Abstract
T-cell factor 4 (TCF4) is an important transcription factor of the Wnt signaling system. β-catenin, an upstream protein of TCF4, accumulates in the cytoplasm, then translocates to the nucleus to activate the β-catenin/T-cell factor/lymphoid enhancer factor (TCF/LEF) transcriptional machinery and regulates target genes. Previous studies showed that TCF4 was involved in cell proliferation and apoptosis. However, its expression and function in central nervous system injury are unclear. We performed a traumatic brain injury (TBI) model in adult rats. The expression of TCF4 in the brain cortex detected by Western blot increased after TBI. Double immunofluorescence staining revealed that TCF4 was expressed by neurons and microglia. In addition, co-localization of TCF4 with active caspase-3 or proliferating cell nuclear antigen was observed in neurons and microglia, respectively, suggesting that TCF4 might participate in neuronal apoptosis and microglial proliferation after TBI. To further investigate the functions of TCF4, PC12 and HAPI cells were employed to establish a neuronal apoptosis and microglial proliferation model in vitro, respectively. Knocking down TCF4 with siRNA proved the pro-apoptotic and pro-proliferation effect of TCF4 in PC12 and HAPI cells, respectively. Taken together, TCF4 might promote neuronal apoptosis and microglial proliferation after TBI.
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References
Antony L, van der Schoor F, Dalrymple SL, Isaacs JT (2014) Androgen receptor (AR) suppresses normal human prostate epithelial cell proliferation via AR/beta-catenin/TCF-4 complex inhibition of c-MYC transcription. Prostate 74(11):1118–1131. doi:10.1002/pros.22828
Archbold HC, Yang YX, Chen L, Cadigan KM (2012) How do they do Wnt they do?: regulation of transcription by the Wnt/beta-catenin pathway. Acta Physiol (Oxf) 204(1):74–109. doi:10.1111/j.1748-1716.2011.02293.x
Bera A, Ghosh-Choudhury N, Dey N, Das F, Kasinath BS, Abboud HE, Choudhury GG (2013) NFkappaB-mediated cyclin D1 expression by microRNA-21 influences renal cancer cell proliferation. Cell Signal 25(12):2575–2586. doi:10.1016/j.cellsig.2013.08.005
Bramlett HM, Dietrich WD (2007) Progressive damage after brain and spinal cord injury: pathomechanisms and treatment strategies. Prog Brain Res 161:125–141. doi:10.1016/S0079-6123(06)61009-1
Byrnes KR, Faden AI (2007) Role of cell cycle proteins in CNS injury. Neurochem Res 32(10):1799–1807. doi:10.1007/s11064-007-9312-2
Cai F, Chen P, Chen L, Biskup E, Liu Y, Chen PC, Chang JF, Jiang W, Jing Y, Chen Y, Jin H, Chen S (2014) Human RAD6 Promotes G1-S Transition and Cell Proliferation through Upregulation of Cyclin D1 Expression. PLoS One 9(11):e113727. doi:10.1371/journal.pone.0113727
Camac KS, Thompson FM, Cummins AG (2007) Activation of beta-catenin in the stem cell region of crypts during growth of the small intestine in infant rats. Dig Dis Sci 52(5):1242–1246. doi:10.1007/s10620-006-9200-7
Dai ZM, Sun S, Wang C, Huang H, Hu X, Zhang Z, Lu QR, Qiu M (2014) Stage-specific regulation of oligodendrocyte development by Wnt/beta-catenin signaling. J Neurosci 34(25):8467–8473. doi:10.1523/JNEUROSCI.0311-14.2014
Fanti M, Singh S, Ledda-Columbano GM, Columbano A, Monga SP (2014) Tri-iodothyronine induces hepatocyte proliferation by protein kinase A-dependent beta-catenin activation in rodents. Hepatology 59(6):2309–2320. doi:10.1002/hep.26775
Garden GA, Moller T (2006) Microglia biology in health and disease. J Neuroimmune Pharmacol 1(2):127–137. doi:10.1007/s11481-006-9015-5
Geng Y, Ju Y, Ren F, Qiu Y, Tomita Y, Tomoeda M, Kishida M, Wang Y, Jin L, Su F, Wei C, Jia B, Li Y, Chang Z (2014) Insulin receptor substrate 1/2 (IRS1/2) regulates Wnt/beta-catenin signaling through blocking autophagic degradation of dishevelled2. J Biol Chem 289(16):11230–11241. doi:10.1074/jbc.M113.544999
Grossman R, Paden CM, Fry PA, Rhodes RS, Biegon A (2012) Persistent region-dependent neuroinflammation, NMDA receptor loss and atrophy in an animal model of penetrating brain injury. Future Neurol 7(3):329–339. doi:10.2217/fnl.12.25
