastoma Malignancy by Inhibiting the Cell Response to NGF. Cancer Res 71, 404–412.
Jackson, S.P., MacDonald, J.J., Lees-Miller, S., and Tjian, R. (1990). GC box binding induces phosphorylation of Sp1 by a DNA-dependent protein kinase. Cell 63, 155–165.
Jansson, M.D., and Lund, A.H. (2012). MicroRNA and cancer. Molecular Oncology 6, 590–610.
Jiang, N.Y., Woda, B.A., Banner, B.F., Whalen, G.F., Dresser, K.A., and Lu, D. (2008). Sp1, a new biomarker that identifies a subset of aggressive pancreatic ductal adenocarcinoma. Cancer Epidemiol. Biomarkers Prev. 17, 1648–1652.
Kageyama, R., Merlino, G.T., and Pastan, I. (1988). Epidermal growth factor (EGF) receptor gene transcription. Requirement for Sp1 and an EGF receptor-specific factor. J. Biol. Chem. 263, 6329–6336.
Karlseder, J., Rotheneder, H., and Wintersberger, E. (1996). Interaction of Sp1 with the growth- and cell cycle-regulated transcription factor E2F. Mol. Cell. Biol. 16, 1659–1667.
Karube, Y., Tanaka, H., Osada, H., Tomida, S., Tatematsu, Y., Yanagisawa, K., Yatabe, Y., Takamizawa, J., Miyoshi, S., Mitsudomi, T., et al. (2005). Reduced expression of Dicer associated with poor prognosis in lung cancer patients. Cancer Science 96, 111–115.
Kavurma, M.M., and Khachigian, L.M. (2004). Vascular smooth muscle cell-specific regulation of cyclin-dependent kinase inhibitor p21(WAF1/Cip1) transcription by Sp1 is mediated via distinct cis-acting positive and negative regulatory elements in the proximal p21(WAF1/Cip1) promoter. J. Cell. Biochem. 93, 904–916.
Kimura, K., Kawamoto, K., Teranishi, S., and Nishida, T. (2006). Role of Rac1 in fibronectin-induced adhesion and motility of human corneal epithelial cells. Invest. Ophthalmol. Vis. Sci. 47, 4323–4329.
Kitadai, Y., Yasui, W., Yokozaki, H., Kuniyasu, H., Haruma, K., Kajiyama, G., and Tahara, E. (1992). The level of a transcription factor Sp1 is correlated with the expression of EGF receptor in human gastric carcinomas. Biochem. Biophys. Res. Commun. 189, 1342–1348.
Knappskog, S., and Lønning, P.E. (2011). Effects of the MDM2 promoter SNP285 and SNP309 on Sp1 transcription factor binding and cancer risk. Transcription 2, 207–210.
Knappskog, S., Bjørnslett, M., Myklebust, L.M., Huijts, P.E.A., Vreeswijk, M.P., Edvardsen, H., Guo, Y., Zhang, X., Yang, M., Ylisaukko-Oja, S.K., et al. (2011). The MDM2 promoter SNP285C/309G haplotype diminishes Sp1 transcription factor binding and reduces risk for breast and ovarian cancer in Caucasians. Cancer Cell 19, 273–282.
Knoop, L.L., and Baker, S.J. (2000). The splicing factor U1C represses EWS/FLI-mediated transactivation. J. Biol. Chem. 275, 24865–24871.
Kolesnikoff, N., Attema, J.L., Roslan, S., Bert, A.G., Schwarz, Q.P., Gregory, P.A., and Goodall, G.J. (2014). Specificity protein 1 (Sp1) maintains basal epithelial expression of the miR-200 family: implications for epithelial-mesenchymal transition. J. Biol. Chem. 289, 11194–11205.
Kong, L.-M., Liao, C.-G., Fei, F., Guo, X., Xing, J.-L., and Chen, Z.-N. (2010). Transcription factor Sp1 regulates expression of cancer-associated molecule CD147 in human lung cancer. Cancer Sci. 101, 1463–1470.
Kong, L.-M., Liao, C.-G., Zhang, Y., Xu, J., Li, Y., Huang, W., Zhang, Y., Bian, H., and Chen, Z.-N. (2014). A regulatory loop involving miR-22, Sp1, and c-Myc modulates CD147 expression in breast cancer invasion and metastasis. Cancer Res. 74, 3764–3778.
