Skip to main content

Advertisement

Log in

Upregulated Expression of NF-YC Contributes to Neuronal Apoptosis via Proapoptotic Protein Bim in Rats’ Brain Hippocampus Following Middle Cerebral Artery Occlusion (MCAO)

  • Published:
Journal of Molecular Neuroscience Aims and scope Submit manuscript

Abstract

Cerebral ischemia represents a severe brain injury that could lead to significant neuronal damage and death. In this study, we performed a middle cerebral artery occlusion (MCAO) in adult rats and observed that a subunit of nuclear factor-Y (NF-Y) transcriptional factor, NF-YC, was accumulated in rat hippocampal CA1 neurons. Immunochemistrical and immunofluorescent analysis revealed that NF-YC was primarily expressed in the nucleus of neurons. Meanwhile, we found that the changes of bim, one of the target genes of NF-Y, were consistent with the expression of NF-YC and Bim was mainly located in the NF-YC positive cells. Moreover, there was a concomitant upregulation of active caspase-3 and TUNEL positive cells. Taken together, these results suggested that the upregulation of NF-YC might play an important role in the pathophysiology via proapoptotic protein Bim after MCAO and further research is needed to have a better understanding of its function and mechanism.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  • Acehan D, Jiang X, Morgan DG, Heuser JE, Wang X, Akey CW (2002) Three-dimensional structure of the apoptosome: implications for assembly, procaspase-9 binding, and activation. Mol Cell 9(2):423–432

    Article  CAS  PubMed  Google Scholar 

  • Beal MF (1992) Mechanisms of excitotoxicity in neurologic diseases. FASEB J 6(15):3338–3344

    CAS  PubMed  Google Scholar 

  • Bederson JB, Pitts LH, Tsuji M, Nishimura MC, Davis RL, Bartkowski H (1986) Rat middle cerebral artery occlusion: evaluation of the model and development of a neurologic examination. Stroke 17(3):472–476

    Article  CAS  PubMed  Google Scholar 

  • Bellorini M, Zemzoumi K, Farina A, Berthelsen J, Piaggio G, Mantovani R (1997) Cloning and expression of human NF-YC. Gene 193(1):119–125

    Article  CAS  PubMed  Google Scholar 

  • Benatti P, Basile V, Merico D, Fantoni LI, Tagliafico E, Imbriano C (2008) A balance between NF-Y and p53 governs the pro- and anti-apoptotic transcriptional response. Nucleic Acids Res 36(5):1415–1428

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Biswas SC, Greene LA (2002) Nerve growth factor (NGF) down-regulates the Bcl-2 homology 3 (BH3) domain-only protein Bim and suppresses its proapoptotic activity by phosphorylation. J Biol Chem 277(51):49511–49516

    Article  CAS  PubMed  Google Scholar 

  • Biswas SC, Liu DX, Greene LA (2005) Bim is a direct target of a neuronal E2F-dependent apoptotic pathway. J Neurosci 25(37):8349–8358

    Article  CAS  PubMed  Google Scholar 

  • Biswas SC, Shi Y, Vonsattel JP, Leung CL, Troy CM, Greene LA (2007) Bim is elevated in Alzheimer’s disease neurons and is required for beta-amyloid-induced neuronal apoptosis. J Neurosci 27(4):893–900

    Article  CAS  PubMed  Google Scholar 

  • Carbajo-Pescador S, Steinmetz C, Kashyap A, Lorenz S, Mauriz JL, Heise M, Galle PR, Gonzalez-Gallego J, Strand S (2013) Melatonin induces transcriptional regulation of Bim by FoxO3a in HepG2 cells. Br J Cancer 108(2):442–449

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ceribelli M, Dolfini D, Merico D, Gatta R, Vigano AM, Pavesi G, Mantovani R (2008) The histone-like NF-Y is a bifunctional transcription factor. Mol Cell Biol 28(6):2047–2058

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Chodosh LA, Baldwin AS, Carthew RW, Sharp PA (1988) Human CCAAT-binding proteins have heterologous subunits. Cell 53(1):11–24

    Article  CAS  PubMed  Google Scholar 

  • Cuende E, Ales-Martinez JE, Ding L, Gonzalez-Garcia M, Martinez C, Nunez G (1993) Programmed cell death by bcl-2-dependent and independent mechanisms in B lymphoma cells. EMBO J 12(4):1555–1560

