Adenovirus E4orf6 targets pp32/LANP to control the fate of ARE-containing mRNAs by perturbing the CRM1-dependent mechanism

E4orf6 plays an important role in the transportation of cellular and viral mRNAs and is known as an oncogene product of adenovirus. Here, we show that E4orf6 interacts with pp32/leucine-rich acidic nuclear protein (LANP). E4orf6 exports pp32/LANP from the nucleus to the cytoplasm with its binding partner, HuR, which binds to an AU-rich element (ARE) present within many protooncogene and cytokine mRNAs. We found that ARE-mRNAs, such as c-fos, c-myc, and cyclooxygenase-2, were also exported to and stabilized in the cytoplasm of E4orf6-expressing cells. The oncodomain of E4orf6 was necessary for both binding to pp32/LANP and effect for ARE-mRNA. C-fos mRNA was exported together with E4orf6, E1B-55kD, pp32/LANP, and HuR proteins. Moreover, inhibition of the CRM1-dependent export pathway failed to block the export of ARE-mRNAs mediated by E4orf6. Thus, E4orf6 interacts with pp32/LANP to modulate the fate of ARE-mRNAs by altering the CRM1-dependent export pathway

Analysis of pRb Family Binding Regions of Adenovirus Type 12 E1A

Adenovirus early 1A (E1A) products can form complexes with cellular pro-teins including the pRb tumor suppressor, pRb-related p107 and p130, and p300 proteins related to the CREB-binding protein (CBP) . Within the E1A sequence, CR2 and CR1 mediate interaction with pRb family proteins, and the amino termi-nus and CR1 are involved in association with p300 protein. These interactions are essential for the transforming activity of ElA proteins of various adenovirus serotypes. Since E1A of highly oncogenic adenovirus type 12 (Ad12) have some differences in transformation efficiency and oncogenicity from non-oncogenic Ad5 E1A, we have analyzed the role of CR1 and CR2 sequences of Ad12 E1A in trans-formation and pRb family binding using specific mutations. On the basis of the characteristic phenotypes of some CR1 mutations we suggest a modification of the previously proposed consensus regarding CR1 sequence for pRb binding. Combinations of CR1 and CR2 mutations revealed different roles for noncon-served residues within the conserved pRb binding motif LXCXE of CR2, and interaction of CR1 and CR2 of Ad12 E1A through specific amino acid residue is suggested. These structural features of Ad12 E1A proteins may explain at least in part the functional differences from Ad5 E1A proteins

Expression of ras Oncogene p21 Product in Malignant and Benign Lesions and Normal Mucosae of the Stomach in China

Expression of c-ras oncogene was analyzed in 75 cases of carcinomas, 38 benign lesions and 22 normal mucosae of the stomach in Chinese subjects by use of the monoclonal antibody rp28, which reacts to the c-Ha-ras and c-Ki-ras p21 products. The incidence of p21 positive cases (more than 20% of total cells stained by rp28) was 90.7% in gastric carcinomas, 10.5% in benign gastric lesions and 4.5% in normal mucosae. While 34/75 gastric carcinomas contained strongly rp28-reactive (+ +) cells, none of the benign lesions or normal mucosae did. The mean percentage of rp28 reactive (+ or ++) cells in each group was 52.2% in gastric carcinomas, 6.3% in benign lesions and 2.3% in normal mucosae. These indicate that ras p21 expression is significantly high in the gas-tric carcinomas compared to the benign lesions and normal mucosae of the stom-ach. Tests of tubular adenocarcinomas with different degrees of differentiation showed significantly higher amounts of p21 product in well differentiated (71.7%) and moderately differentiated (67.3%) samples than in poorly differentiated adenocarcinomas (40.9%), which contained more, in tern, than mucinous adenocarcinomas (39.2%) and undifferentiated carcinomas (27.5%). This sug-gests that Ha- and/or Ki-ras p21 expression may have some roles in the mainte-nance of the glandular structure in gastric carcinomas

Human Papillomavirus Genome in Oral Carcinoma and Their Metastatic Cervical Lymph Node Tissues.

