Abstract
Neuronal apoptosis is an important process of secondary brain injury which is induced by neurochemical signaling cascades after traumatic brain injury (TBI). Present study was designed to investigate whether FOS-like antigen 1 (Fra-1) is involved in the neuronal apoptosis. Western blot analysis and immunohistochemistry in a rat TBI model revealed a significant increase in the expression of Fra-1 in the ipsilateral brain cortex, which was in parallel with increase in the expression of active caspase-3. With immunofluorescence double-labeling, Fra-1 was colocalized with active caspase-3 and with NeuN, a neuronal marker. In an in vitro cell injury model, H2O2 exposure induced cell apoptosis and reduced cell viability and at the same time, a similar increased expression of active caspase-3, p53 and Fra-1 was found in PC12 cells. Down-regulation of Fra-1 through transfection with Fra-1 siRNA remarkably elevated cell viability, reduced the expression of active caspase-3 and p53, and decreased apoptosis of PC12 cells after H2O2 exposure. Taken together, present findings suggest that Fra-1 may be involved in the induction of neuronal apoptosis through up-regulating p53 signaling pathway and that this action may contribute to the secondary neuropathological process after TBI.
Similar content being viewed by others
References
Ai Z, Li C, Li L, He G (2015) Resveratrol inhibits beta-amyloid-induced neuronal apoptosis via regulation of p53 acetylation in PC12 cells. Mol Med Rep 11(4):2429–2434. https://doi.org/10.3892/mmr.2014.3034
Brynczka C, Merrick BA (2007) Nerve growth factor potentiates p53 DNA binding but inhibits nitric oxide-induced apoptosis in neuronal PC12 cells. Neurochem Res 32(9):1573–1585. https://doi.org/10.1007/s11064-007-9362-5
Casalino L, Bakiri L, Talotta F, Weitzman JB, Fusco A, Yaniv M, Verde P (2007) Fra-1 promotes growth and survival in RAS-transformed thyroid cells by controlling cyclin a transcription. EMBO J 26(7):1878–1890. https://doi.org/10.1038/sj.emboj.7601617
Chen, M. M., Zhao, G. W., He, P., Jiang, Z. L., Xi, X., Xu, S. H.,. .. Wang, G. H. (2015). Improvement in the neural stem cell proliferation in rats treated with modified "Shengyu" decoction may contribute to the neurorestoration. J Ethnopharmacol, 165, 9–19. https://doi.org/10.1016/j.jep.2015.02.037
Cheng B, Lu H, Bai B, Chen J (2013) d-beta-Hydroxybutyrate inhibited the apoptosis of PC12 cells induced by H2O2 via inhibiting oxidative stress. Neurochem Int 62(5):620–625. https://doi.org/10.1016/j.neuint.2012.09.011
Cohen DR, Ferreira PC, Gentz R, Franza BR Jr, Curran T (1989) The product of a fos-related gene, fra-1, binds cooperatively to the AP-1 site with Jun: transcription factor AP-1 is comprised of multiple protein complexes. Genes Dev 3(2):173–184
Culmsee C, Mattson MP (2005) p53 in neuronal apoptosis. Biochem Biophys Res Commun 331(3):761–777. https://doi.org/10.1016/j.bbrc.2005.03.149
Debinski W, Gibo DM (2011) Fos-related antigen 1 (Fra-1) pairing with and transactivation of JunB in GBM cells. Cancer Biol Ther 11(2):254–262
Faure A, Conde F, Cheruel F, el Massioui N (2006) Learning-dependent activation of Fra-1: involvement of ventral hippocampus and SNc/VTA complex in learning and habit formation. Brain Res Bull 68(4):233–248. https://doi.org/10.1016/j.brainresbull.2005.08.017
Fleischmann A, Hafezi F, Elliott C, Reme CE, Ruther U, Wagner EF (2000) Fra-1 replaces c-Fos-dependent functions in mice. Genes Dev 14(21):2695–2700
Gillardon F, Lenz C, Waschke KF, Krajewski S, Reed JC, Zimmermann M, Kuschinsky W (1996) Altered expression of Bcl-2, Bcl-X, Bax, and c-Fos colocalizes with DNA fragmentation and ischemic cell damage following middle cerebral artery occlusion in rats. Brain Res Mol Brain Res 40(2):254–260
Hamdi, M., Popeijus, H. E., Carlotti, F., Janssen, J. M., van der Burgt, C., Cornelissen-Steijger, P.,. .. van Dam, H. (2008). ATF3 and Fra1 have opposite functions in JNK- and ERK-dependent DNA damage responses. DNA Repair (Amst), 7(3), 487–496. https://doi.org/10.1016/j.dnarep.2007.12.004
He J, Zhu G, Gao L, Chen P, Long Y, Liao S et al (2015) Fra-1 is upregulated in gastric cancer tissues and affects the PI3K/Akt and p53 signaling pathway in gastric cancer. Int J Oncol 47(5):1725–1734. https://doi.org/10.3892/ijo.2015.3146