Kong, X., Peng, B., Yang, Y., Zhang, P., Qin, B., Han, D., Wang, C., Dang, Y., Liu, J.O., and Yu, L. (2013). p53 Represses Transcription of RING Finger LIM Domain-Binding Protein RLIM through Sp1. PLOS ONE 8, e62832.
Kotak, S., Busso, C., and Gönczy, P. (2013). NuMA phosphorylation by CDK1 couples mitotic progression with cortical dynein function. The EMBO Journal 32, 2517–2529.
Koutsodontis, G., Moustakas, A., and Kardassis, D. (2002). The role of Sp1 family members, the proximal GC-rich motifs, and the upstream enhancer region in the regulation of the human cell cycle inhibitor p21WAF-1/Cip1 gene promoter. Biochemistry 41, 12771–12784.
Lee, J.-H., Park, S.-J., Jeong, S.-Y., Kim, M.-J., Jun, S., Lee, H.-S., Chang, I.-Y., Lim, S.-C., Yoon, S.P., Yong, J., et al. (2015). MicroRNA-22 Suppresses DNA Repair and Promotes Genomic Instability through Targeting of MDC1. Cancer Res. 75, 1298–1310.
Lee, J.S., Galvin, K.M., and Shi, Y. (1993). Evidence for physical interaction between the zinc-finger transcription factors YY1 and Sp1. Proc Natl Acad Sci U S A 90, 6145–6149.
Lee, J.S., Galvin, K.M., See, R.H., Eckner, R., Livingston, D., Moran, E., and Shi, Y. (1995). Relief of YY1 transcriptional repression by adenovirus E1A is mediated by E1A-associated protein p300. Genes Dev. 9, 1188–1198.
Leggett, R.W., Armstrong, S.A., Barry, D., and Mueller, C.R. (1995). Sp1 is phosphorylated and its DNA-binding activity down-regulated upon terminal differentiation of the liver. Journal of Biological Chemistry 270, 25879–25884.
Li, L., and Davie, J.R. (2010). The role of Sp1 and Sp3 in normal and cancer cell biology. Annals of Anatomy - Anatomischer Anzeiger 192, 275–283.
Lin, S.Y., Black, A.R., Kostic, D., Pajovic, S., Hoover, C.N., and Azizkhan, J.C. (1996). Cell cycle-regulated association of E2F1 and Sp1 is related to their functional interaction. Mol. Cell. Biol. 16, 1668–1675.
Ling, B., Wang, G.-X., Long, G., Qiu, J.-H., and Hu, Z.-L. (2012). Tumor suppressor miR-22 suppresses lung cancer cell progression through post-transcriptional regulation of ErbB3. J. Cancer Res. Clin. Oncol. 138, 1355–1361.
Liou, Y.-C., Zhou, X.Z., and Lu, K.P. (2011). Prolyl isomerase Pin1 as a molecular switch to determine the fate of phosphoproteins. Trends Biochem. Sci. 36, 501–514.
Loyer, P., Trembley, J.H., Katona, R., Kidd, V.J., and Lahti, J.M. (2005). Role of CDK/cyclin complexes in transcription and RNA splicing. Cellular Signalling 17, 1033–1051.
Lu, K.P., and Zhou, X.Z. (2007). The prolyl isomerase PIN1: a pivotal new twist in phosphorylation signalling and disease. Nat. Rev. Mol. Cell Biol 8, 904–916.
Lu, K.P., Hanes, S.D., and Hunter, T. (1996). A human peptidyl–prolyl isomerase essential for regulation of mitosis. , Published Online: 11 April 1996; | doi:10.1038/380544a0 380, 544–547.
Matsui, Y., Nakayama, Y., Okamoto, M., Fukumoto, Y., and Yamaguchi, N. (2012). Enrichment of cell populations in metaphase, anaphase, and telophase by synchronization using nocodazole and blebbistatin: A novel method suitable for examining dynamic changes in proteins during mitotic progression. European Journal of Cell Biology 91, 413–419.
Meccia, E., Bottero, L., Felicetti, F., Peschle, C., Colombo, M.P., and Carè, A. (2003). HOXB7 expression is regulated by the transcription factors NF-Y, YY1, Sp1 and USF-1. Biochim. Biophys. Acta 1626, 1–9.
