Tumor suppressor KIF1Bß regulates mitochondrial apoptosis in collaboration with YME1L1.

KIF1Bß, a member of the kinesin superfamily of motor proteins, is a haploinsufficient tumor suppressor mapped to chromosome 1p36.2, which is frequently deleted in neural crest-derived tumors, including neuroblastoma and pheochromocytoma. While KIF1Bß acts downstream of the nerve growth factor (NGF) pathway to induce apoptosis, further molecular functions of this gene product have largely been unexplored. In this study, we report that KIF1Bß destabilizes the morphological structure of mitochondria, which is critical for cell survival and apoptosis. We identified YME1L1, a mitochondrial metalloprotease responsible for the cleavage of the mitochondrial GTPase OPA1, as a physical interacting partner of KIF1Bß. KIF1Bß interacted with YME1L1 through its death-inducing region, as initiated the protease activity of YME1L1 to cleave the long forms of OPA1, resulting in mitochondrial fragmentation. Overexpression of YME1L1 promoted apoptosis, while knockdown of YME1L1 promoted cell growth. High YME1L1 expression was significantly associated with a better prognosis in neuroblastoma. Furthermore, in NGF-deprived PC12 cells, KIF1Bß and YME1L1 were upregulated, accompanied by mitochondrial fragmentation and apoptotic cell death. Small interfering RNA-mediated knockdown of either protein alone, however, remarkably inhibited the NGF depletion-induced apoptosis. Our findings indicate that tumor suppressor KIF1Bß plays an important role in intrinsic mitochondria-mediated apoptosis through the regulation of structural and functional dynamics of mitochondria in collaboration with YME1L1. Dysfunction of the KIF1Bß/YME1L1/OPA1 mechanism may be involved in malignant biological features of neural crest-derived tumors as well as the initiation and progression of neurodegenerative diseases.

[Granulomatous pleuritis and chylothorax caused by calcite inhalation in a Galgo Español dog]. / Granulomatöse Pleuritis und Chylothorax durch Kalzitinhalation bei einem Galgo Español.

A 6-year-old, male Galgo Español dog was presented with severe dyspnea. Radiography and ultrasonography revealed pleural effusion. Approximately 4 l of a milky and slightly reddish fluid were aspirated and drained from the thoracic cavity. Clinical chemistry examination of the fluid indicated a modified transudate with a high amount of triglycerides. On cytological examination, degenerated neutrophilic granulocytes, small lymphocytes, macrophages and chylomicrons were found. A chest tube was placed and computed tomography was performed, which indicated thickening of parietal and visceral pleura and enlargement of the sternal lymph node without abnormal findings in the lungs. During subsequent thoracoscopy disseminated proliferative masses, appearing as small white nodules, covering nearly the entire pleural surface were found and biopsies were taken for further analysis. Histopathologic diagnosis was a granulomatous pleuritis with intralesional birefringent foreign material. Energy dispensive x-ray emission analysis was used to determine the origin of the material. Scanning electron microscopy revealed high amounts of calcium containing foreign material (calcite) within the granulomas. An extended clinical history of the dog gave evidence that the animal had lived next to a construction site 15 months earlier and may well have inhaled the calcium-containing dust. Treatment with prednisolone was initiated, however the dog developed gastro-intestinal side effects and treatment was stalled after 10 weeks. Dyspnea and liquidothorax re-occurred 4 months later. A further attempt of immunosupressive treatment was commenced, using a combination of prednisolone and ciclosporine, which again was not tolerated by the patient. The dog finally developed pneumonia and was euthanized by the owner's request.

Protein stability and function of p73 are modulated by a physical interaction with RanBPM in mammalian cultured cells.

Upon a certain DNA damage including cisplatin treatment, p73 is stabilized and exerts its growth-suppressive and/or proapoptotic function. However, the precise molecular basis by which the intracellular levels of p73 are regulated remains unclear. In the present study, we have identified RanBPM as a novel binding partner of p73alpha by yeast-based two-hybrid screening, and also found that RanBPM has an ability to stabilize p73alpha. GST pull-down assays and co-immunoprecipitation experiments revealed that RanBPM directly bound to the extreme COOH-terminal region of p73alpha, whereas it failed to interact with p53. Co-expression of RanBPM with p73alpha resulted in the nuclear translocation of RanBPM, and both proteins co-localized in cell nucleus as examined by indirect immunofluorescent staining. It is worth noting that the expression of RanBPM inhibited the ubiquitination of p73alpha, and thereby prolonged its half-life. Subsequent studies demonstrated that the proapoptotic activity of p73alpha was significantly enhanced in the presence of RanBPM. Taken together, our present findings implicate a novel role for RanBPM in the regulation of p73 stability and function.

Soft tissue healing at one-piece zirconia implants compared to titanium and PEEK implants of identical design: a histomorphometric study in the dog.

This study aimed to histomorphometrically evaluate the soft tissue reactions of one-piece zirconia implants versus titanium implants in regard to their insertion depth. Four one-piece implants of identical geometry were inserted on each side of six mongrel dogs: an uncoated zirconia implant, a zirconia implant coated with a calcium liberating titanium oxide, a titanium implant, and an experimental implant made of a synthetic material. Using a split-mouth design, they were inserted in both submerged and nonsubmerged healing modes. After 4 months, dissected blocks were stained with toluidine blue to histologically assess the marginal portion of the implant mucosa, apical extension of the barrier epithelium, and margin level of bone-to-implant contact. The inflammation status at the crestal part of the implant was assessed as well. The histomorphology presented the typical soft tissue configuration of barrier epithelium and connective tissue near the bone-to-implant contact. Histomorphometrically, the length of the barrier epithelium did not differ significantly concerning material type or healing modality. Furthermore, the inflammation signs were higher with nonsubmerged implants. The submerged uncoated zirconia implants, however, showed few signs of inflammation. Within the limits of this study, it is concluded that uncoated and coated zirconia implants are capable of establishing sufficient soft tissue configurations that are comparable to those of titanium implants.