RNASEL mutation screening and association study in Ashkenazi and non-Ashkenazi prostate cancer patients.

Epidemiologic and genetic studies support the considerable effect of heritable factors on prostate tumorigenesis, although to date, no unequivocal susceptibility gene has been identified. The extensive study of RNASEL in prostate cancer patients worldwide has yielded conflicting results. We reevaluated the role of the RNASEL 471delAAAG Ashkenazi founder mutation in 1,642 Ashkenazi patients with prostate, bladder, breast/ovarian, and colon cancers; Ashkenazi controls; and in non-Ashkenazi prostate cancer patients and controls. The entire RNASEL coding sequence was also screened using denaturing high-performance liquid chromatography and multiplex ligation-dependent probe amplification for possible sequence variations or copy number changes in a population of prostate cancer patients. The 471delAAAG mutation was detected in 2.4% of the Ashkenazi prostate cancer patients; in 1.9% of patients with bladder, breast/ovarian, and colon cancers; and in 2.0% of the Ashkenazi controls. Seven additional variants were detected in RNASEL, including a novel potentially pathogenic splice site mutation, IVS5+1delG, although none were associated with increased prostate cancer risk. Multiplex ligation-dependent probe amplification analysis showed two RNASEL gene copies in all 300 prostate cancer patients tested. We estimated that the RNASEL 471delAAAG founder mutation, which was detected in 2% of the Ashkenazi Jews, originated between the 2nd and 5th centuries A.D., compared with the less frequent (1%) BRCA1 185delAG founder mutation, which originated hundreds of years earlier. Taken together, our analysis does not support a role for the RNASEL 471delAAAG Ashkenazi mutation nor for the other alterations detected in RNASEL in prostate cancer risk in Jewish men.

Functional analysis of the Aurora Kinase A Ile31 allelic variant in human prostate.

Overexpression of the centrosome-associated serine/threonine kinase Aurora Kinase A (AURKA) has been demonstrated in both advanced prostate cancer and high-grade prostatic intraepithelial neoplasia lesions. The single-nucleotide polymorphism T91A (Phe31Ile) has been implicated in AURKA overexpression and has been suggested as a low-penetrance susceptibility allele in multiple human cancers, including prostate cancer. We studied the transcriptional consequences of the AURKA Ile31 allele in 28 commercial normal prostate tissue RNA samples (median age, 27 years). Significant overexpression of AURKA was demonstrated in homozygous and heterozygous AURKA Ile31 prostate RNA (2.07-fold and 1.93-fold, respectively; P < .05). Expression levels of 1509 genes differentiated between samples homozygous for Phe31 alleles and samples homozygous for Ile31 alleles (P = .05). Gene Ontology classification revealed overrepresentation of cell cycle arrest, ubiquitin cycle, antiapoptosis, and angiogenesis-related genes. When these hypothesis-generating results were subjected to more stringent statistical criteria, overexpression of a novel transcript of the natural killer tumor recognition sequence (NKTR) gene was revealed and validated in homozygous Ile31 samples (2.6-fold; P < .05). In summary, our data suggest an association between the AURKA Ile31 allele and an altered transcriptome in normal non-neoplastic prostates.

Mutation screening and association study of the candidate prostate cancer susceptibility genes MSR1, PTEN, and KLF6.

BACKGROUND: MSR1, PTEN, and KLF6 have been implicated as candidate susceptibility genes for prostate tumorigenesis. METHODS: Three hundred Jewish prostate cancer patients were screened for alterations in these genes. RESULTS: MSR1 was conserved in all patients. PTEN screening revealed a novel missense mutation and a silent change. Five KLF6 alterations were detected in 17 patients, including Q160X, the only nonsense KLF6 germline mutation described to date in a cancer patient. The KLF6 IVS1-27G>A polymorphism, recently associated with prostate cancer risk, was detected in 11.9% of the patients and 17.3% of the controls (P = 0.043). IVS1-27A allele frequency was significantly lower in prostate cancer patients (P = 0.030), specifically in Ashkenazi patients (P = 0.047) compared to controls. CONCLUSIONS: We found no evidence that MSR1 and PTEN germline mutations are associated with prostate cancer risk in Jews. The negative association between KLF6 IVS1-27A and prostate cancer risk supports a population-specific effect of susceptibility alleles in prostate tumorigenesis.

A novel plant cysteine protease has a dual function as a regulator of 1-aminocyclopropane-1-carboxylic Acid synthase gene expression.

The hormone ethylene influences plant growth, development, and some defense responses. The fungal elicitor Ethylene-Inducing Xylanase (EIX) elicits ethylene biosynthesis in tomato (Lycopersicon esculentum) and tobacco (Nicotiana tabacum) leaves by induction of 1-aminocyclopropane-1-caboxylic acid synthase (Acs) gene expression. A minimal promoter element in the LeAcs2 gene required for EIX responsiveness was defined by deletion analysis in transgenic tomato plants. The sequence between -715 and -675 of the tomato Acs2 gene was found to be essential for induction by EIX. A Cys protease (LeCp) was isolated that specifically binds to this cis element in vitro. Ectopic expression of LeCp in tomato leaves induced the expression of Acs2. Moreover, chromatin immunoprecipitation showed that LeCp binds in vivo to the Acs promoter. We propose a mechanism for the dual function of the LeCp protein. The protease acts enzymatically in the cytoplasm. Then, upon signaling, a small ubiquitin-related modifier protein binds to it, enabling entrance into the nucleus, where it acts as a transcription factor. Thus, LeCp can be considered a dual-function protein, having enzymatic activity and, upon elicitor signaling, exhibiting transcriptional factor activity that induces LeAcs2 expression.