Medina, P.P., Nolde, M., and Slack, F.J. (2010). OncomiR addiction in an in vivo model of microRNA-21-induced pre-B-cell lymphoma. Nature 467, 86–90.
Merchant, J.L., Du, M., and Todisco, A. (1999). Sp1 Phosphorylation by Erk 2 Stimulates DNA-binding. Biochemical and Biophysical Research Communications 254, 454–461.
Merdes, A., Ramyar, K., Vechio, J.D., and Cleveland, D.W. (1996). A Complex of NuMA and Cytoplasmic Dynein Is Essential for Mitotic Spindle Assembly. Cell 87, 447–458.
Merritt, W.M., Lin, Y.G., Han, L.Y., Kamat, A.A., Spannuth, W.A., Schmandt, R., Urbauer, D., Pennacchio, L.A., Cheng, J.-F., Nick, A.M., et al. (2008). Dicer, Drosha, and Outcomes in Patients with Ovarian Cancer. New England Journal of Medicine 359, 2641–2650.
Milanini-Mongiat, J., Pouysségur, J., and Pagès, G. (2002). Identification of two Sp1 phosphorylation sites for p42/p44 mitogen-activated protein kinases: their implication in vascular endothelial growth factor gene transcription. J. Biol. Chem 277, 20631–20639.
Mitsudomi, T., and Yatabe, Y. (2010). Epidermal growth factor receptor in relation to tumor development: EGFR gene and cancer. FEBS J. 277, 301–308.
Mukhopadhyay, D., KNEB, Ipswich, MA, USAelmann, B., Cohen, H.T., Ananth, S., and Sukhatme, V.P. (1997). The von Hippel-Lindau tumor suppressor gene product interacts with Sp1 to repress vascular endothelial growth factor promoter activity. Mol. Cell. Biol. 17, 5629–5639.
Murshudov, G.N., Skubak, P., Lebedev, A.A., Pannu, N.S., Steiner, R.A., Nicholls, R.A., Winn, M.D., Long, F., and Vagin, A.A. (2011). REFMAC5 for the refinement of macromolecular crystal structures. Acta Crystallogr D Biol Crystallogr 67, 355–367.
Nasim, M.T., Chernova, T.K., Chowdhury, H.M., Yue, B.-G., and Eperon, I.C. (2003). HnRNP G and Tra2beta: opposite effects on splicing matched by antagonism in RNA binding. Hum. Mol. Genet. 12, 1337–1348.
Pagès, G., and Pouysségur, J. (2005). Transcriptional regulation of the Vascular Endothelial Growth Factor gene--a concert of activating factors. Cardiovasc. Res. 65, 564–573.
Paronetto, M.P. (2013). Ewing Sarcoma Protein: A Key Player in Human Cancer. Int J Cell Biol 2013.
Pastorino, L., Sun, A., Lu, P.-J., Zhou, X.Z., Balastik, M., Finn, G., Wulf, G., Lim, J., Li, S.-H., Li, X., et al. (2006). The prolyl isomerase Pin1 regulates amyloid precursor protein processing and amyloid-β production. Nature 440, 528–534.
Pic-Taylor, A., Darieva, Z., Morgan, B.A., and Sharrocks, A.D. (2004). Regulation of Cell Cycle-Specific Gene Expression through Cyclin-Dependent Kinase-Mediated Phosphorylation of the Forkhead Transcription Factor Fkh2p. Mol Cell Biol 24, 10036–10046.
Polioudakis, D., Bhinge, A.A., Killion, P.J., Lee, B.-K., Abell, N.S., and Iyer, V.R. (2013). A Myc-microRNA network promotes exit from quiescence by suppressing the interferon response and cell-cycle arrest genes. Nucleic Acids Res. 41, 2239–2254.
Poolman, T.M., Farrow, S.N., Matthews, L., Loudon, A.S., and Ray, D.W. (2013). Pin1 promotes GR transactivation by enhancing recruitment to target genes. Nucl. Acids Res. gkt624.
Pore, N., Liu, S., Shu, H.-K., Li, B., Haas-Kogan, D., Stokoe, D., Milanini-Mongiat, J., Pages, G., O’Rourke, D.M., Bernhard, E., et al. (2004). Sp1 is involved in Akt-mediated induction of VEGF expression through an HIF-1-independent mechanism. Mol. Biol. Cell 15, 4841–4853.
