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

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, 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/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-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

The relation between the patient health questionnaire-15 and DSM somatic diagnoses

Abstract Background Our purpose was to examine the reliability and validity of the Chinese version of the Patient Health Questionnaire-15 (PHQ-15) in Taiwan, and to explore its relation to somatoform disorders (DSM-IV) and to somatic symptom and related disorders (DSM-5). Methods We recruited 471 individuals, 151 with somatoform disorders and 200 with somatic symptom and related disorders. Subjects completed the Chinese version of the PHQ-15, Beck Depression Inventory-II (BDI-II), Beck Anxiety Inventory (BAI), and received a DSM-IV- and DSM-5-based diagnostic interview. We performed exploratory factor analysis and assessed test-retest reliability, internal consistency, and correlation with BDI-II/BAI to confirm reliability and validity, and carried out ROC curve analysis to determine suitability for evaluation or screening purposes. PHQ-15 scores were compared between patients with various DSM-IV psychiatric diagnoses (such as DSM-IV somatoform disorders, panic disorder, other anxiety/depressive disorders) or no DSM-IV diagnosis and patients with DSM-5 somatic symptom and related disorders or no DSM-5 diagnosis. Results The Chinese version identified cardiopulmonary, pain-fatigue, and gastrointestinal as major factors and had good reliability (0.803–0.930), internal consistency (0.637–0.861), and correlation coefficients with BDI-II/BAI (0.407–0.619, 0.536–0.721, respectively). The PHQ-15 scores were similar in patients with somatoform disorders and patients with panic disorder; higher in patients with somatoform disorders and panic disorder than in patients with other anxiety/depressive disorders; and significantly higher in patients with somatic symptom and related disorders than in patients without this diagnosis. The AUC of the PHQ-15 was 0.678 (cutoff 6/7) for screening somatoform disorders (DSM-IV) and 0.725 (cutoff 4/5) for screening somatic symptom and related disorders (DSM-5). Conclusions The Chinese version of the PHQ-15 is suitable for evaluating somatic symptom and related disorders. The preponderance of somatic symptom disorder in our sample, lack of evaluation of functional disorders, and recruitment solely from psychiatric clinics are possible limitations

Expression of WW Domain-Containing Oxidoreductase WOX1 in Human Nervous System Tumors

Background and ObjectiveS: We aimed to evaluate the expression levels of the tumor suppressor WOX1 in nervous system tumors and its co-expression with p53 and neurofibromatosis type 2/merlin (NF2) tumor suppressor gene products

Transforming Growth Factor β1 Signaling via Interaction with Cell Surface Hyal-2 and Recruitment of WWOX/WOX1*

Transforming growth factor β (TGF-β) initiates multiple signal pathways and activates many downstream kinases. Here, we determined that TGF-β1 bound cell surface hyaluronidase Hyal-2 on microvilli in type II TGF-β receptor-deficient HCT116 cells, as determined by immunoelectron microscopy. This binding resulted in recruitment of proapoptotic WOX1 (also named WWOX or FOR) and formation of Hyal-2·WOX1 complexes for relocation to the nuclei. TGF-β1 strengthened the binding of the catalytic domain of Hyal-2 with the N-terminal Tyr-33-phosphorylated WW domain of WOX1, as determined by time lapse fluorescence resonance energy transfer analysis in live cells, co-immunoprecipitation, and yeast two-hybrid domain/domain mapping. In promoter activation assay, ectopic WOX1 or Hyal-2 alone increased the promoter activity driven by Smad. In combination, WOX1 and Hyal-2 dramatically enhanced the promoter activation (8–9-fold increases), which subsequently led to cell death (>95% of promoter-activated cells). TGF-β1 supports L929 fibroblast growth. In contrast, transiently overexpressed WOX1 and Hyal-2 sensitized L929 to TGF-β1-induced apoptosis. Together, TGF-β1 invokes a novel signaling by engaging cell surface Hyal-2 and recruiting WOX1 for regulating the activation of Smad-driven promoter, thereby controlling cell growth and death