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


RESULTS
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, p-c-Jun, NF-kappaB 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-kappaB (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-kappaB. WOX1 directly activated NF-kappaB-regulated promoter via its WW domains. Smad4 and p53 were not involved in the delayed loss of small DRG neurons.


CONCLUSIONS
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-kappaB 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-kappaB promoter activation (which turns to be proapoptotic). Evidently, WOX1 is the potential target for drug intervention in mitigating symptoms associated with neuronal injury.
Li
Meng-Yen
MY
Department of Cell Biology & Anatomy, National Cheng Kung University Medical College, Tainan, Taiwan.
Lai
Feng-Jie
FJ
Hsu
Li-Jin
LJ
Lo
Chen-Peng
CP
Cheng
Ching-Li
CL
Lin
Sing-Ru
SR
Lee
Ming-Hui
MH
Chang
Jean-Yun
JY
Subhan
Dudekula
D
Tsai
Ming-Shu
MS
Sze
Chun-I
CI
Pugazhenthi
Subbiah
S
Chang
Nan-Shan
NS
Chen
Shur-Tzu
ST
D000818:Animals; D017209:Apoptosis; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004789:Enzyme Activation; D005727:Ganglia, Spinal / Q000378:metabolism*; D008297:Male; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010088:Oxidoreductases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000601:surgery*; D014157:Transcription Factors / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation
C508137:Creb1 protein, rat; D017362:Cyclic AMP Response Element-Binding Protein; D016328:NF-kappa B; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D010088:Oxidoreductases; D048055:Mitogen-Activated Protein Kinase 8