No abstract

Prion proteins (PrPs) cause prion diseases, such as bovine spongiform encephalopathy. The conversion of a normal cellular form (PrPC) of PrP into an abnormal form (PrPSc) is thought to be associated with the pathogenesis. An RNA aptamer that tightly binds to and stabilizes PrPC is expected to block this conversion and to thereby prevent prion diseases. Here, we show that an RNA aptamer comprising only 12 residues, r(GGAGGAGGAGGA) (R12), reduces the PrPSc level in mouse neuronal cells persistently infected with the transmissible spongiform encephalopathy agent. Nuclear magnetic resonance analysis revealed that R12, folded into a unique quadruplex structure, forms a dimer and that each monomer simultaneously binds to two portions of the N-terminal half of PrPC, resulting in tight binding. Electrostatic and stacking interactions contribute to the affinity of each portion. Our results demonstrate the therapeutic potential of an RNA aptamer as to prion diseases.

No abstract

population controls, and 114 male low-risk controls. Both missense alleles, Leu217 and Thr541, were carried at higher frequency in Japanese patients than in the controls (Leu217, P ϭ 0.0012; Thr541, P ϭ 0.0145), and the odds ratios associated with carrying these sequence variants were higher in Japanese than in Caucasians. Although the Leu217 and Thr541 variants of ELAC2 are less common in Japanese than in Caucasians, both variants confer significantly increased risk of prostate cancer in Japanese. Carriage of these variants was not associated with age at diagnosis, tumor stage, or tumor grade in these Japanese prostate cancer patients. The allele-specific pattern of risk observed in Japanese and familial Caucasian patients was qualitatively similar; however, the magnitude of that risk was considerably greater in Japanese than in Caucasians.

We performed detailed molecular analyses of a suspected homozygous deletion on chromosome 9q32-q33 in a bladder-cancer cell line (KYBTDS) derived from a superficial papillary transitional cell carcinoma (TCC). We examined 13 sequence-tagged site (STS) markers mapped along 9q32-q33 by polymerase chain reaction (PCR), and used 13 bacterial artificial chromosome (BAC)/bacteriophage P1-derived artificial chromosome (PAC) genomic clone probes representing these STS markers as probes for dualcolor fluorescence in situ hybridization (FISH) analyses to define the deleted region cytogenetically and at the molecular level. Southern blotting confirmed the findings. This combination of techniques revealed that the homozygous deletion in the KYBTDS cell line involved less than 1 megabase of DNA, flanked by markers A003P42 and SGC33380. This interval overlaps part of a common region of deletion observed in a number of primary bladder cancers; moreover, the DNA sequence within the 1-Mb segment corresponds to part of a YAC genomic clone that encompasses a putative tumor suppressor gene, DBCCR1.

Genes encoding the serine proteinase inhibitor B family (SERPINBs) are mainly clustered on human chromosome 18 (18q21). Several serpins are known to affect malignant phenotypes of tumor cells, so aberrant genetic variants in this molecular family are candidates for conferring susceptibility for risk of cancer. We investigated whether eight selected non-synonymous variations within SERPINB loci at 18q21 might be associated with risk of prostate cancer in Japanese men. A case-control study involving 292 prostate-cancer patients and 384 controls revealed significant differences in regard to distribution of four missense variations in genes encoding plasminogen activator inhibitor 2 (PAI2) and SERPINB10. The most significant association was detected for the N120D polymorphism in the PAI2 gene (P=5.0·10 À5 ); men carrying the 120-N allele (120-N/N and 120-N/D genotypes) carried a 2.4-fold increased risk of prostate cancer (95% confidence interval 1.45-4.07). Associations were also detected for three other missense polymorphisms in those two genes. Strong linkage disequilibrium in the region encompassing PAI2 and SER-PINB10 extended to about 50 kbp. The results suggested that missense variations in one or both of these genes confer important risks for prostate cancer, and may be themselves tumorigenic. Although confirmative replication studies on larger cohorts are awaited, clinical examination of these variations may become useful for identifying individuals at high risk for prostate cancer.

No abstract

Human cancers derived from breast, esophageal, or ovarian tissues frequently show allelic losses on chromosome band 17q25. Moreover, a locus responsible for hereditary focal nonepidermolytic palmoplantar keratoderma, a condition associated with esophageal cancer (TOC; tylosis with oesophageal cancer), has been mapped to the same band. During efforts to sequence, by shotgun methods, a 1-Mb target region that we had defined as the DNA segment harboring the putative tumor suppressor gene(s) involved in these events, we identified a novel cDNA. The full-length cDNA is 2495 bp long and is expressed predominantly in skeletal muscle, heart, kidney, and placenta. The predicted product, a 627-amino-acid protein, exhibited significant sequence homology to the canine 68-kd subunit of the signal recognition particle that has been implicated in the transport of secreted and membrane proteins to the endoplasmic reticulum for proper processing. We confirmed the location of this gene at chromosome 17q25.1 by radiationhybrid mapping and by fluorescence in situ hybridization.