Prostate-associated gene 4 (PAGE4), an intrinsically disordered cancer/testis antigen, is a novel therapeutic target for prostate cancer / 亚洲男科学杂志(英文版)

Prostate-associated gene 4 (PAGE4) is a remarkably prostate-specific Cancer/Testis Antigen that is highly upregulated in the human fetal prostate and its diseased states but not in the adult normal gland. PAGE4 is an intrinsically disordered protein (IDP) that functions as a stress-response protein to suppress reactive oxygen species as well as prevent DNA damage. In addition, PAGE4 is also a transcriptional regulator that potentiates transactivation by the oncogene c-Jun. c-Jun forms the AP-1 complex by heterodimerizing with members of the Fos family and plays an important role in the development and pathology of the prostate gland, underscoring the importance of the PAGE4/c-Jun interaction. HIPK1, also a component of the stress-response pathway, phosphorylates PAGE4 at T51 which is critical for its transcriptional activity. Phosphorylation induces conformational and dynamic switching in the PAGE4 ensemble leading to a new cellular function. Finally, bioinformatics evidence suggests that the PAGE4 mRNA could be alternatively spliced resulting in four potential isoforms of the polypeptide alluding to the possibility of a range of conformational ensembles with latent functions. Considered together, the data suggest that PAGE4 may represent the first molecular link between stress and prostate cancer (PCA). Thus, pharmacologically targeting PAGE4 may be a novel opportunity for treating and managing patients with PCA, especially patients with low-risk disease.

Activation of Transcription Factor NF-kappaB and c-Jun/AP-1 by Various Compositions of Particles in Osteoclast Precursor Cells

PURPOSE: This study was performed in order to investigate the effects of various particle preparations on NF-kappaB and c-Jun/AP-1 activity in osteoclast precursor cells. MATERIALS AND METHODS: Osteoclast precursor cells isolated from C57BL mice were treated with PMMA (polymethylmethacrylate) spheres, polystyrene, titanium particles, and retrieved metal particles from failed cementless total hip replacements. NF-kappaB and c-Jun/AP-1 DNA binding activities were analyzed using electrophoretic mobility shift assays (EMSA). RESULTS: Commercially available PMMA and polystyrene spheres routinely showed negativity on endotoxin assays, but titanium particles and retrieved metal particles consistently showed positivity. PMMA spheres, with a maximal response noted at 30 minutes with an optimal concentration of 0.6 mg/ml, were potent stimulator of NF-kappaB and c-Jun/AP-1 activity in osteoclast precursor cells. Other particles (polystyrene, titanium, metal retrievals) also activated transcription factor NF-kappaB and c-Jun/AP-1 compared to controls. Endotoxin removal from retrieved metal particles diminished the biologic effect by approximately 40%. CONCLUSION: Particles of various compositions and sizes (PMMA, polystyrene, titanium, and retrieved metal particles) activated the NF-kappaB and c-Jun/AP-1 signaling pathways. This suggests that NF-kappaB and c-Jun/AP-1 may have important roles in the pathogenesis of periprosthetic osteolysis.

Oncogenes and tumor suppressor gene expressed in human bladder tumor / 대한비뇨기과학회지

Bladder tumor, like many other types of solid tumors, is expected to arise through a series of genertic changes that lead to tumor progression. These changes have been directly identified as alterations of various genes usually involved in cell growth and proliferation. Two basic types of these cellular genes have been identified as oncogenes and tumor suppressor genes.25 transitional cell carcinoma and 1 squamous cell carcinoma specimens of the human bladder were analyzed immunohistochemically to detect the expression of ras family(H-, K-, N- ras), c-myc, c-jun/AP-1, and p53 proteins.The expression of these proteins was not detected in 1 case of squamous cell carcinoma. In 25 transitional cell carcinomas, the positive staining of H-ras and p53 proteins was observed in 8 cases (32%) and 6 cases (24%), respectively. H-ras was expressed in 1 Ta (1/6), 6 T1 (6/11), 1 T3b (1/2), and in 3 grade I (3/10), 4 grade II (4/11), 1 grade III (1/4), but the positive staining was not significantly correlated with tumor stage and grade. The expression of p53 was found in 2 T1 (2/11), 1 T2 (1/3), 1 T3a (1/3), 2 T3b (2/2), and 1 grade I (1/10), 1 grade II (1/11), 4 grade III (4/4). The tumor grade was significantly correlated with the positivity of p53(p<0.005). Although the expression of p53 in higher state tumor tended to be higher than lower stage tumor, there was no correlation between stage and p53 expression. Probably due to the expression of p53 correlated with histological grade and individual positive tumor cell showing a malignant feature, p53 expression might be related to tumor progression.In 4 cases of high stage and grade transitional cell carcinoma, both H-ras and p53 proteins were expressed. These data suggested that H-ras and p53 might act on tumorigenesis and malignant potential in bladder transitional cell carcinoma collaboratively. But, K-ras, N-ras, c-jun/AP-1, and c-myc oncoproteins were not detected at all.