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Proepithelin, a previously unrecognized growth factor in cartilage, has recently emerged as an important regulator for cartilage formation and function. In the present study, we provide several lines of evidences in proepithelin-mediated induction of cell proliferation, differentiation, and apoptosis in the metatarsal growth plate. Proepithelin-mediated stimulation of metatarsal growth and growth plate chondrogenesis was neutralized by pyrrolidine dithiocarbamate, a known NF-κB inhibitor. In rat growth plate chondrocytes, proepithelin induced NF-κB-p65 nuclear translocation, and nuclear NF-κB-p65 initiated its target gene cyclin D1 to regulate chondrocyte functions. The inhibition of NF-κB-p65 expression and activity (by p65 short interfering RNA (siRNA) and pyrrolidine dithiocarbamate, respectively) in chondrocytes reversed the proepithelin-mediated induction of cell proliferation and differentiation and the proepithelin-mediated prevention of cell apoptosis. Moreover, the inhibition of the phosphatidylinositol 3-kinase and Akt abolished the effects of proepithelin on NF-κB activation. Finally, using siRNA and antisense strategies, we demonstrated that endogenously produced proepithelin by chondrocytes is important for chondrocyte growth in serum-deprived conditions. These results support the hypothesis that the induction of NF-κB activity of in growth plate chondrocytes is critical in proepithelin-mediated growth plate chondrogenesis and longitudinal bone growth.

Background Mutations in the GRN (granulin precursor) are a frequent cause of frontotemporal dementia (FTD) and other atypical parkinsonian disorders. However, the frequency of GRN mutations in Asian patients with atypical parkinsonian disorders is still uncertain. Methods We screened GRN mutations by sequencing cDNA from 98 patients with FTD or atypical parkinsonian disorders. The functional properties of the identified mutation were evaluated by overexpression in human embryonic kidney (HEK)-293 cells. Results We identified a new missense (GRN p.T487I) mutation in a female patient with undefined atypical parkinsonism. The overexpression experiment further demonstrated that p.T487I mutation reduced the progranulin protein level and stability in HEK-293 cells. Conclusion GRN p.T487I mutation, which decreases the stability of progranulin protein, could be a new causative mutation in patients with atypical parkinsonian disorders.

BACKGROUND/AIM Proepithelin is a growth factor that may play a critical role in bladder cancer. Its over-expression in urine of bladder cancer patients gave us the impetus to evaluate its potential suitability as a biomarker for bladder cancer diagnosis and/or prognosis. METHODS proepithelin was estimated in 86 voided urine samples, including 59 bladder cancer patients and 27 healthy volunteers using quantitative sandwich enzyme immunoassay technique. Urinary proepithelin level was expressed in ng/100 mg creatinine. RESULTS Urinary proepithelin was significantly higher in bladder cancer patients compared to control subjects (means: 17.5 ± 10 and 8.9 ± 3.5 ng/100 mg creatinine, respectively; p < 0.001), and the test sensitivity and specificity to detect the presence of bladder cancer were 74.6 and 85.2%, respectively. Furthermore, patients with low-grade/non-muscle invasive stages bladder cancer showed significantly lower urinary proepithelin compared to high-grade/non-muscle invasive stages and high-grade/invasive stages ones (means: 11.6 ± 9, 20.2 ± 8.1 and 23.8 ± 11.9 ng/100 mg creatinine, respectively; p= 0.005 and 0.002, respectively). CONCLUSIONS This preliminary study suggests that urinary proepithelin may be considered as a non-invasive, sensitive, and specific urine-based test for bladder cancer diagnosis and/or prognosis.

Using the yeast two-hybrid system, we screened a human placenta cDNA library and identified two proteins that interacted with the Tat protein of the caprine arthritis encephalitis virus (CAEV): the EGF-like repeats 1–6 of the extracellular domain of the human Notch2 receptor and the epithelin/granulin growth factor precursor. This interaction was also confirmed in mammalian cells. Using in vitro mutagenesis assays, we showed that each one of the three cysteine residues located within the cysteine-rich domain of the CAEV Tat protein is essential for the binding of Tat to both the Notch2 and the epithelin/granulin protein. It is thus suggested that the cysteine-rich domain of Tat plays a role in the interaction between the Tat and either Notch2 or the epithelin/granulin domains, both of which exhibit EGF-like-repeat-imposed spatial conformation. It is assumed that such interactions might modulate the physiological functions of Notch2 and epithelin/granulin, thereby affecting various pathologies associated with CAEV.

e18103 Background: GP88, is an 88 kDa glycoprotein autocrine growth factor belonging to a newly identified family of growth modulators characterized by unique cysteine-rich motif and playing a role...

551 Background: The identification of a measurable biomarker that is also a therapeutic target of malignant transformation or malignant progression of breast carcinoma (BC) is needed. PCDGF/GP88, a...