Hughes PE, Alexi T, Schreiber SS (1997) A role for the tumour suppressor gene p53 in regulating neuronal apoptosis. Neuroreport 8(15):v-xii
Jochum W, Passegue E, Wagner EF (2001) AP-1 in mouse development and tumorigenesis. Oncogene 20(19):2401–2412. https://doi.org/10.1038/sj.onc.1204389
Kabadi SV, Faden AI (2014) Selective CDK inhibitors: promising candidates for future clinical traumatic brain injury trials. Neural Regen Res 9(17):1578–1580. https://doi.org/10.4103/1673-5374.141779
Konigsmark BW, Murphy EA (1970) Neuronal populations in the human brain. Nature 228(5278):1335–1336
Lakin ND, Jackson SP (1999) Regulation of p53 in response to DNA damage. Oncogene 18(53):7644–7655
Laposa RR, Huang EJ, Cleaver JE (2007) Increased apoptosis, p53 up-regulation, and cerebellar neuronal degeneration in repair-deficient Cockayne syndrome mice. Proc Natl Acad Sci U S A 104(4):1389–1394. https://doi.org/10.1073/pnas.0610619104
Lewen A, Matz P, Chan PH (2000) Free radical pathways in CNS injury. J Neurotrauma 17(10):871–890
Liu X, Yang X, Zhu R, Dai M, Zhu M, Shen Y et al (2017) Involvement of Fra-1 in retinal ganglion cell apoptosis in rat light-induced retina damage model. Cell Mol Neurobiol 37(1):83–92. https://doi.org/10.1007/s10571-016-0346-3
Macleod, K., Mullen, P., Sewell, J., Rabiasz, G., Lawrie, S., Miller, E.,. .. Langdon, S. P. (2005). Altered ErbB receptor signaling and gene expression in cisplatin-resistant ovarian cancer. Cancer Res, 65(15), 6789–6800. https://doi.org/10.1158/0008-5472.CAN-04-2684
Martin LJ, Kaiser A, Yu JW, Natale JE, Al-Abdulla NA (2001) Injury-induced apoptosis of neurons in adult brain is mediated by p53-dependent and p53-independent pathways and requires Bax. J Comp Neurol 433(3):299–311
Motrich RD, Castro GM, Caputto BL (2013) Old players with a newly defined function: Fra-1 and c-Fos support growth of human malignant breast tumors by activating membrane biogenesis at the cytoplasm. PLoS One 8(1):e53211. https://doi.org/10.1371/journal.pone.0053211
Napieralski JA, Raghupathi R, McIntosh TK (1999) The tumor-suppressor gene, p53, is induced in injured brain regions following experimental traumatic brain injury. Brain Res Mol Brain Res 71(1):78–86
Pozas E, Aguado F, Ferrer I (1999) Fra-1 immunoreactivity in the rat brain during normal postnatal development and after injury in adulthood. Neurosci Res 33(2):137–145
Quillinan N, Herson PS, Traystman RJ (2016) Neuropathophysiology of brain injury. Anesthesiol Clin 34(3):453–464. https://doi.org/10.1016/j.anclin.2016.04.011
Shaulian E, Karin M (2002) AP-1 as a regulator of cell life and death. Nat Cell Biol 4(5):E131–E136. https://doi.org/10.1038/ncb0502-e131
Sheng Y, Liu G, Wang M, Lv Z, Du P (2017) A selenium polysaccharide from Platycodon grandiflorum rescues PC12 cell death caused by H2O2 via inhibiting oxidative stress. Int J Biol Macromol 104(Pt A):393–399. https://doi.org/10.1016/j.ijbiomac.2017.06.052
Shirsat NV, Shaikh SA (2003) Overexpression of the immediate early gene fra-1 inhibits proliferation, induces apoptosis, and reduces tumourigenicity of c6 glioma cells. Exp Cell Res 291(1):91–100
Wang DB, Kinoshita C, Kinoshita Y, Morrison RS (2014) p53 and mitochondrial function in neurons. Biochim Biophys Acta 1842(8):1186–1197. https://doi.org/10.1016/j.bbadis.2013.12.015
Yuan J (2009) Neuroprotective strategies targeting apoptotic and necrotic cell death for stroke. Apoptosis 14(4):469–477. https://doi.org/10.1007/s10495-008-0304-8
Acknowledgments
This work was supported by the National Natural Science Foundation of China (81371367, 812713681), the Youth Program of National Natural Science Foundation of China (81401013), 333 High-level Talent Project in Jiangsu Province (BRA2014347), “Talent Innovation Fund” in Nantong University (CXZR201308), and Nantong Municipal Science and Technology Innovation and Demonstration Project Special Social Programs of 2013 (HS2013068).
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Xu, X., Jiang, R., Gong, P. et al. Up-regulation of FOS-like antigen 1 contributes to neuronal apoptosis in the cortex of rat following traumatic brain injury. Metab Brain Dis 33, 115–125 (2018). https://doi.org/10.1007/s11011-017-0129-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11011-017-0129-7