Gu X, Yao L, Ma G, Cui L, Li Y, Liang W, Zhao B, Li K (2014) TCTP promotes glioma cell proliferation in vitro and in vivo via enhanced beta-catenin/TCF-4 transcription. Neuro Oncol 16(2):217–227. doi:10.1093/neuonc/not194
Guo Y, Saunders T, Su H, Kim H, Akkoc D, Saloner DA, Hetts SW, Hess C, Lawton MT, Bollen AW, Pourmohamad T, McCulloch CE, Tihan T, Young WL, University of California SFBAMSP (2012) Silent intralesional microhemorrhage as a risk factor for brain arteriovenous malformation rupture. Stroke 43(5):1240–1246. doi:10.1161/STROKEAHA.111.647263
Hanisch UK, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 10(11):1387–1394. doi:10.1038/nn1997
Hilton GD, Stoica BA, Byrnes KR, Faden AI (2008) Roscovitine reduces neuronal loss, glial activation, and neurologic deficits after brain trauma. J Cereb Blood Flow Metab 28(11):1845–1859. doi:10.1038/jcbfm.2008.75
Irmady K, Jackman KA, Padow VA, Shahani N, Martin LA, Cerchietti L, Unsicker K, Iadecola C, Hempstead BL (2014) Mir-592 regulates the induction and cell death-promoting activity of p75NTR in neuronal ischemic injury. J Neurosci 34(9):3419–3428. doi:10.1523/JNEUROSCI.1982-13.2014
Koch JC, Tonges L, Barski E, Michel U, Bahr M, Lingor P (2014) ROCK2 is a major regulator of axonal degeneration, neuronal death and axonal regeneration in the CNS. Cell Death Dis 5:e1225. doi:10.1038/cddis.2014.191
Komuta Y, Teng X, Yanagisawa H, Sango K, Kawamura K, Kawano H (2010) Expression of transforming growth factor-beta receptors in meningeal fibroblasts of the injured mouse brain. Cell Mol Neurobiol 30(1):101–111. doi:10.1007/s10571-009-9435-x
Kruman II, Wersto RP, Cardozo-Pelaez F, Smilenov L, Chan SL, Chrest FJ, Emokpae R Jr, Gorospe M, Mattson MP (2004) Cell cycle activation linked to neuronal cell death initiated by DNA damage. Neuron 41(4):549–561
Langlois JA, Rutland-Brown W, Wald MM (2006) The epidemiology and impact of traumatic brain injury: a brief overview. J Head Trauma Rehabil 21(5):375–378
Lazarus RC, Buonora JE, Jacobowitz DM, Mueller GP (2014) Protein carbonylation after traumatic brain injury: cell specificity, regional susceptibility, and gender differences. Free Radic Biol Med 78C:89–100. doi:10.1016/j.freeradbiomed.2014.10.507
Lee HP, Kudo W, Zhu X, Smith MA, Lee HG (2011) Early induction of c-Myc is associated with neuronal cell death. Neurosci Lett 505(2):124–127. doi:10.1016/j.neulet.2011.10.004
Lien WH, Polak L, Lin M, Lay K, Zheng D, Fuchs E (2014) In vivo transcriptional governance of hair follicle stem cells by canonical Wnt regulators. Nat Cell Biol 16(2):179–190. doi:10.1038/ncb2903
Loncarevic-Vasiljkovic N, Pesic V, Todorovic S, Popic J, Smiljanic K, Milanovic D, Ruzdijic S, Kanazir S (2012) Caloric restriction suppresses microglial activation and prevents neuroapoptosis following cortical injury in rats. PLoS One 7(5):e37215. doi:10.1371/journal.pone.0037215
Ma B, Zhong L, van Blitterswijk CA, Post JN, Karperien M (2013) T cell factor 4 is a pro-catabolic and apoptotic factor in human articular chondrocytes by potentiating nuclear factor kappaB signaling. J Biol Chem 288(24):17552–17558. doi:10.1074/jbc.M113.453985
Morganti-Kossmann MC, Yan E, Bye N (2010) Animal models of traumatic brain injury: is there an optimal model to reproduce human brain injury in the laboratory? Injury 41(Suppl 1):S10–S13. doi:10.1016/j.injury.2010.03.032
Nobs L, Nestel S, Kulik A, Nitsch C, Atanasoski S (2013) Cyclin D1 is required for proliferation of Olig2-expressing progenitor cells in the injured cerebral cortex. Glia 61(9):1443–1455. doi:10.1002/glia.22533
Park DS, Obeidat A, Giovanni A, Greene LA (2000) Cell cycle regulators in neuronal death evoked by excitotoxic stress: implications for neurodegeneration and its treatment. Neurobiol Aging 21(6):771–781
Park HK, Fernandez II, Dujovny M, Diaz FG (1999) Experimental animal models of traumatic brain injury: medical and biomechanical mechanism. Crit Rev Neurosurg 9(1):44–52
Ramlackhansingh AF, Brooks DJ, Greenwood RJ, Bose SK, Turkheimer FE, Kinnunen KM, Gentleman S, Heckemann RA, Gunanayagam K, Gelosa G, Sharp DJ (2011) Inflammation after trauma: microglial activation and traumatic brain injury. Ann Neurol 70(3):374–383. doi:10.1002/ana.22455
