Skip to main content
Log in

GADD45A induces neuropathic pain by activating P53 apoptosis pathway in mice

  • Research Article
  • Published:
Genes & Genomics Aims and scope Submit manuscript

Abstract

Background

Neuropathic pain is a common condition with current heights of varying etiology. The therapeutic drugs are also poorly work and often limited by side effects such as dizziness.

Objective

This study aimed to explore the function mechanism of GADD45A in neuropathic pain.

Methods

The DEGs in neuropathic pain mouse model chip were screened by bioinformatics analysis. The expression of GADD45A in SNL model was determined by RT-qPCR and Immunofluorescence assay. The protein expression of p53-apoptosis pathway proteins was determined by western blotting.

Results

Combination analysis of bioinformatics methods revealed that the expression of GADD45A was upregulated in SNL. The results of RT-qPCR assay and Immunofluorescence assay revealed that GADD45A was overexpressed in all of time points SNL model. Furthermore, knockdown of GADD45A in SNL remarkably antagonized the malignance phenotype compared with the Ad-GFP treated SNL. In addition, knockdown of GADD45A downregulated the expression of p53 and reduced the apoptosis of spinal cord nerve cells.

Conclusions

Our study suggests that GADD45A may be a biomarker in the neuropathic pain of mice.

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

Similar content being viewed by others

References

  • Abdollahi A, Lord KA, Hoffman-Liebermann B, Liebermann DA (1991) Sequence and expression of a cDNA encoding MyD118: a novel myeloid differentiation primary response gene induced by multiple cytokines. Oncogene 6:165–167

    CAS  PubMed  Google Scholar 

  • Audic S, Claverie JM (1997) The significance of digital gene expression profiles. Genome Res 7:986–995

    Article  CAS  Google Scholar 

  • Beadling C, Johnson KW, Smith KA (1993) Isolation of interleukin 2-induced immediate-early genes. Proc Natl Acad Sci USA 90:2719–2723

    Article  CAS  Google Scholar 

  • Befort K, Karchewski L, Lanoue C, Woolf CJ (2003) Selective up-regulation of the growth arrest DNA damage-inducible gene Gadd45 alpha in sensory and motor neurons after peripheral nerve injury. Eur J Neurosci 18:911–922

    Article  Google Scholar 

  • Burke D, Fullen BM, Stokes D, Lennon O (2017) Neuropathic pain prevalence following spinal cord injury: a systematic review and meta-analysis. Eur J Pain 21:29–44

    Article  CAS  Google Scholar 

  • Chen YC, Pristera A, Ayub M, Swanwick RS, Karu K, Hamada Y, Rice AS, Okuse K (2013) Identification of a receptor for neuropeptide VGF and its role in neuropathic pain. J Biol Chem 288:34638–34646

    Article  CAS  Google Scholar 

  • Chi F, Wang Z, Li Y, Chang N (2020) Knockdown of GINS2 inhibits proliferation and promotes apoptosis through the p53/GADD45A pathway in non-small-cell lung cancer. Biosci Rep 40

  • Dong L, Yu L, Bai C, Liu L, Long H, Shi L, Lin Z (2018) USP27-mediated cyclin E stabilization drives cell cycle progression and hepatocellular tumorigenesis. Oncogene 37:2702–2713

    Article  CAS  Google Scholar 

  • Dong L, Yu L, Li H, Shi L, Luo Z, Zhao H, Liu Z, Yin G, Yan X, Lin Z (2020) An NAD(+)-dependent deacetylase SIRT7 promotes HCC development through deacetylation of USP39. iScience 23:101351

  • Fornace AJ Jr, Nebert DW, Hollander MC, Luethy JD, Papathanasiou M, Fargnoli J, Holbrook NJ (1989) Mammalian genes coordinately regulated by growth arrest signals and DNA-damaging agents. Mol Cell Biol 9:4196–4203

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gao Y, Sun N, Wang L, Wu Y, Ma L, Hong J, Ren J, Zhu B, Yu L, Yan M (2018) Bioinformatics analysis identifies p53 as a candidate prognostic biomarker for neuropathic pain. Front Genet 9:320