    CAS  PubMed Central  PubMed  Google Scholar 

  • Cui DR, Wang L, Jiang W, Qi AH, Zhou QH, Zhang XL (2013) Propofol prevents cerebral ischemia-triggered autophagy activation and cell death in the rat hippocampus through the NF-kappaB/p53 signaling pathway. Neuroscience 246:117–132

    Article  CAS  PubMed  Google Scholar 

  • Dirnagl U, Iadecola C, Moskowitz MA (1999) Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci 22(9):391–397

    Article  CAS  PubMed  Google Scholar 

  • Engel T, Plesnila N, Prehn JH, Henshall DC (2011) In vivo contributions of BH3-only proteins to neuronal death following seizures, ischemia, and traumatic brain injury. J Cereb Blood Flow Metab 31(5):1196–1210

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Gatta R, Dolfini D, Mantovani R (2011) NF-Y joins E2Fs, p53 and other stress transcription factors at the apoptosis table. Cell Death Dis 2:e162

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Gross A, McDonnell JM, Korsmeyer SJ (1999) BCL-2 family members and the mitochondria in apoptosis. Genes Dev 13(15):1899–1911

    Article  CAS  PubMed  Google Scholar 

  • Guan H, Song L, Cai J, Huang Y, Wu J, Yuan J, Li J, Li M (2011) Sphingosine kinase 1 regulates the Akt/FOXO3a/Bim pathway and contributes to apoptosis resistance in glioma cells. PLoS One 6(5):e19946

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Gusev EI, Skvortsova VI (2002) Glutamate neurotransmission and calcium metabolism in cerebral ischaemia and under normal conditions. Usp Fiziol Nauk 33(4):80–93

    CAS  PubMed  Google Scholar 

  • Hatamochi A, Golumbek PT, Van Schaftingen E, de Crombrugghe B (1988) A CCAAT DNA binding factor consisting of two different components that are both required for DNA binding. J Biol Chem 263(12):5940–5947

    CAS  PubMed  Google Scholar 

  • He J, Klag MJ, Wu Z, Whelton PK (1995) Stroke in the People’s Republic of China. II. Meta-analysis of hypertension and risk of stroke. Stroke 26(12):2228–2232

    Article  CAS  PubMed  Google Scholar 

  • Hetz C, Thielen P, Fisher J, Pasinelli P, Brown RH, Korsmeyer S, Glimcher L (2007) The proapoptotic BCL-2 family member BIM mediates motoneuron loss in a model of amyotrophic lateral sclerosis. Cell Death Differ 14(7):1386–1389

    Article  CAS  PubMed  Google Scholar 

  • Hossmann KA (1996) Excitotoxic mechanisms in focal ischemia. Adv Neurol 71:69–74

    CAS  PubMed  Google Scholar 

  • Huang DC, Strasser A (2000) BH3-Only proteins-essential initiators of apoptotic cell death. Cell 103(6):839–842

    Article  CAS  PubMed  Google Scholar 

  • Hughes R, Kristiansen M, Lassot I, Desagher S, Mantovani R, Ham J (2011) NF-Y is essential for expression of the proapoptotic bim gene in sympathetic neurons. Cell Death Differ 18(6):937–947

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kanareikin KF, Kutchak EN, Kniazeva GR (1977) Transient ischemic attacks and stroke. Zh Nevropatol Psikhiatr Im S S Korsakova 77(8):1121–1125

    CAS  PubMed  Google Scholar 

  • Katsura K, Kristian T, Nair R, Siesjo BK (1994) Regulation of intra- and extracellular pH in the rat brain in acute hypercapnia: a re-appraisal. Brain Res 651(1–2):47–56

    Article  CAS  PubMed  Google Scholar 

  • Kirino T (1982) Delayed neuronal death in the gerbil hippocampus following ischemia. Brain Res 239(1):57–69

    Article  CAS  PubMed  Google Scholar 

  • Kopycinska J, Kempinska-Podhorodecka A, Haas T, Elias E, DePinho RA, Paik J, Milkiewicz P, Milkiewicz M (2013) Activation of FoxO3a/Bim axis in patients with primary biliary cirrhosis. Liver Int 33(2):231–238

    Article  CAS  PubMed  Google Scholar 

  • Leist M, Nicotera P (1998) Apoptosis versus necrosis: the shape of neuronal cell death. Results Probl Cell Differ 24:105–135

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Chopp M, Zhang ZG, Zaloga C, Niewenhuis L, Gautam S (1994) p53-immunoreactive protein and p53 mRNA expression after transient middle cerebral artery occlusion in rats. Stroke 25(4):849–855