Rafty, L.A., and Khachigian, L.M. (2001). Sp1 phosphorylation regulates inducible expression of platelet-derived growth factor B-chain gene via atypical protein kinase C-zeta. Nucleic Acids Res. 29, 1027–1033.
Rajbhandari, P., Finn, G., Solodin, N.M., Singarapu, K.K., Sahu, S.C., Markley, J.L., Kadunc, K.J., Ellison-Zelski, S.J., Kariagina, A., Haslam, S.Z., et al. (2011). Regulation of ERα N-terminus conformation and function by peptidyl prolyl isomerase Pin1. Mol. Cell. Biol.
Ramalingam, P., Palanichamy, J.K., Singh, A., Das, P., Bhagat, M., Kassab, M.A., Sinha, S., and Chattopadhyay, P. (2014). Biogenesis of intronic miRNAs located in clusters by independent transcription and alternative splicing. RNA 20, 76–87.
Reisinger, K., Kaufmann, R., and Gille, J. (2003). Increased Sp1 phosphorylation as a mechanism of hepatocyte growth factor (HGF/SF)-induced vascular endothelial growth factor (VEGF/VPF) transcription. J. Cell. Sci 116, 225–238.
Reynolds, D., Shi, B.J., McLean, C., Katsis, F., Kemp, B., and Dalton, S. (2003). Recruitment of Thr 319-phosphorylated Ndd1p to the FHA domain of Fkh2p requires Clb kinase activity: a mechanism for CLB cluster gene activation. Genes Dev. 17, 1789–1802.
Rippmann, J.F., Hobbie, S., Daiber, C., Guilliard, B., Bauer, M., Birk, J., Nar, H., Garin-Chesa, P., Rettig, W.J., and Schnapp, A. (2000). Phosphorylation-dependent proline isomerization catalyzed by Pin1 is essential for tumor cell survival and entry into mitosis. Cell Growth Differ. 11, 409–416.
Rohlff, C., Ahmad, S., Borellini, F., Lei, J., and Glazer, R.I. (1997). Modulation of Transcription Factor Sp1 by cAMP-dependent Protein Kinase. J. Biol. Chem. 272, 21137–21141.
Ryu, H., Lee, J., Olofsson, B.A., Mwidau, A., Dedeoglu, A., Escudero, M., Flemington, E., Azizkhan-Clifford, J., Ferrante, R.J., Ratan, R.R., et al. (2003). Histone deacetylase inhibitors prevent oxidative neuronal death independent of expanded polyglutamine repeats via an Sp1-dependent pathway. Proc. Natl. Acad. Sci. U.S.A 100, 4281–4286.
Schäfer, G., Cramer, T., Suske, G., Kemmner, W., Wiedenmann, B., and Höcker, M. (2003). Oxidative stress regulates vascular endothelial growth factor-A gene transcription through Sp1- and Sp3-dependent activation of two proximal GC-rich promoter elements. J. Biol. Chem. 278, 8190–8198.
Shen, M., Stukenberg, P.T., Kirschner, M.W., and Lu, K.P. (1998). The essential mitotic peptidyl–prolyl isomerase Pin1 binds and regulates mitosis-specific phosphoproteins. Genes Dev 12, 706–720.
Song, S.J., and Pandolfi, P.P. (2014). miR-22 in tumorigenesis. Cell Cycle 13, 11–12.
Song, S.J., Poliseno, L., Song, M.S., Ala, U., Webster, K., Ng, C., Beringer, G., Brikbak, N.J., Yuan, X., Cantley, L.C., et al. (2013). MicroRNA-antagonism regulates breast cancer stemness and metastasis via TET-family-dependent chromatin remodeling. Cell 154, 311–324.
Spengler, M.L., and Brattain, M.G. (2006). Sumoylation inhibits cleavage of Sp1 N-terminal negative regulatory domain and inhibits Sp1-dependent transcription. J. Biol. Chem 281, 5567–5574.
Spiegelman, B.M., and Ginty, C.A. (1983). Fibronectin modulation of cell shape and lipogenic gene expression in 3T3-adipocytes. Cell 35, 657–666.
Stoner, M., Wormke, M., Saville, B., Samudio, I., Qin, C., Abdelrahim, M., and Safe, S. (2004). Estrogen regulation of vascular endothelial growth factor gene expression in ZR-75 breast cancer cells through interaction of estrogen receptor alpha and SP proteins. Oncogene 23, 1052–1063.