Twenty cases of oral squamous cell carcinoma (SCC) with cervical lymph node metastasis were investigated. Both primary lesions and metastatic lymph nodes were analyzed for the involvement of human papillomavirus (HPV) DNAs utilizing the polymerase chain reaction (PCR) method and dot blot hybridization. HPV DNAs were detected in five cases. Four primary lesions contained HPV-16 DNA, and one contained both HPV-16 and HPV-18 DNAs out of 20 cases examined. No HPV DNAs were detected in metastatic lymph node tissues in cases where HPV DNAs could not be detected in primary cancer tissues. The same types of HPV DNAs as those found in primary lesions were detected in metastatic lymph nodes including those with HPV-16 and HPV-18

Wild-type p53 Expression Overcomes p21-mediated G1 Arrest and Induces Apoptosis in Cancer Cells Expressing Bax

Tumor suppression by p53 is deficient in the majority of human cancers. Previous studies have suggested that expression of p53 in human cancer cells can result in either growth arrest or apoptosis. The biological and genetic de-terminants that dictate which of these two pathway - apoptosis or arrest - will be chosen by a particular cell following p53 expression are largely un-known. To investigate the basis of this difference, we evaluated the role of p21, a mediator of p53-induced growth arrest. We generated a replication-deficient adenoviral recombinant which expresses p21 and com-pared its tumor suppressive abilities with Ad-p53. Infection with Ad-p21 re-sulted in high levels of p21 expression and suppressed the growth of human cancer cells, through the Gl arrest of the cell cycle. We then examined the effects of combined infection with Ad-p21 and Ad-p53 to investigate which of these molecules had the dominant function. Introduction of exogenous p53 in RERF-LC-OK, BT549 and ZR-75-1 cells overcame p21-mediated cell cycle arrest at G1 and induced apoptosis, suggesting that this affect is a general event among human cancer cell lines. We then evaluated the role of Bax/Bcl-2 in the response to p53. A Significantly greater amount of Bax protein was pre-sent in cell lines undergoing apoptosis than in cells with arrested growth,suggesting that Bax might be an important component of the p53-mediated apoptosis of cancer cells

Detection of Human Papillomavirus (HPV) DNA Sequences in Normal Oral Scrapes Using the Nested PCR.

We investigated the prevalence rate of HPV DNAs in normal mucosa in the oral region. The nested PCR method was utilized to detect target DNA sequences using HPV E6/E7 consensus primer pairs. Of 56 patients examined, HPV 6 and HPV 16 DNA sequences were detected in a 46-year-old male and a 35-year-old female, respectively. These results suggest that HPVs are uncom-mon in normal oral epithelium, and that we should carry out careful follow-up in HPV DNA-positive cases

Tumor-Derived Microvesicles Induce Proangiogenic Phenotype in Endothelial Cells via Endocytosis

Background: Increasing evidence indicates that tumor endothelial cells (TEC) differ from normal endothelial cells (NEC). Our previous reports also showed that TEC were different from NEC. For example, TEC have chromosomal abnormality and proangiogenic properties such as high motility and proliferative activity. However, the mechanism by which TEC acquire a specific character remains unclear. To investigate this mechanism, we focused on tumor-derived microvesicles (TMV). Recent studies have shown that TMV contain numerous types of bioactive molecules and affect normal stromal cells in the tumor microenvironment. However, most of the functional mechanisms of TMV remain unclear. Methodology/Principal Findings: Here we showed that TMV isolated from tumor cells were taken up by NEC through endocytosis. In addition, we found that TMV promoted random motility and tube formation through the activation of the phosphoinositide 3-kinase/Akt pathway in NEC. Moreover, the effects induced by TMV were inhibited by the endocytosis inhibitor dynasore. Our results indicate that TMV could confer proangiogenic properties to NEC partly via endocytosis. Conclusion: We for the first time showed that endocytosis of TMV contributes to tumor angiogenesis. These findings offer new insights into cancer therapies and the crosstalk between tumor and endothelial cells mediated by TMV in the tumor microenvironment

Carbonyl Reductase 3 (CBR3) Mediates 9-cis-Retinoic Acid-Induced Cytostatis and is a Potential Prognostic Marker for Oral Malignancy

The molecular mechanisms of growth suppression by retinoic acid (RA) were examined. Our results suggest that the cytostatic effects of RA could be mediated by the activation of endogenous CBR3 gene in oral squamous cell carcinomas (OSCCs), and the expression is a potential marker for oral malignancy

Synovial chondromatosis of the temporomandibular joint accompanied by loose bodies in both the superior and inferior joint compartments : case report

Synovial chondromatosis (SC) of the temporomandibular joint (TMJ) is a benign lesion characterized by the formation of metaplastic cartilaginous nodules. SC of the TMJ usually only affects the superior joint compartment of the TMJ. We report a rare case of SC of the TMJ affecting the inferior as well as superior joint compartments