Chinese Journal of Physiology

: 2019  |  Volume : 62  |  Issue : 2  |  Page : 63--69

Knockdown of protein kinase CK2 blocked gene expression mediated by brain-derived neurotrophic factor-induced serum response element

Shu-Ping Yang1, Chi-Yi Lo1, Hui-Min Tseng1, Chih-Chang Chao2,  
1 Institute of Neurosciences, National Chengchi University, Taipei, Taiwan
2 Institute of Neurosciences, National Chengchi University; Research Center for Mind, Brian and Learning, National Chengchi University, Taipei, Taiwan

Correspondence Address:
Dr. Chih-Chang Chao
Institute of Neurosciences, National Chengchi University, Taipei; Research Center for Mind, Brian and Learning, National Chengchi University, Taipei


One of the principal signaling pathway outcomes from brain-derived neurotrophic factor (BDNF) is the activation of antiapoptotic pathways. In addition to the role of extracellular signal-regulated kinase 1/2 and phosphatidylinositol-3 kinase, BDNF activates protein kinase CK2 to mediate its neuroprotective effect. The inhibition of CK2 activity has been shown to induce apoptosis. Although serum response element (SRE)-mediated transcription has been reported to be activated by BDNF and that the phosphorylation of serum response factor (SRF) by CK2 has been shown to enhance its DNA binding activity, the biological relevance of these interactions remains largely unclear. In the present study, we found that SRE-mediated transcription, CK2 activity, and SRF phosphorylation increased in PC12 cells under BDNF treatment. The transfection of CK2α siRNA blocked the enhancing effect of BDNF on SRE-mediated transcription, SRF phosphorylation, and Mcl-1 gene expression. Moreover, the blockade of CK2 diminished the antiapoptotic effects of BDNF on SRE-mediated transcription, Mcl-1 gene expression, and cell viability under rotenone-induced cytotoxicity. Our data may assist in the development of therapeutic strategies for inhibiting apoptosis during neurodegeneration.

How to cite this article:
Yang SP, Lo CY, Tseng HM, Chao CC. Knockdown of protein kinase CK2 blocked gene expression mediated by brain-derived neurotrophic factor-induced serum response element.Chin J Physiol 2019;62:63-69

How to cite this URL:
Yang SP, Lo CY, Tseng HM, Chao CC. Knockdown of protein kinase CK2 blocked gene expression mediated by brain-derived neurotrophic factor-induced serum response element. Chin J Physiol [serial online] 2019 [cited 2019 May 24 ];62:63-69
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Full Text


Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family and is widely distributed in the mammalian brain. Its multiprominent functions include control of neuronal development, modulation of synaptic communication, and neuroprotection. Such a wide spectrum of processes can be explained by the triggering of several signaling pathways.[1],[2] One of the principal signaling pathway outcomes from BDNF is the activation of antiapoptotic pathways. BDNF protects neurons from hypoxia-ischemia injury or phencyclidine-induced cell death through the mediation of extracellular signal-regulated kinase 1/2 (ERK1/2) or phosphatidylinositol-3 kinase (PI3-K) pathways.[3],[4] In addition to the role of ERK1/2 and PI3-K, BDNF activates protein kinase CK2 (formally termed casein kinase II) to mediate its neuroprotective effect.[5]

Protein kinase CK2 is a ubiquitous and multifunctional serine/threonine protein kinase composed of 2 catalytic α or α' subunits and 2 regulatory β subunits.[6] Inhibition of CK2 activity has been shown to induce apoptosis in cancer cells and thus plays a key role in suppressing apoptosis.[7],[8] The global mechanism for inhibiting caspase signaling pathways during apoptosis is thought to be through CK2-mediated phosphorylation.[9] The inhibition of CK2 activity reduces phosphorylation levels of an apoptosis repressor and renders cancer cells susceptible to apoptosis.[10] Moreover, CK2 enhances cell survival through the phosphorylation of the transcription factor NF-κB or serum response factor (SRF) and the subsequent activation of NF-κB- or SRF-mediated pathways.[11],[12]