Stuart, D., and Wittenberg, C. (1995). CLN3, not positive feedback, determines the timing of CLN2 transcription in cycling cells. Genes Dev. 9, 2780–2794.
Tan, N.Y., and Khachigian, L.M. (2009). Sp1 phosphorylation and its regulation of gene transcription. Mol. Cell. Biol 29, 2483–2488.
Tan, N.Y., Midgley, V.C., Kavurma, M.M., Santiago, F.S., Luo, X., Peden, R., Fahmy, R.G., Berndt, M.C., Molloy, M.P., and Khachigian, L.M. (2008). Angiotensin II-inducible platelet-derived growth factor-D transcription requires specific Ser/Thr residues in the second zinc finger region of Sp1. Circ. Res. 102, e38-51.
Tan, Y., Yin, H., Zhang, H., Fang, J., Zheng, W., Li, D., Li, Y., Cao, W., Sun, C., Liang, Y., et al. (2015). Sp1-driven up-regulation of miR-19a decreases RHOB and promotes pancreatic cancer. Oncotarget.
Tischer, E., Mitchell, R., Hartman, T., Silva, M., Gospodarowicz, D., Fiddes, J.C., and Abraham, J.A. (1991). The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. J. Biol. Chem. 266, 11947–11954.
Torres, A., Torres, K., Paszkowski, T., Jodłowska-Jędrych, B., Radomański, T., Książek, A., and Maciejewski, R. (2011). Major regulators of microRNAs biogenesis Dicer and Drosha are down-regulated in endometrial cancer. Tumor Biol. 32, 769–776.
Tsuchiya, N., Izumiya, M., Ogata-Kawata, H., Okamoto, K., Fujiwara, Y., Nakai, M., Okabe, A., Schetter, A.J., Bowman, E.D., Midorikawa, Y., et al. (2011). Tumor suppressor miR-22 determines p53-dependent cellular fate through post-transcriptional regulation of p21. Cancer Res. 71, 4628–4639.
Tyan, Y.-C., Wu, H.-Y., Su, W.-C., Chen, P.-W., and Liao, P.-C. (2005). Proteomic analysis of human pleural effusion. Proteomics 5, 1062–1074.
Tyers, M., Tokiwa, G., and Futcher, B. (1993). Comparison of the Saccharomyces cerevisiae G1 cyclins: Cln3 may be an upstream activator of Cln1, Cln2 and other cyclins. EMBO J. 12, 1955–1968.
Varkonyi-Gasic, E., Wu, R., Wood, M., Walton, E.F., and Hellens, R.P. (2007). Protocol: a highly sensitive RT-PCR method for detection and quantification of microRNAs. Plant Methods 3, 12.
Wang, X.-B., Peng, W.-Q., Yi, Z.-J., Zhu, S.-L., and Gan, Q.-H. (2007). [Expression and prognostic value of transcriptional factor sp1 in breast cancer]. Ai Zheng 26, 996–1000.
Wang, Y.-T., Chuang, J.-Y., Shen, M.-R., Yang, W.-B., Chang, W.-C., and Hung, J.-J. (2008). Sumoylation of specificity protein 1 augments its degradation by changing the localization and increasing the specificity protein 1 proteolytic process. J. Mol. Biol 380, 869–885.
Wang, Y.-T., Yang, W.-B., Chang, W.-C., and Hung, J.-J. (2011). Interplay of posttranslational modifications in Sp1 mediates Sp1 stability during cell cycle progression. J. Mol. Biol. 414, 1–14.
Won, J., Yim, J., and Kim, T.K. (2002). Sp1 and Sp3 recruit histone deacetylase to repress transcription of human telomerase reverse transcriptase (hTERT) promoter in normal human somatic cells. J. Biol. Chem. 277, 38230–38238.
Wong, C.F., Barnes, L.M., Dahler, A.L., Smith, L., Popa, C., Serewko-Auret, M.M., and Saunders, N.A. (2005). E2F suppression and Sp1 overexpression are sufficient to induce the differentiation-specific marker, transglutaminase type 1, in a squamous cell carcinoma cell line. Oncogene 24, 3525–3534.
Wu, C., Fields, A.J., Kapteijn, B.A., and McDonald, J.A. (1995). The role of alpha 4 beta 1 integrin in cell motility and fibronectin matrix assembly. J. Cell. Sci. 108 ( Pt 2), 821–829.
