Kei Honda

Aurora-B associated protein phosphatases as negative regulators of kinase activation

The human serine/threonine kinase Aurora-B is structurally related to the protein kinase Ipl1p from S cerevisiae and aurora from Drosophila melanogaster, which are key regulators of mitosis. The present study shows that human Aurora-B is activated by okadaic acid and forms complexes with the protein serine/threonine phosphatase type 1 (PP1) or PP2A, but not with PP5. These data identified Aurora-B associated protein phosphatases as negative regulators of kinase activation. We then used a series of substrates based on a histone H3 phosphorylation site (residues 5–15) to determine the substrate specificity of human Aurora-B. We found that this enzyme is an arginine-directed kinase that can phosphorylate histone H3 at serines 10 and 28 in vitro, suggesting that human Aurora-B is a mitotic histone H3 kinase.

Degradation of human Aurora2 protein kinase by the anaphase-promoting complex-ubiquitin-proteasome pathway

Human Aurora2 was originally identified by its close homology to yeast IPL1 and fly aurora, which are key regulators of chromosome segregation and a family of serine/threonine kinases. Here we demonstrate that the Aurora2 protein is degraded rapidly after G2/M phase release in mammalian cells. Aurora2 protein has a rapid turnover rate with a half-life of approximately 2 h. In eukaryotic cells, the ubiquitin-proteasome pathway is the major mechanism for the targeted degradation of unstable proteins. The treatment of mammalian cells with proteasome inhibitors blocks Aurora2 degradation. Furthermore, Aurora2 is polyubiquitinated in vivo and in vitro using anaphase-promoting complex (APC). These results demonstrate that Aurora2 protein is turned over through the APC-ubiquitin-proteasome pathway.

Degradation of human Aurora-A protein kinase is mediated by hCdh1

Human Aurora‐A is related to a protein kinase originally identified by its close homology to Ipl1p from Saccharomyces cerevisiae and aurora from Drosophila melanogaster, which are key regulators of the structure and function of the mitotic spindle. We previously showed that human Aurora‐A is turned over through the anaphase promoting complex/cyclosome (APC/C)–ubiquitin–proteasome pathway. The association of two distinct WD40 repeat proteins known as Cdc20 and Cdh1, respectively, sequentially activates the APC/C. The present study shows that Aurora‐A degradation is dependent on hCdh1 in vivo, not on hCdc20, and that Aurora‐A is targeted for proteolysis through distinct structural features of the destruction box, the KEN box motifs and its kinase activity.

Intraductal mucinous tumors occurring simultaneously in the liver and pancreas

A case of simultaneous intraductal mucinous tumors of the liver and pancreas in a 67-year-old man is described. Abdominal ultrasonography and computed tomography (CT) revealed the presence of cystic lesions with intraluminal septae both in the caudate lobe of the liver and in the uncinate process of the pancreas; these cystic lesions communicated with the hepatic duct and pancreatic duct, respectively. Mucin retention was observed in the cysts, and cholestasis was induced by mucin secretion into the common bile duct. The lesions were resected by left hepatic lobectomy with caudate lobectomy, and segmental pancreatectomy. Both lesions were multilocular cystic tumors with no papillary projections or focal mass effect in their walls. Histologically, both cystic lesions were a mixture of hyperplasia and adenoma lined by low papillary columnar epithelium. There were no cellular or histological features to suggest malignant change. The fibrous intratumor interstitium lacked any mesenchymal or ovarian-like stroma. The hepatic lesion was considered to be of a similar nature to intraductal papillary mucinous tumor (IPMT) of the pancreas. However, the two lesions occurred simultaneously in the liver and pancreas. This case is of interest in regard to the diagnosis and management of mucinous hepatopancreatobiliary lesions.