The transcription factor SRF is activated by serum growth factors and intracellular calcium. In resting cells, SRF mediates the rapid activation of the immediate-early gene c-fos.[13] The mitogen-activated protein kinase, Ca2+/calmodulin-dependent kinase, and Rho/actin signaling cascades can trigger SRF-mediated downstream signaling[14] through SRF binding to the serum response element (SRE) in respective promoter regions.[15] In addition to the role of SRF in the regulation of cell growth and differentiation, SRF deficiency leads to decreased antiapoptotic Bcl-2 gene expression during development or MPTP-induced oxidative stress.[16]

Although SRE-mediated transcription is activated by BDNF[17] and the phosphorylation of SRF by CK2 enhances the DNA binding activity of SRF in vitro,[18],[19] the biological relevance of these interactions remains unclear. The aim of our study was to determine whether CK2 is involved in the neuroprotective effects of BDNF through the regulation of SRE-mediated transcription.

 Materials and Methods

Cell culture

Rat pheochromocytoma (PC12) cells were cultured on the plate precoated with poly-L-lysine and maintained in Dulbecco's modified Eagle's Medium (DMEM) (Gibco) containing 5% fetal bovine serum (FBS) (Gibco) and 10% horse serum (Invitrogen). Cells were incubated at 37°C in a humidified atmosphere with 5% CO2.

Plasmid construction, siRNA, and transfection

The constructed pGL2-5X SRE-SV40pr by cloning 5 SREs containing ETS-binding sites in front of the SV40 late promoter, and the following firefly luciferase gene of pGL2-Promoter plasmid (Promega) was provided by Dr. Eminy HY Lee.[20] Two sets of CK2α siRNA were used in our previous study.[5] Silencer Negative Control #1 siRNA was used as a control (Ambion). The plasmid and siRNA were transfected to PC12 cells using the Lipofectamine 2000 Transfection Reagent (Invitrogen).

Kinase activity assay

The CK2 enzyme activity assay was performed using the CycLexA CK2 Assay/Inhibitor Screening Kit (MBL International Corporation) according to the manufacturer's instructions. The principle of the experiment was to add a cell extract protein containing CK2 to react with the receptor proteins p53 and ATP and then to use peroxidase-coupled antiphospho-p53 serine46 monoclonal antibody as a reporter molecule, adding cold light reagent to detect cold light signal intensity using the Victor X4 Multilabel Plate Reader (Perkin Elmer).

Promoter-luciferase assay

PC12 cells seeded at a density of 5.4 × 105 cells per well in 12-well clusters were cotransfected with 0.5 μg of pGL2-5X SRE-SV40pr plasmid and 50 ng of internal control Renilla luciferase-encoding plasmid phRG-TK (or cotransfected with siRNA). After 36 h, the medium was replaced with DMEM containing 0.5% FBS. Cells were incubated for 12 h and then subjected to a normal medium (or one containing BDNF) for 6 h for a luciferase activity assay using the FB12 Luminometer (Berthold) with the Dual-Glo Luciferase Assay System (Promega). The ratio of firefly luciferase activity to Renilla luciferase activity was calculated and normalized to the vector control.

Real-time quantitative polymerase chain reaction

Total RNA was isolated from cells as per our previous study.[5] Real-time quantitative polymerase chain reaction (qPCR) analysis was performed using the Applied Biosystems 7300 real-time PCR system with the SYBR Green method according to the instruction manual (Life Technologies). The forward and reverse primer sequences for Mcl-1 mRNA were 5'-CTTATTTCTTTTGGTGCCTTTGTG-3' and 5'-TCGATGCAGCTTTCTTGGTTT-3', respectively. The endogenous hypoxanthine phosphoribosyl transferase (HPRT) gene was used as an internal control. The forward and reverse primer sequences used were 5'-GCCGACCGGTTCTGTCAT-3' and 5'-TCATAACCTGGTTCATCATCACTAATC-3', respectively. The amount of Mcl-1 and HPRT mRNA from each sample was measured simultaneously in separate reactions.

