No abstract

The human MUC6 gene, which is reported to be expressed in the stomach and gall bladder, is clustered on chromosome 11p15.5 with other secreted mucins. In this study, the genomic structure of MUC6 has been analyzed and five VNTR (minisatellites; MS1-MS5) were identified. These minisatellites were analyzed in genomic DNA extracted from 1,103 controls, 470 gastric cancer patients, and multigenerational families. Five novel minisatellites were found to be polymorphic and transmitted through meiosis by Mendelian inheritance in families. We evaluated allelic variation in these minisatellites to determine if such variation affected the susceptibility to gastric cancer. A significant association (odds ratio [OR]=7.08) between short rare MUC6-MS5 alleles and relative risks were observed for gastric cancer (95% confidence interval [CI], 1.43-35.19; P=0.005). To investigate the function of minisatellite alleles of MUC6-MS5, we examined the effects on gene expression from luciferase reporters when inserted with minisatellites. Interestingly, when the shortest allele (7TR) was inserted in the promoter, the expression level decreased over 20-fold (P<0.001) in normal and cancer cell lines. Furthermore, the cancer-specific rare allele (TR8) also showed decreased expression levels in cancer cells. Therefore, we suggest that the short rare MUC6-MS5 alleles may be related to cancer development by the regulation of MUC6 expression.

No abstract

Aberrant centrosome numbers are detected in virtually all human cancers where they can contribute to chromosomal instability by promoting mitotic spindle abnormalities. Despite their widespread occurrence, the molecular mechanisms that underlie centrosome amplification are only beginning to emerge. Here, we present evidence for a novel regulatory circuit involved in centrosome overduplication that centers on RNA polymerase II (pol II). We found that human papillomavirus type 16 E7 (HPV-16 E7)-and hydroxyurea (HU)-induced centriole overduplication are abrogated by a-amanitin, a potent and specific RNA pol II inhibitor. In contrast, normal centriole duplication proceeded undisturbed in a-amanitin-treated cells. Centriole overduplication was significantly reduced by siRNA-mediated knock down of CREB-binding protein (CBP), a transcriptional co-activator. We identified cyclin A2 as a key transcriptional target of RNA pol II during HU-induced centriole overduplication. Collectively, our results show that ongoing RNA pol II transcription is required for centriole overduplication whereas it may be dispensable for normal centriole duplication. Given that many chemotherapeutic agents function through inhibition of transcription, our results may help to develop strategies to target centrosomemediated chromosomal instability for cancer therapy and prevention.