Skip to main content
Log in

Cold-Inducible Protein RBM3 Protects UV Irradiation-Induced Apoptosis in Neuroblastoma Cells by Affecting p38 and JNK Pathways and Bcl2 Family Proteins

Journal of Molecular Neuroscience Aims and scope Submit manuscript

Cite this article


Induced by hypothermia, cold-inducible protein RBM3 (RNA-binding protein motif 3), has been implicated in neuroprotection against various toxic insults such as hypoxia and ischemia. However, whether mild hypothermia and RBM3 prevent neural cells from UV irradiation-elicited apoptosis is unclear. In the present study, human neuroblastoma cell line SH-SY5Y was used as a cell model for neural cell death, and it was demonstrated that mild hypothermia protects SH-SY5Y cells from UV irradiation-induced apoptosis. However, the protective effect of mild hypothermia was abrogated when RBM3 was silenced. Conversely, the overexpression of RBM3 rescued SH-SY5Y cells from UV-induced apoptosis, as indicated by the decreased levels of cleaved caspase-3 and PARP, and increased cell survival. The analysis on the mechanism underlying RBM3-mediated neuroprotection against UV insult showed that RBM3 could substantially block the activation of p38 and JNK signaling pathways. In addition, the overexpression of RBM3 reduced the expression of pro-apoptotic proteins Bax and Bad, leaving the pro-survival protein Bcl-2 unaffected. In conclusion, RBM3 is the key mediator of mild hypothermia-related protection against UV in neuroblastoma cells, and the neuroprotective effect might be exerted through interfering with pro-apoptotic signaling pathways p38 and JNK and regulating pro-apoptotic proteins Bax and Bad.

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.

Institutional subscriptions

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


  • Arias-Vasquez A, de Lau L, Pardo L, Liu F, Feng BJ, Bertoli-Avella A et al (2007) Relationship of the Ubiquilin 1 gene with Alzheimer's and Parkinson's disease and cognitive function. Neurosci Lett 424:1–5

    Article  CAS  PubMed  Google Scholar 

  • Baig S, Kehoe PG, Love S (2008) MMP-2, −3 and −9 levels and activity are not related to Abeta load in the frontal cortex in Alzheimer's disease. Neuropathol App Neurobiol 34:205–215

    Article  CAS  Google Scholar 

  • Bastide A, Peretti D, Knight JR, Grosso S, Spriggs RV, Pichon X et al (2017) RTN3 is a novel cold-induced protein and mediates neuroprotective effects of RBM3. Cur Biol 27:638–650

    Article  CAS  Google Scholar 

  • Caricchio R, McPhie L, Cohen PL (2003) Ultraviolet B radiation-induced cell death: critical role of ultraviolet dose in inflammation and lupus autoantigen redistribution. J Immunol 171:5778–5786

    Article  CAS  PubMed  Google Scholar 

  • Chip S, Zelmer A, Ogunshola OO, Felderhoff-Mueser U, Nitsch C, Buhrer C, Wellmann S (2011) The RNA-binding protein RBM3 is involved in hypothermia induced neuroprotection. Neurobiol Dis 43:388–396

    Article  CAS  PubMed  Google Scholar 

  • Darwazeh R, Yan Y (2013) Mild hypothermia as a treatment for central nervous system injuries: positive or negative effects. Neural Regen Res 8:2677–2686

    PubMed  PubMed Central  Google Scholar 

  • Dhanasekaran DN, Reddy EP (2008) JNK signaling in apoptosis. Oncogene 27:6245–6251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Enomoto A, Yamada J, Morita A, Miyagawa K (2017) Bisdemethoxycurcumin enhances X-ray-induced apoptosis possibly through p53/Bcl-2 pathway. Mutat Res 815:1–5

    Article  CAS  PubMed  Google Scholar 

  • Gupta M, Gupta SK, Hoffman B, Liebermann DA (2006) Gadd45a and Gadd45b protect hematopoietic cells from UV-induced apoptosis via distinct signaling pathways, including p38 activation and JNK inhibition. J Biol Chem 281:17552–17558

    Article  CAS  PubMed  Google Scholar 

  • Hypothermia after Cardiac Arrest Study Group (2002) Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 346:549–556

    Article  Google Scholar 

  • Islamov RR, Rizvanov AA, Mukhamedyarov MA, Salafutdinov II, Garanina EE, Fedotova VY et al (2015) Symptomatic improvement, increased life-span and sustained cell homing in amyotrophic lateral sclerosis after transplantation of human umbilical cord blood cells genetically modified with adeno-viral vectors expressing a neuro-protective factor and a neural cell adhesion molecule. Curr Gene Ther 15:266–276