Western blotting

The cells were lysed in a RIPA buffer (50 mM Tris-HCl, 150 mM NaCl, 2 mM EDTA, and 1% IGEPAL CA-630, pH 7.4) with Protease Inhibitor Cocktail Set I (Calbiochem) and the protein Phosphatase Inhibitor Cocktail Set IV (Calbiochem). Equal amounts of lysate samples (20 μg of protein) were subjected to 10% SDS-PAGE and transferred to PVDF membranes (Millipore). The PVDF membranes were blocked with 2% BSA in 0.05% Tween 20 Tris-buffered saline buffer before incubation with one of the following primary antibodies: Anti-pS103SRF (1:1000; Cell Signaling), anti-SRF (1:1000; Millipore), anti-CK2α (1:4000; Abcam), or anti-β-actin (1:10,000; Millipore). A horseradish peroxidase (HRP)-conjugated secondary antibody (Perkin Elmer) was used for all Western blots. The protein bands were visualized using a chemiluminescent HRP substrate and the X-Lite Imaging System (Avegene, Taipei, Taiwan). The density of each band was quantified using ImageJ (NIH).

3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay

Cells were incubated with 3-(4,5-dimethythiazol- 2-yl)-2,5-diphenyl tetrazolium bromide (MTT) reagent (Sigma-Aldrich) at 37°C for 4 h. The amount of MTT formazan product was quantified by measuring its absorbance at 570 and 630 nm using the Victor X4 Multilabel Plate Reader (Perkin Elmer).

Statistical analyses

The data in the present study were evaluated using either Student's t test or a one-way ANOVA, followed by a post hoc Newman–Keuls multiple comparison test, the results of which are expressed as q values.


Brain-derived neurotrophic factor enhances serum response element-mediated transcription, CK2 activity, and serum response factor phosphorylation

We first examined the effect of BDNF on SRE-mediated gene expression and CK2α enzyme activity. The luciferase assay results revealed that BDNF significantly increased SRE-mediated gene expression [t1,16 = 9.8, P < 0.001; [Figure 1]a. Although the total CK2α protein level did not increase [t1,10 = 0.59, P > 0.05; [Figure 1]b, the BDNF treatment increased CK2 enzyme activity [t1,16 = 20.4, P < 0.001; [Figure 1]c. Because CK2 was shown to phosphorylate SRF at Ser103 and upregulate its transcriptional activity, we also examined the effect of BDNF on SRF phosphorylation at this residue. The BDNF treatment also increased SRF phosphorylation at Ser103 (identical to Ser99 of human SRF) [t1,16 = 6.0, P < 0.001; [Figure 1]d.{Figure 1}

CK2 regulated serum response element-mediated transcription, serum response factor phosphorylation, and Mcl-1 gene expression

To demonstrate that SRE-mediated gene expression can be regulated by CK2, CK2α siRNA was used to knockdown CK2α protein expression. The results revealed that CK2α siRNA transfection reduced CK2α protein levels [t1,16 = 14.3, P < 0.001; [Figure 2]a. Cotransfection of pGL2-5X SRE-SV40pr plasmid with CK2α siRNA reduced luciferase activity compared with pGL2-5X SRE-SV40pr plasmid transfection alone [t1,16 = 11.7, P < 0.001; [Figure 2]b, and SRF phosphorylation at Ser99 also decreased in the CK2α siRNA treatment group [t1,16 = 3.67, P < 0.01; [Figure 2]c. Because the SRE element was identified in the promoter region of the antiapoptotic Mcl-1 gene, the expression of the Mcl-1 gene was examined using qPCR. The results demonstrated that the Mcl-1 mRNA level was lower in the cells transfected with CK2α siRNA compared with the control cells [t1,16 = 12.1, P < 0.001; [Figure 2]d.{Figure 2}

CK2-mediated the effects of brain-derived neurotrophic factor on serum response element-mediated transcription, serum response factor phosphorylation, and Mcl-1 gene expression