Xiang, M., Birkbak, N.J., Vafaizadeh, V., Walker, S.R., Yeh, J.E., Liu, S., Kroll, Y., Boldin, M., Taganov, K., Groner, B., et al. (2014). STAT3 Induction of miR-146b Forms a Feedback Loop to Inhibit the NF-κB to IL-6 Signaling Axis and STAT3-Driven Cancer Phenotypes. Sci. Signal. 7, ra11-ra11.
Xiong, J., Du, Q., and Liang, Z. (2010). Tumor-suppressive microRNA-22 inhibits the transcription of E-box-containing c-Myc target genes by silencing c-Myc binding protein. Oncogene 29, 4980–4988.
Xu, W., Zhu, Q., Wu, Z., Guo, H., Wu, F., Mashausi, D.S., Zheng, C., and Li, D. (2012). A novel evolutionarily conserved element is a general transcriptional repressor of p21WAF1/CIP1. Cancer Res. 72, 6236–6246.
Yang, L., Chansky, H.A., and Hickstein, D.D. (2000). EWS.Fli-1 fusion protein interacts with hyperphosphorylated RNA polymerase II and interferes with serine-arginine protein-mediated RNA splicing. J. Biol. Chem. 275, 37612–37618.
Yang, W.-B., Chen, P.-H., Hsu, T., Fu, T.-F., Su, W.-C., Liaw, H., Chang, W.-C., and Hung, J.-J. (2014). Sp1-mediated microRNA-182 expression regulates lung cancer progression. Oncotarget 5, 740–753.
Yang, W.-M., Inouye, C., Zeng, Y., Bearss, D., and Seto, E. (1996). Transcriptional repression by YY1 is mediated by interaction with a mammalian homolog of the yeast global regulator RPD3. Proc Natl Acad Sci U S A 93, 12845–12850.
Yao, J.C., Wang, L., Wei, D., Gong, W., Hassan, M., Wu, T.-T., Mansfield, P., Ajani, J., and Xie, K. (2004). Association between expression of transcription factor Sp1 and increased vascular endothelial growth factor expression, advanced stage, and poor survival in patients with resected gastric cancer. Clin. Cancer Res. 10, 4109–4117.
Yu, D., Zhou, H., Xun, Q., Xu, X., Ling, J., and Hu, Y. (2012). microRNA-103 regulates the growth and invasion of endometrial cancer cells through the downregulation of tissue inhibitor of metalloproteinase 3. Oncol Lett 3, 1221–1226.
Yu, F., Yao, H., Zhu, P., Zhang, X., Pan, Q., Gong, C., Huang, Y., Hu, X., Su, F., Lieberman, J., et al. (2007). let-7 Regulates Self Renewal and Tumorigenicity of Breast Cancer Cells. Cell 131, 1109–1123.
Zhang, D., Paley, A.J., and Childs, G. (1998). The Transcriptional Repressor ZFM1 Interacts with and Modulates the Ability of EWS to Activate Transcription. J. Biol. Chem. 273, 18086–18091.
Zhang, Y., Daum, S., Wildemann, D., Zhou, X.Z., Verdecia, M.A., Bowman, M.E., Lucke, C., Hunter, T., Lu, K.-P., Fischer, G., et al. (2007). Structural Basis for High-Affinity Peptide Inhibition of Human Pin1. ACS Chem Biol 2, 320–328.
Zhang, Y., Qu, X., Li, C., Fan, Y., Che, X., Wang, X., Cai, Y., Hu, X., and Liu, Y. (2015). miR-103/107 modulates multidrug resistance in human gastric carcinoma by downregulating Cav-1. Tumour Biol. 36, 2277–2285.
Zhao, S., Venkatasubbarao, K., Li, S., and Freeman, J.W. (2003). Requirement of a specific Sp1 site for histone deacetylase-mediated repression of transforming growth factor beta Type II receptor expression in human pancreatic cancer cells. Cancer Res. 63, 2624–2630.
Zhou, X.Z., Kops, O., Werner, A., Lu, P.J., Shen, M., Stoller, G., Küllertz, G., Stark, M., Fischer, G., and Lu, K.P. (2000). Pin1-dependent prolyl isomerization regulates dephosphorylation of Cdc25C and tau proteins. Mol. Cell 6, 873–883.