    Article  CAS  PubMed  Google Scholar 

  • Jackson TC, Manole MD, Kotermanski SE, Jackson EK, Clark RS, Kochanek PM (2015) Cold stress protein RBM3 responds to temperature change in an ultra-sensitive manner in young neurons. Neuroscience 305:268–278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kang ES, Iwata K, Ikami K, Ham SA, Kim HJ, Chang KC et al (2011) Aldose reductase in keratinocytes attenuates cellular apoptosis and senescence induced by UV radiation. Free Radic Biol Med 50:680–688

    Article  CAS  PubMed  Google Scholar 

  • Kim W, Yang HJ, Youn H, Yun YJ, Seong KM, Youn B (2010) Myricetin inhibits Akt survival signaling and induces bad-mediated apoptosis in a low dose ultraviolet (UV)-B-irradiated HaCaT human immortalized keratinocytes. J Radiat Res 51:285–296

    Article  CAS  PubMed  Google Scholar 

  • Kontos CK, Christodoulou MI, Scorilas A (2014) Apoptosis-related BCL2-family members: key players in chemotherapy. Anti Cancer Agents Med Chem 14:353–374

    Article  CAS  Google Scholar 

  • Kwon SH, Kim JA, Hong SI, Jung YH, Kim HC, Lee SY, Jang CG (2011) Loganin protects against hydrogen peroxide-induced apoptosis by inhibiting phosphorylation of JNK, p38, and ERK 1/2 MAPKs in SH-SY5Y cells. Neurochem Int 58:533–541

    Article  CAS  PubMed  Google Scholar 

  • Li G, Gleinich A, Lau H, Zimmermann M (2012) Staurosporine-induced apoptosis presents with unexpected cholinergic effects in a differentiated neuroblastoma cell line. Neurochem Int 61:1011–1020

    Article  CAS  PubMed  Google Scholar 

  • Li S, Guan H, Qian Z, Sun Y, Gao C, Li G et al (2017) Taurine inhibits 2,5-hexanedione-induced oxidative stress and mitochondria-dependent apoptosis in PC12 cells. Ind Health 55:108–118

    Article  PubMed  Google Scholar 

  • Liu J, Lin A (2005) Role of JNK activation in apoptosis: a double-edged sword. Cell Res 15:36–42

    Article  PubMed  Google Scholar 

  • Liu S, Geng X, Forreider B, Xiao Y, Kong Q, Ding Y, Ji X (2015) Enhanced beneficial effects of mild hypothermia by phenothiazine drugs in stroke therapy. Neurol Res 37:454–460

    Article  CAS  PubMed  Google Scholar 

  • Ma SP, Fei J, Zhang YP, Shi X, Zhuang RJ, Xue H et al (2017) Cold-inducible protein RBM3 protects neuroblastoma cells from retinoic acid-induced apoptosis via AMPK, p38 and JNK signaling. J Funct Foods 35:175–184

    Article  CAS  Google Scholar 

  • Maekawa T, Yamashita S, Nagao S, Hayashi N, Ohashi Y, Brain-Hypothermia Study G (2015) Prolonged mild therapeutic hypothermia versus fever control with tight hemodynamic monitoring and slow rewarming in patients with severe traumatic brain injury: a randomized controlled trial. J Neurotrauma 32:422–429

    Article  PubMed  PubMed Central  Google Scholar 

  • Papadima EM, Niola P, Melis C, Pisanu C, Congiu D, Cruceanu C, Lopez JP, Turecki G, Ardau R, Severino G, Chillotti C, Del Zompo M, Squassina A (2017) Evidence towards RNA binding motif (RNP1, RRM) protein 3 (RBM3) as a potential biomarker of lithium response in bipolar disorder patients. J Mol Neurosci 62:304-308

  • Peretti D, Bastide A, Radford H, Verity N, Molloy C, Marti MG et al (2015) RBM3 mediates structural plasticity and protective effects of cooling in neurodegeneration. Nature 518:236–239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Phul RK, Shaw PJ, Ince PG, Smith ME (2000) Expression of nitric oxide synthase isoforms in spinal cord in amyotrophic lateral sclerosis amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the world Federation of Neurology, Research Group on Motor Neuron Diseases 1:259–267

  • Pilotte J, Dupont-Versteegden EE, Vanderklish PW (2011) Widespread regulation of miRNA biogenesis at the dicer step by the cold-inducible RNA-binding protein, RBM3. PLoS One 6:e28446

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sterz F, Holzer M, Roine R, Zeiner A, Losert H, Eisenburger P, Uray T, Behringer W (2003) Hypothermia after cardiac arrest: a treatment that works. Curr Opin Crit Care 9:205–210

  • Talma N, Kok WF, de Veij Mestdagh CF, Shanbhag NC, Bouma HR, Henning RH (2016) Neuroprotective hypothermia - why keep your head cool during ischemia and reperfusion. Biochim Biophys Acta 1860:2521–2528