We then examined whether CK2 mediates the effect of BDNF on SRE-mediated gene expression. The results revealed that BDNF consistently increased luciferase activity [F3,38 = 264.3, P < 0.001; q = 20.0, P < 0.001; [Figure 3]a and that CK2α siRNA decreased luciferase activity (q = 16.9, P < 0.001). However, CK2α siRNA further antagonized the effect of BDNF on luciferase activity (q = 32.5, P < 0.001, comparing the BDNF + CK2α siRNA group and BDNF group). Similar results were obtained with SRF phosphorylation; BDNF increased the level of SRF phosphorylation (F3,38 = 61.7, q = 10.6, P < 0.001). CK2α siRNA alone decreased this level (q = 7.57, P < 0.001), but it also blocked the effect of BDNF on SRF phosphorylation [q = 10.9, P < 0.001; comparing the BDNF + CK2α siRNA group and BDNF group; [Figure 3]b. In analyzing the Mcl-1 mRNA level, we revealed that BDNF consistently increased Mcl-1 mRNA expression [F3,33 = 80.2, P < 0.001; q = 16.0, P < 0.001; [Figure 3]c. Moreover, CK2α siRNA alone reduced the Mcl-1 mRNA level (q = 5.55, P < 0.001), but it antagonized the effect of BDNF on Mcl-1 mRNA expression (q = 11.9, P < 0.001; comparing the BDNF + CK2α siRNA group and BDNF group).{Figure 3}

CK2-mediated signaling of brain-derived neurotrophic factor protected cell survival under rotenone-induced cytotoxicity

To determine whether this CK2-mediated signaling contributes to the protective effects of BDNF under stressful stimuli, we examined the signaling pathway under rotenone treatment, because this neurotoxin is widely applied in experimental models of Parkinson disease.[21] CK2α siRNA was transfected into PC12 cells. Transfection occurred for 48 h and then we added BDNF to the medium for 6 h. The cells were then treated with rotenone and incubated for 24 h. The results from the luciferase activity assay showed that rotenone treatment significantly reduced SRE-mediated transcription compared with the control group [F4,50 = 192.3, P < 0.001; q = 28.9, P < 0.001; [Figure 4]a and CK2α siRNA aggravated this reduction (q = 6.1, P < 0.001 compared with the rotenone group). Prior BDNF treatment prevented rotenone-induced reduction (q = 13.6, P < 0.001 compared with the rotenone group), but CK2α siRNA blocked the reversal effect of BDNF (q = 11.6, P < 0.001; compared with the BDNF group). Moreover, a qPCR analysis revealed that the Mcl-1 mRNA level decreased under rotenone treatment compared with that in the control group [F4,30 = 134.6, P < 0.001; q = 19.9, P < 0.001; [Figure 4]b and CK2α siRNA exacerbated this reduction (q = 9.4, P < 0.001 compared with the rotenone group). However, rotenone-induced reduction was prevented by prior BDNF treatment (q = 14.4, P < 0.001 compared with the rotenone group). However, CK2α siRNA blocked this preventative effect of BDNF (q = 9.8, P < 0.001 compared with the BDNF group). Furthermore, rotenone treatment reduced cell viability [F4,49 = 174.1, P < 0.001; q = 21.3, P < 0.001; compared with the control group; [Figure 4]c and CK2α siRNA encouraged this reduction (q = 13.1, P < 0.001 compared with the rotenone group). However, prior BDNF treatment promoted cell viability compared with rotenone treatment alone (q = 12.5, P < 0.001). The blockade of CK2α by siRNA diminished the protective effect of BDNF on cell survival (q = 13.8, P < 0.001). In order to verify the protective signaling by BDNF is activated under the rotenone-induced stress, we examined the Akt phosphorylation at Ser473 residue. The rotenone treatment decreased Akt phosphorylation but prior BDNF treatment prevented this reduction [Figure 4]d.{Figure 4}