Rojo LE, Fernandez JA, Maccioni AA, Jimenez JM, Maccioni RB (2008) Neuroinflammation: implications for the pathogenesis and molecular diagnosis of Alzheimer’s disease. Arch Med Res 39(1):1–16. doi:10.1016/j.arcmed.2007.10.001
Saegusa M, Hashimura M, Kuwata T (2010) Pin1 acts as a modulator of cell proliferation through alteration in NF-kappaB but not beta-catenin/TCF4 signalling in a subset of endometrial carcinoma cells. J Pathol 222(4):410–420. doi:10.1002/path.2773
Schmidt-Edelkraut U, Daniel G, Hoffmann A, Spengler D (2014) Zac1 regulates cell cycle arrest in neuronal progenitors via Tcf4. Mol Cell Biol 34(6):1020–1030. doi:10.1128/MCB.01195-13
Schreiber S, Bueche CZ, Garz C, Kropf S, Angenstein F, Goldschmidt J, Neumann J, Heinze HJ, Goertler M, Reymann KG, Braun H (2012) The pathologic cascade of cerebrovascular lesions in SHRSP: is erythrocyte accumulation an early phase? J Cereb Blood Flow Metab 32(2):278–290. doi:10.1038/jcbfm.2011.122
Sharp DJ, Scott G, Leech R (2014) Network dysfunction after traumatic brain injury. Nat Rev Neurol 10(3):156–166. doi:10.1038/nrneurol.2014.15
Shin HW, Choi H, So D, Kim YI, Cho K, Chung HJ, Lee KH, Chun YS, Cho CH, Kang GH, Kim WH, Park JW (2014) ITF2 prevents activation of the beta-catenin-TCF4 complex in colon cancer cells and levels decrease with tumor progression. Gastroenterology 147(2):430–442e438. doi:10.1053/j.gastro.2014.04.047
Stoica BA, Faden AI (2010) Cell death mechanisms and modulation in traumatic brain injury. Neurotherapeutics 7(1):3–12. doi:10.1016/j.nurt.2009.10.023
Takayama S, Rogatsky I, Schwarcz LE, Darimont BD (2006) The glucocorticoid receptor represses cyclin D1 by targeting the Tcf-beta-catenin complex. J Biol Chem 281(26):17856–17863. doi:10.1074/jbc.M602290200
Turtzo LC, Budde MD, Dean DD, Gold EM, Lewis BK, Janes L, Lescher J, Coppola T, Yarnell A, Grunberg NE, Frank JA (2015) Failure of intravenous or intracardiac delivery of mesenchymal stromal cells to improve outcomes after focal traumatic brain injury in the female rat. PLoS One 10(5):e0126551. doi:10.1371/journal.pone.0126551
Villapol S, Balarezo MG, Affram K, Saavedra JM, Symes AJ (2015) Neurorestoration after traumatic brain injury through angiotensin II receptor blockage. Brain 138(11):3299-3315. doi: 10.1093/brain/awv172
Wang GH, Zhang XG, Jiang ZL, Li X, Peng LL, Li YC, Wang Y (2010) Neuroprotective effects of hyperbaric oxygen treatment on traumatic brain injury in the rat. J Neurotrauma 27(9):1733–1743. doi:10.1089/neu.2009.1175
Wu J, Richards MH, Huang J, Al-Harthi L, Xu X, Lin R, Xie F, Gibson AW, Edberg JC, Kimberly RP (2011) Human FasL gene is a target of beta-catenin/T-cell factor pathway and complex FasL haplotypes alter promoter functions. PLoS One 6(10):e26143. doi:10.1371/journal.pone.0026143
Yoo JH, Lee HJ, Kang K, Jho EH, Kim CY, Baturen D, Tunsag J, Nho CW (2010) Lignans inhibit cell growth via regulation of Wnt/beta-catenin signaling. Food Chem Toxicol 48(8–9):2247–2252. doi:10.1016/j.fct.2010.05.056
Zhang H, Zhang X, Ji S, Hao C, Mu Y, Sun J, Hao J (2014) Sohlh2 inhibits ovarian cancer cell proliferation by upregulation of p21 and downregulation of cyclin D1. Carcinogenesis 35(8):1863–1871. doi:10.1093/carcin/bgu113
Acknowledgments
This work was supported in part by the National Natural Science Foundation of China (nos. 81401365, 81373223, 81200918, 81172879, 30770666, 30973143, 31201083), a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).
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Xia Liu and Yuwei Huang contributed to the paper equally.
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Liu, X., Huang, Y., Zhang, Y. et al. T-cell factor (TCF/LEF1) binding elements (TBEs) of FasL (Fas ligand or CD95 ligand) bind and cluster Fas (CD95) and form complexes with the TCF-4 and b-catenin transcription factors in vitro and in vivo which result in triggering cell death and/or cell activation. Cell Mol Neurobiol 36, 1001–1013 (2016). https://doi.org/10.1007/s10571-015-0290-7
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DOI: https://doi.org/10.1007/s10571-015-0290-7