    Article  CAS  PubMed  Google Scholar 

  • Lindsberg PJ, Frerichs KU, Burris JA, Hallenbeck JM, Feuerstein G (1991) Cortical microcirculation in a new model of focal laser-induced secondary brain damage. J Cereb Blood Flow Metab 11(1):88–98

    Article  CAS  PubMed  Google Scholar 

  • Longa EZ, Weinstein PR, Carlson S, Cummins R (1989) Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20(1):84–91

    Article  CAS  PubMed  Google Scholar 

  • Luo H, Yang Y, Duan J, Wu P, Jiang Q, Xu C (2013) PTEN-regulated AKT/FoxO3a/Bim signaling contributes to reactive oxygen species-mediated apoptosis in selenite-treated colorectal cancer cells. Cell Death Dis 4:e481

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ly LL, Suyari O, Yoshioka Y, Tue NT, Yoshida H, Yamaguchi M (2013) dNF-YB plays dual roles in cell death and cell differentiation during drosophila eye development. Gene 520(2):106–118

    Article  CAS  PubMed  Google Scholar 

  • Magan N, Szremska AP, Isaacs RJ, Stowell KM (2003) Modulation of DNA topoisomerase II alpha promoter activity by members of the Sp (specificity protein) and NF-Y (nuclear factor Y) families of transcription factors. Biochem J 374(Pt 3):723–729

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Mantovani R (1998) A survey of 178 NF-Y binding CCAAT boxes. Nucleic Acids Res 26(5):1135–1143

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Mantovani R (1999) The molecular biology of the CCAAT-binding factor NF-Y. Gene 239(1):15–27

    Article  CAS  PubMed  Google Scholar 

  • Martinou JC, Youle RJ (2011) Mitochondria in apoptosis: Bcl-2 family members and mitochondrial dynamics. Dev Cell 21(1):92–101

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • McCord JM (1985) Oxygen-derived free radicals in postischemic tissue injury. N Engl J Med 312(3):159–163

    Article  CAS  PubMed  Google Scholar 

  • McDaniel WF, Fjordbak T, Schmidt MS, Tucker JC, Davis BK (1991) The behavioral effects of bilateral middle cerebral artery hemorrhagic ischemia in rat. Neuroreport 2(11):699–702

    Article  CAS  PubMed  Google Scholar 

  • McNabb DS, Xing Y, Guarente L (1995) Cloning of yeast HAP5: a novel subunit of a heterotrimeric complex required for CCAAT binding. Genes Dev 9(1):47–58

    Article  CAS  PubMed  Google Scholar 

  • Murray CJ, Lopez AD (1997) Global mortality, disability, and the contribution of risk factors: global burden of disease study. Lancet 349(9063):1436–1442

    Article  CAS  PubMed  Google Scholar 

  • O’Connor L, Strasser A, O’Reilly LA, Hausmann G, Adams JM, Cory S, Huang DC (1998) Bim: a novel member of the Bcl-2 family that promotes apoptosis. EMBO J 17(2):384–395

    Article  PubMed Central  PubMed  Google Scholar 

  • Okuno S, Saito A, Hayashi T, Chan PH (2004) The c-Jun N-terminal protein kinase signaling pathway mediates Bax activation and subsequent neuronal apoptosis through interaction with Bim after transient focal cerebral ischemia. J Neurosci 24(36):7879–7887

    Article  CAS  PubMed  Google Scholar 

  • Pirttila TR, Kauppinen RA (1992) Recovery of intracellular pH in cortical brain slices following anoxia studied by nuclear magnetic resonance spectroscopy: role of lactate removal, extracellular sodium and sodium/hydrogen exchange. Neuroscience 47(1):155–164

    Article  CAS  PubMed  Google Scholar 

  • Pulsinelli WA, Levy DE, Duffy TE (1982) Regional cerebral blood flow and glucose metabolism following transient forebrain ischemia. Ann Neurol 11(5):499–502

    Article  CAS  PubMed  Google Scholar 

  • Putcha GV, Le S, Frank S, Besirli CG, Clark K, Chu B, Alix S, Youle RJ, LaMarche A, Maroney AC, Johnson EM Jr (2003) JNK-mediated BIM phosphorylation potentiates BAX-dependent apoptosis. Neuron 38(6):899–914

    Article  CAS  PubMed  Google Scholar 

  • Putcha GV, Moulder KL, Golden JP, Bouillet P, Adams JA, Strasser A, Johnson EM (2001) Induction of BIM, a proapoptotic BH3-only BCL-2 family member, is critical for neuronal apoptosis. Neuron 29(3):615–628