    Article  Google Scholar 

  • Han N, Yuan F, Xian P, Liu N, Liu J, Zhang H, Zhang H, Yao K, Yuan G (2019) GADD45a mediated cell cycle inhibition is regulated by P53 in bladder cancer. Onco Targets Ther 12:7591–7599

    Article  CAS  Google Scholar 

  • Hildesheim J, Bulavin DV, Anver MR, Alvord WG, Hollander MC, Vardanian L, Fornace AJ Jr (2002) Gadd45a protects against UV irradiation-induced skin tumors, and promotes apoptosis and stress signaling via MAPK and p53. Cancer Res 62:7305–7315

    CAS  PubMed  Google Scholar 

  • Hollander MC, Kovalsky O, Salvador JM, Kim KE, Patterson AD, Haines DC, Fornace AJ Jr (2001) Dimethylbenzanthracene carcinogenesis in Gadd45a-null mice is associated with decreased DNA repair and increased mutation frequency. Cancer Res 61:2487–2491

    CAS  PubMed  Google Scholar 

  • Jang EH, Bae YH, Yang EM, Gim Y, Suh HJ, Kim S, Park SM, Park JB, Hur EM (2021) Comparing axon regeneration in male and female mice after peripheral nerve injury. J Neurosci Res 99:2874–2887

    Article  CAS  Google Scholar 

  • Jiang T, Soprano DR, Soprano KJ (2007) GADD45A is a mediator of CD437 induced apoptosis in ovarian carcinoma cells. J Cell Physiol 212:771–779

    Article  CAS  Google Scholar 

  • Jin S, Mazzacurati L, Zhu X, Tong T, Song Y, Shujuan S, Petrik KL, Rajasekaran B, Wu M, Zhan Q (2003) Gadd45a contributes to p53 stabilization in response to DNA damage. Oncogene 22:8536–8540

    Article  CAS  Google Scholar 

  • Lin CR, Yang CH, Huang CE, Wu CH, Chen YS, Sheen-Chen SM, Huang HW, Chen KH (2011) GADD45A protects against cell death in dorsal root ganglion neurons following peripheral nerve injury. J Neurosci Res 89:689–699

    Article  CAS  Google Scholar 

  • Liu C, Liu H, Sun Q, Zhang P (2021) MicroRNA 1283 alleviates cardiomyocyte damage caused by hypoxia /reoxygenation via targeting GADD45A and inactivating the JNK and p38 MAPK signaling pathways. Kardiol Pol 79:147–155

    Article  Google Scholar 

  • Lu G, Xu H, Zhao W, Zhang J, Rao D, Xu S (2018) Upregulation of long noncoding RNA Gadd45a is associated with sevoflurane-induced neurotoxicity in rat neural stem cells. NeuroReport 29:605–614

    Article  CAS  Google Scholar 

  • Malumbres M, Barbacid M (2009) Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer 9:153–166

    Article  CAS  Google Scholar 

  • Nagy A, Lanczky A, Menyhart O, Gyorffy B (2018) Validation of miRNA prognostic power in hepatocellular carcinoma using expression data of independent datasets. Sci Rep 8:9227

    Article  Google Scholar 

  • Sakai A, Saitow F, Miyake N, Miyake K, Shimada T, Suzuki H (2013) miR-7a alleviates the maintenance of neuropathic pain through regulation of neuronal excitability. Brain 136:2738–2750

    Article  Google Scholar 

  • Sakai A, Suzuki H (2013) Nerve injury-induced upregulation of miR-21 in the primary sensory neurons contributes to neuropathic pain in rats. Biochem Biophys Res Commun 435:176–181

    Article  CAS  Google Scholar 

  • Salvador JM, Brown-Clay JD, Fornace AJ Jr (2013) Gadd45 in stress signaling, cell cycle control, and apoptosis. Adv Exp Med Biol 793:1–19

