Molecular functional analysis of the tumor suppressor gene PDCD4

Das Pdcd4-Gen (Programmed Cell Death 4) ist ein neues Tumorsupressorgen, das ursprünglich als ein während der Apoptose aktiviertes Gen identifiziert wurde. Um die molekularen Funktionen des Pdcd4 Tumorsuppressorgens zu charakterisieren, wurde ein Knock-Down-System mittels RNAi Technologie und ein Knock Out System mittels homologer Rekombination entwickelt. Mittels der 1D SDS PAGE- und der 2D-SDS-PAGE-Analyse konnten einige Transkriptionsfaktoren (ATF 2, c Myc, c Jun, CEBPß) sowie folgende Proteine als Pdcd4-Zielproteine identifiziert werden: Cytokeratin 17 (CK 17), Cytokeratin 8 (CK 8) und C2 und C3, die zur Familie der Aldo-Keton-Reduktase 1 (AKR1) gehören, sowie die Glutamyl Prolyl Bifunctional tRNA synthetase (GluProRS). Diese beiden hier entwickelten Systeme sowie die hier identifizierten Zielproteine könnten zur Klärung der molekularen Funktionen des Tumorsuppressor Pdcd4 beitragen. The Programmed Cell Death 4 gene (Pdcd4) is a novel tumor suppressor gene originally identified as a gene upregulated during apoptosis. To study the molecular functions of the Pdcd4 tumor suppressor gene by a reverse genetic approach, a knock down system and a knock-out system were developed in the HeLa cells using siRNA mediated RNA interference (RNAi) and in the DT40 cells using homologous recombination, respectively. The 1D and 2D SDS PAGE analysis in HeLa cells identified several transcription factors (ATF-2, c-Myc, c-Jun, CEBPß) and proteins viz., cytokeratin 17 (CK 17), Aldo Keto Reductase 1 (AKR1) family members C2 and C3, cytokeratin 8 (CK 8) and Glutamyl Prolyl Bifunctional tRNA synthetase (GluProRS) as novel molecular targets of Pdcd4. The two systems developed in the present work will be useful in further elucidating the molecular functions of tumor suppressor Pdcd4 by utilizing the molecular targets identified here

PHIP:a novel candidate breast cancer susceptibility locus on 6q14.1

Abstract Most non-BRCA1/2 breast cancer families have no identified genetic cause. We used linkage and haplotype analyses in familial and sporadic breast cancer cases to identify a susceptibility locus on chromosome 6q. Two independent genome-wide linkage analysis studies suggested a 3 Mb locus on chromosome 6q and two unrelated Swedish families with a LOD >2 together seemed to share a haplotype in 6q14.1. We hypothesized that this region harbored a rare high-risk founder allele contributing to breast cancer in these two families. Sequencing of DNA and RNA from the two families did not detect any pathogenic mutations. Finally, 29 SNPs in the region were analyzed in 44,214 cases and 43,532 controls from BCAC, and the original haplotypes in the two families were suggested as low-risk alleles for European and Swedish women specifically. There was also some support for one additional independent moderate-risk allele in Swedish familial samples. The results were consistent with our previous findings in familial breast cancer and supported a breast cancer susceptibility locus at 6q14.1 around the PHIP gene