Ruptured mucinous cystic neoplasm with an associated invasive carcinoma of pancreatic head in a pregnant woman: Report of a case and review of literature

Mucinous cystic neoplasm (MCN) of the pancreas is characterized by mucin‐producing columnar epithelium and an ovarian‐type stroma. It occurs almost exclusively in women and is almost always located in the pancreatic body or tail. Here, we report a case of large MCN located in the pancreatic head but not in the body nor tail in a 32‐year‐old pregnant woman, which was thought to have grown rapidly during pregnancy. It was ruptured at 34 weeks of gestation and the patient was admitted to the emergency department of the University of Fukui Hospital with an acute abdomen. Emergency cesarean section followed by pancreaticoduodenectomy was performed. The tumor consisted of many small cysts lined by a single‐layer of mucinous epithelium with papillary growth and partial solid parts showing invasive growth and sarcomatoid changes, indicating mucinous cystic neoplasm with an associated invasive carcinoma (previously referred as mucinous cystadenocarcinoma). Thickened septa revealed ovarian‐type stroma strongly positive for α‐inhibin and partly positive for progesterone receptor immunohistochemically. We also review and discuss previous reports of MCNs including those with an associated invasive carcinoma in pregnant patients.

Chemo-hyperthermic peritoneal perfusion (CHPP) for appendiceal pseudomyxoma peritonei

BackgroundPseudomyxoma peritonei is derived mostly from the rupture of an appendiceal cystic tumor and produces a large quantity of mucinous substance. Though its malignancy level is low, radical resection is difficult and its prognosis is poor. In some institutes in European countries and the United States, multidisciplinary treatment with chemo-hyperthermia at a relatively low temperature is performed following subtotal peritonectomy. We carried out high-temperature chemo-hyperthermic peritoneal perfusion following incomplete resections of mucinous tumors in six patients.MethodsAfter resection of the main tumor and macroscopic gross tumor resection of dissemination, heated perfusate containing anticancer agents was poured into the peritoneal cavity and stirred and pumped into a circulation between the abdomen and a reservoir. The temperature of the surface of the peritoneum was maintained at around 43°C.ResultsThe intraperitoneal space was sufficiently heated without severe complications. The pathological diagnosis in four of the patients was peritoneal mucinous carcinomatosis, and in the other two patients, it was intermediate type between peritoneal mucinous carcinomatosis and disseminated peritoneal adenomucinosis. Two patients died, 15 and 26 months after the treatment. The other four patients have survived for 4, 24, 26, and 80 months now, and two of them, who have survived for 26 and 80 months, received a second treatment 18 and 32 months, respectively, after the initial treatment. These results seemed not to be inferior to those in the reports from institutes in Europe and the United States which performed subtotal peritonectomy and then used mild hyperthermia in chemo-hyperthermia.ConclusionFor treating pseudomyxoma peritonei, hightemperature chemo-hyperthermic peritoneal perfusion following incomplete tumor resection is effective even without peritonectomy.

Biliopancreatic fistula and abscess formation in the bursa omentalis associated with intraductal papillary mucinous cancer of the pancreas.

We describe an unusual case of biliopancreatic fistula, free perforation, and subsequent abscess formation within the lesser peritoneal sac associated with intraductal papillary mucinous carcinoma (IPMC). A 71-year-old man presented with general fatigue and loss of appetite that had persisted for 1 month. Abdominal computed tomography (CT) revealed findings consistent with an intraductal papillary mucinous neoplasm (IPMN) of the pancreas, accompanied by abscess formation in the bursa omentalis. Gastrointestinal fiberscopy revealed a swollen papilla of Vater expanded by sticky mucus, and a communication between the pancreatic duct and bile duct was demonstrated by the injection of indigo carmine solution into the pancreatic duct. Percutaneous transhepatic abscess drainage (PTAD) was performed on the day of admission. After this procedure, the patient was managed for 1 month and supported nutritionally with glycemic control for diabetes mellitus. After admission, the patient had an episode of obstructive jaundice that was treated by retrograde biliary drainage. Pancreaticoduodenectomy with lymph node dissection was then performed. Pathological examination revealed IPMN with patchy, scattered carcinoma of the pancreatic head and uncinate process with the formation of a biliopancreatic fistula. Bile duct epithelium in the area of the biliopancreatic fistula demonstrated atypical papillary epithelium suggestive of tumor invasion.