    Article  CAS  PubMed  Google Scholar 

  • Reisner H (1972) Differential diagnosis of cerebral infarct and cerebral hemorrhage. Verh Dtsch Ges Inn Med 78:461–466

    CAS  PubMed  Google Scholar 

  • Rothwell NJ, Hopkins SJ (1995) Cytokines and the nervous system II: actions and mechanisms of action. Trends Neurosci 18(3):130–136

    Article  CAS  PubMed  Google Scholar 

  • Saka O, McGuire A, Wolfe C (2009) Cost of stroke in the United Kingdom. Age Ageing 38(1):27–32

    Article  PubMed  Google Scholar 

  • Sanphui P, Biswas SC (2013) FoxO3a is activated and executes neuron death via Bim in response to beta-amyloid. Cell Death Dis 4:e625

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Shi L, Gong S, Yuan Z, Ma C, Liu Y, Wang C, Li W, Pi R, Huang S, Chen R, Han Y, Mao Z, Li M (2005) Activity deprivation-dependent induction of the proapoptotic BH3-only protein Bim is independent of JNK/c-Jun activation during apoptosis in cerebellar granule neurons. Neurosci Lett 375(1):7–12

    Article  CAS  PubMed  Google Scholar 

  • Shibata M, Hattori H, Sasaki T, Gotoh J, Hamada J, Fukuuchi Y (2002) Temporal profiles of the subcellular localization of Bim, a BH3-only protein, during middle cerebral artery occlusion in mice. J Cereb Blood Flow Metab 22(7):810–820

    Article  CAS  PubMed  Google Scholar 

  • Siegel RM (2006) Caspases at the crossroads of immune-cell life and death. Nat Rev Immunol 6(4):308–317

    Article  CAS  PubMed  Google Scholar 

  • Thornberry NA (1998) Caspases: key mediators of apoptosis. Chem Biol 5(5):R97–103

    Article  CAS  PubMed  Google Scholar 

  • Tsuchiya T, Bonner HP, Engel T, Woods I, Matsushima S, Ward MW, Taki W, Henshall DC, Concannon CG, Prehn JH (2011) Bcl-2 homology domain 3-only proteins Puma and Bim mediate the vulnerability of CA1 hippocampal neurons to proteasome inhibition in vivo. Eur J Neurosci 33(3):401–408

    Article  PubMed  Google Scholar 

  • Ullah N, Naseer MI, Ullah I, Lee HY, Koh PO, Kim MO (2011) Protective effect of pyruvate against ethanol-induced apoptotic neurodegeneration in the developing rat brain. Neuropharmacology 61(8):1248–1255

    Article  CAS  PubMed  Google Scholar 

  • Wang X, Jiang G, Choi BC, Wang D, Wu T, Pan Y, Boulton M (2009) Surveillance of trend and distribution of stroke mortality by subtype, age, gender, and geographic areas in Tianjin, China, 1999–2006. Int J Stroke 4(3):169–174

    Article  CAS  PubMed  Google Scholar 

  • Watson BD, Ginsberg MD (1989) Ischemic injury in the brain. Role of oxygen radical-mediated processes. Ann N Y Acad Sci 559:269–281

    Article  CAS  PubMed  Google Scholar 

  • Zhao D, Liu J, Wang W, Zeng Z, Cheng J, Sun J, Wu Z (2008) Epidemiological transition of stroke in China: twenty-one-year observational study from the Sino-MONICA-Beijing Project. Stroke 39(6):1668–1674

    Article  PubMed  Google Scholar 

  • Zhu S, Evans S, Yan B, Povsic TJ, Tapson V, Goldschmidt-Clermont PJ, Dong C (2008) Transcriptional regulation of Bim by FOXO3a and Akt mediates scleroderma serum-induced apoptosis in endothelial progenitor cells. Circulation 118(21):2156–2165

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Natural Science Foundation of China (no. 81300720).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Junkang Jiang or Gang Cui.

Additional information

Yunfeng Wang, Chunhua Wan, Junkang Jiang, and Gang Cui have contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, Y., Wan, C., Yu, S. et al. Upregulated Expression of NF-YC Contributes to Neuronal Apoptosis via Proapoptotic Protein Bim in Rats’ Brain Hippocampus Following Middle Cerebral Artery Occlusion (MCAO). J Mol Neurosci 52, 552–565 (2014). https://doi.org/10.1007/s12031-013-0111-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12031-013-0111-8

Keywords

Navigation