    Article  CAS  Google Scholar 

  • Salvador JM, Hollander MC, Nguyen AT, Kopp JB, Barisoni L, Moore JK, Ashwell JD, Fornace AJ Jr (2002) Mice lacking the p53-effector gene Gadd45a develop a lupus-like syndrome. Immunity 16:499–508

    Article  CAS  Google Scholar 

  • Smyth GK, Speed T (2003) Normalization of cDNA microarray data. Methods 31:265–273

    Article  CAS  Google Scholar 

  • Wang H, Huang Z, Zhao X, Guo B, Ji Z (2020) miR-4270 regulates cell proliferation and apoptosis in patients with Sertoli cell-only syndrome by targeting GADD45A and inactivating the NOTCH signaling pathway. Am J Transl Res 12:5730–5740

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang XW, Zhan Q, Coursen JD, Khan MA, Kontny HU, Yu L, Hollander MC, O’Connor PM, Fornace AJ Jr, Harris CC (1999) GADD45 induction of a G2/M cell cycle checkpoint. Proc Natl Acad Sci USA 96:3706–3711

    Article  CAS  Google Scholar 

  • Yamashita A, Matsuoka Y, Matsuda M, Kawai K, Sawa T, Amaya F (2019) Dysregulation of p53 and parkin induce mitochondrial dysfunction and leads to the diabetic neuropathic pain. Neuroscience 416:9–19

    Article  CAS  Google Scholar 

  • Yang YH, Dudoit S, Luu P, Lin DM, Peng V, Ngai J, Speed TP (2002) Normalization for cDNA microarray data: a robust composite method addressing single and multiple slide systematic variation. Nucleic Acids Res 30:e15

  • Yuan C, Liu X, Liu X, Yang N, Liu Z, Yan S, Shen K, Kong B (2015) The GADD45A (1506T>C) polymorphism is associated with ovarian cancer susceptibility and prognosis. PLoS One 10:e0138692

  • Zhan Q, Antinore MJ, Wang XW, Carrier F, Smith ML, Harris CC, Fornace AJ Jr (1999) Association with Cdc2 and inhibition of Cdc2/Cyclin B1 kinase activity by the p53-regulated protein Gadd45. Oncogene 18:2892–2900

    Article  CAS  Google Scholar 

  • Zhang RP, Shao JZ, Xiang LX (2011) GADD45A protein plays an essential role in active DNA demethylation during terminal osteogenic differentiation of adipose-derived mesenchymal stem cells. J Biol Chem 286:41083–41094

    Article  CAS  Google Scholar 

  • Zhao H, Duan LJ, Sun QL, Gao YS, Yang YD, Tang XS, Zhao DY, Xiong Y, Hu ZG, Li CH et al (2020) Identification of key pathways and genes in L4 dorsal root ganglion (DRG) after sciatic nerve injury via microarray analysis. J Invest Surg 33:172–180

    Article  Google Scholar 

  • Zhou Y, Zhou B, Pache L, Chang M, Khodabakhshi AH, Tanaseichuk O, Benner C, Chanda SK (2019) Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun 10:1523

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

JL and JC designed the study, supervised the data collection, JL analyzed the data, interpreted the data, JC prepare the manuscript for publication and reviewed the draft of the manuscript. All authors have read and approved the manuscript.

Corresponding author

Correspondence to Jia Chen.

Ethics declarations

Conflict of interest

Jing Li and Jia Chen state that there are no conflicts of interest to disclose.

Ethics approval

Ethical approval was obtained from the Ethics Committee of the 3rd Affiliated Hospital of Changchun University of Chinese Medicine.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

13258_2022_1226_MOESM1_ESM.jpg

Figure S GADD45A overexpression induced p53 upregulation. The expression of apoptosis related proteins and p53 in mice model with sham, SNL, SNL+NC, SNL+GADD45A treatment, respectively, analyzed by western blotting. (JPG 724 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, J., Chen, J. GADD45A induces neuropathic pain by activating P53 apoptosis pathway in mice. Genes Genom 44, 1051–1060 (2022). https://doi.org/10.1007/s13258-022-01226-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13258-022-01226-z

Keywords

Navigation