The present study demonstrated that the activation of SRE-mediated gene transcription by BDNF can be blocked through knockdown of protein kinase CK2. This result is consistent with the previous study showed that SRE-mediated gene expression as a downstream for the neuroprotective mechanism of BDNF[17] and CK2 signaling is an alternative pathway, enabling BDNF to produce its effect independent of ERK1/2 and PI3-K activation.[5] Severe impairment of SRE-driven promoter activity was observed in apoptotic cells through the activation of death receptors.[22] A set of genes that have SRF sites in their promoters are also repressed in breast epithelial cells under Myc-induced apoptosis.[23] In the present study, SRE-driven luciferase activity significantly decreased under the rotenone treatment, parallel with cell viability, but was restored by the BDNF treatment. These results are consistent with a study that reported that the knockdown of SRF augmented rotenone-induced toxicity[24] and a study that reported that BDNF secreted from astrocytes significantly attenuated rotenone-induced DA neuron injury in vitro.[25]

The PI3-K/Akt and ERK1/2 pathways are thought to be predominant downstream cascades of BDNF that control numerous prosurvival mechanisms, such as CREB-Bcl-2 and NFκB-Bcl-xL expressions.[1] In our previous study, we showed that BDNF, as an alternative pathway, could enhance Bcl-xL expression through CK2-NFκB signaling[5] and CK2 also increased apoptotic Mcl-1 gene expression in an SRF-dependent manner.[12] Inhibition CK2 is reported to cause elevated levels of ROS and mitochondrial dysfunction.[26] Furthermore, aripiprazole, an atypical antipsychotic drug, has been reported to restore reduced BDNF and phospho-CK2α expression caused by Aβ1-42.[27] Our current results also showed that BDNF-induced SRF phosphorylation was reduced by the knockdown of CK2. Taken together, these results indicate that CK2-mediated signaling contributes to the antiapoptotic effects of BDNF. BDNF is known to possess other neuroprotective effects including anti-oxidation and suppression of autophagy.[28] Further, BDNF enhances sestrin2 expression to confer neuronal resistance against oxidative stress through activation of PKG/NF-κB signaling pathway.[29] Whether CK2 signaling cascades cross-talk with other BDNF-activated signaling pathways to regulate neuroprotective effects warrants further investigation.

The promoter of Mcl-1 contains a functional SRE.[30] The reduction in Mcl-1 gene expression and induction of apoptosis were found in smooth muscle cells by the silence of SRF.[31] Furthermore, overexpression of SRF cofactor MRTF-A was found to trigger the transcription activity of the Mcl-1 reporter gene in cortical neurons.[32] The blockade of SRF reversed the subtle dosage of a glutamate-induced increase in Mcl-1 protein level.[12] Thus, the above-mentioned studies have suggested that the regulation of Mcl-1 gene expression occurs in an SRF-dependent manner. In addition to SRF, the phosphorylation of STAT1 by CK2 or SGK has been shown to promote Mcl-1 gene expression.[33],[34] Mcl-1 gene expression was also downregulated under CREB suppression.[35],[36] How SRF synergizes with other transcription factors to upregulate Mcl-1 gene expression warrants further investigation. In addition, an increase in Mcl-1 mRNA and protein levels in AICAR-preconditioned cortical neurons was reported.[37] Such antiapoptotic functions in diseased cells suggest that Mcl-1 is a potential target for clinical therapy.


In summary, the blockade of CK2 inhibited BDNF-induced SRE-mediated transcription, such as antiapoptotic Mcl-1 gene expression. Our findings suggest an alternative cellular mechanism for the attenuation of cell death, which may assist in the development of therapeutic strategies for inhibiting apoptosis.


The authors would like to thank Dr. Eminy HY Lee from the Institute of Biomedical Sciences, Academia Sinica in Taiwan for providing plasmids. This manuscript was edited by Wallace Academic Editing.

Financial support and sponsorship

This work was supported by a grant from the Ministry of Science and Technology, Taiwan, Republic of China (NSC 96-2320-B-320-012-MY2).

Conflicts of interest

There are no conflicts of interest.


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