Dramatic co-activation of WWOX/WOX1 with CREB and NF-κB in delayed loss of small dorsal root ganglion neurons upon sciatic nerve transection in rats

Meng Yen Li, Feng Jie Lai, Li Jin Hsu, Chen Peng Lo, Ching Li Cheng, Sing Ru Lin, Ming Hui Lee, Jean Yun Chang, Dudekula Subhan, Ming Shu Tsai, Chun I. Sze, Subbiah Pugazhenthi, Nan Shan Chang, Shur Tzu Chen

研究成果: Article

37 引文 斯高帕斯(Scopus)

摘要

Background: Tumor suppressor WOX1 (also named WWOX or FOR) is known to participate in neuronal apoptosis in vivo. Here, we investigated the functional role of WOX1 and transcription factors in the delayed loss of axotomized neurons in dorsal root ganglia (DRG) in rats. Methodology/Principal Findings: Sciatic nerve transection in rats rapidly induced JNK1 activation and upregulation of mRNA and protein expression of WOX1 in the injured DRG neurons in 30 min. Accumulation of p-WOX1, p-JNK1, p-CREB, pc-Jun, NF-κB and ATF3 in the nuclei of injured neurons took place within hours or the first week of injury. At the second month, dramatic nuclear accumulation of WOX1 with CREB (>65% neurons) and NF-κB (40-65%) occurred essentially in small DRG neurons, followed by apoptosis at later months. WOX1 physically interacted with CREB most strongly in the nuclei as determined by FRET analysis. Immunoelectron microscopy revealed the complex formation of p-WOX1 with p-CREB and p-c-Jun in vivo. WOX1 blocked the prosurvival CREB-, CRE-, and AP-1-mediated promoter activation in vitro. In contrast, WOX1 enhanced promoter activation governed by c-Jun, Elk-1 and NF-κB. WOX1 directly activated NF-κB-regulated promoter via its WW domains. Smad4 and p53 were not involved in the delayed loss of small DRG neurons. Conclusions/Significance: Rapid activation of JNK1 and WOX1 during the acute phase of injury is critical in determining neuronal survival or death, as both proteins functionally antagonize. In the chronic phase, concurrent activation of WOX1, CREB, and NF-κB occurs in small neurons just prior to apoptosis. Likely in vivo interactions are: 1) WOX1 inhibits the neuroprotective CREB, which leads to eventual neuronal death, and 2) WOX1 enhances NF-κB promoter activation (which turns to be proapoptotic). Evidently, WOX1 is the potential target for drug intervention in mitigating symptoms associated with neuronal injury.

原文English
文章編號e7820
期刊PloS one
4
發行號11
DOIs
出版狀態Published - 2009 十一月 12

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Li, M. Y., Lai, F. J., Hsu, L. J., Lo, C. P., Cheng, C. L., Lin, S. R., Lee, M. H., Chang, J. Y., Subhan, D., Tsai, M. S., Sze, C. I., Pugazhenthi, S., Chang, N. S., & Chen, S. T. (2009). Dramatic co-activation of WWOX/WOX1 with CREB and NF-κB in delayed loss of small dorsal root ganglion neurons upon sciatic nerve transection in rats. PloS one, 4(11), [e7820]. https://doi.org/10.1371/journal.pone.0007820