    Article  CAS  PubMed  Google Scholar 

  • Tolosa L, Mir M, Olmos G, Llado J (2009) Vascular endothelial growth factor protects motoneurons from serum deprivation-induced cell death through phosphatidylinositol 3-kinase-mediated p38 mitogen-activated protein kinase inhibition. Neuroscience 158:1348–1355

    Article  CAS  PubMed  Google Scholar 

  • Wellmann S, Truss M, Bruder E, Tornillo L, Zelmer A, Seeger K, Buhrer C (2010) The RNA-binding protein RBM3 is required for cell proliferation and protects against serum deprivation-induced cell death. Pediatr Res 67:35–41

    Article  CAS  PubMed  Google Scholar 

  • Wu X, Gu W, Lu H, Liu C, Yu B, Xu H et al (2016) Soluble receptor for advanced glycation end product ameliorates chronic intermittent hypoxia induced renal injury, inflammation, and apoptosis via P38/JNK signaling pathways. Oxidative Med Cell Longev 2016:1015390

    Google Scholar 

  • Yang H, Xia Y, Lu SQ, Soong TW, Feng ZW (2008) Basic fibroblast growth factor-induced neuronal differentiation of mouse bone marrow stromal cells requires FGFR-1, MAPK/ERK, and transcription factor AP-1. J Biol Chem 283:5287–5295

    Article  CAS  PubMed  Google Scholar 

  • Yang HJ, Ma SP, Ju F, Zhang YP, Li ZC, Zhang BB et al (2016) Thrombospondin-4 promotes neuronal differentiation of NG2 cells via the ERK/MAPK pathway. J Mol Neurosci 60:517–524

    Article  CAS  PubMed  Google Scholar 

  • Yang HJ, Ju F, Guo XX, Ma SP, Wang L, Cheng BF et al (2017) RNA-binding protein RBM3 prevents NO-induced apoptosis in human neuroblastoma cells by modulating p38 signaling and miR-143. Sci Rep 7:41738

    Article  PubMed  PubMed Central  Google Scholar 

  • Yin X, Cao L, Kang R, Yang M, Wang Z, Peng Y et al (2011) UV irradiation resistance-associated gene suppresses apoptosis by interfering with BAX activation. EMBO Rep 12:727–734

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zarubin T, Han J (2005) Activation and signaling of the p38 MAP kinase pathway. Cell Res 15:11–18

    Article  CAS  PubMed  Google Scholar 

  • Zhang JC, Lu W, Xie XM, Pan H, Wu ZQ, Yang GT (2016) Mild hypothermia attenuates post-resuscitation brain injury through a V-ATPase mechanism in a rat model of cardiac arrest. Genet Mol Res 15(2).

  • Zhu X, Buhrer C, Wellmann S (2016a) Cold-inducible proteins CIRP and RBM3, a unique couple with activities far beyond the cold. Cel Mol Life Sci 73:3839–3859

    Article  CAS  Google Scholar 

  • Zhu X, Zelmer A, Kapfhammer JP, Wellmann S (2016b) Cold-inducible RBM3 inhibits PERK phosphorylation through cooperation with NF90 to protect cells from endoplasmic reticulum stress. FASEB J 30:624–634

    Article  CAS  PubMed  Google Scholar 

Download references


We thank LetPub ( for the linguistic assistance during the preparation of this manuscript. This work was sponsored by National Natural Science Foundation of China (81771336), Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine (XTCX-2015-ZD3), Disciplinary group of Psychology and Neuroscience of Xinxiang Medical University, Henan Key Laboratory of Biological Psychiatry (ZDSYS2015005), Graduate Scientific Research Innovation Support Project of Xinxiang Medical University (YJSCX201649Y), Henan Program for Science and Technology Development (162102310490), and Henan Educational Committee Program for Science and Technology Development of Universities (16A180015).

Author information

Authors and Affiliations


Corresponding authors

Correspondence to Zhi-Wei Feng or Hai-Jie Yang.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Electronic supplementary material

Fig. S1

UV irradiation induces cytotoxicity in SH-SY5Y neuroblastoma cells. Cells were treated UV irradiation at various doses and cell viability was assessed by MTT assay. ***p < 0.001 versus control group. All results shown are representative of three independent experiments. (GIF 18 kb)

High resolution image (TIFF 523 kb)

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhuang, RJ., Ma, J., Shi, X. et al. Cold-Inducible Protein RBM3 Protects UV Irradiation-Induced Apoptosis in Neuroblastoma Cells by Affecting p38 and JNK Pathways and Bcl2 Family Proteins. J Mol Neurosci 63, 142–151 (2017).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: