Biomedical subjects

Frank Schoenen

Publications and source records attributed to Frank Schoenen.

4 recordsLinked to original sources

PubMed2006

The zinc finger protein ZNF297B interacts with BDP1, a subunit of TFIIIB.

The human gene BDP1, localized on chromosome 5q13 in close proximity to the spinal muscular atrophy determining gene SMN, encodes a large protein consisting of 2254 amino acids (aa). In the first third of the gene, the subunit of the RNA polymerase III (Pol III) transcription factor complex (TFIIIB alpha/beta) is encoded. To further characterize the function of BDP1, we carried out a yeast two-hybrid screen using various parts of BDP1. With the clone BDP1-(1-640) we identified a novel interaction partner, ZNF297B. The ZNF297B gene is localized on chromosome 9q24 and encodes a zinc finger protein of 467 aa possessing the typical structure of a transcription factor. The interaction found in yeast was confirmed by co-immunoprecipitation and refined to the N-terminal region of ZNF297B-(1-127) containing the BTB/POZ domain and the N-terminal end of BDP1-(1-299). The ZNF297B transcript is 5.7 kb in length and ubiquitously expressed, with highest levels found in muscles. Immunofluorescence staining revealed a speckled pattern in the nuclei of HEK293 cells. Due to the essential role of BDP1 in Pol III transcription, we propose that ZNF297B may also regulate these transcriptional pathways.

Base Sequence↗

PubMed2003

Evidence for a modifying pathway in SMA discordant families: reduced SMN level decreases the amount of its interacting partners and Htra2-beta1.

Proximal spinal muscular atrophy (SMA) is a neuromuscular disorder caused by homozygous mutations of the SMN1 gene. SMN1 interacts with multiple proteins with functions in snRNP biogenesis, pre-mRNA splicing and presumably neural transport. SMN2, a nearly identical copy of SMN1, produces predominantly exon 7-skipped transcripts, whereas SMN1 mainly produces full-length transcripts. The SR-like splicing factor Htra2-beta1 facilitates correct splicing of SMN2 exon 7 through direct interaction with an exonic splicing enhancer within exon 7. In rare cases, siblings with identical 5q13-homologues and homozygous absence of SMN1 show variable phenotypes, suggesting that SMA is modified by other factors. By analysing nine SMA discordant families, we demonstrate that in all families unaffected siblings produce significantly higher amounts of SMN, Gemin2, Gemin3, ZPR1 and hnRNP-Q protein in lymphoblastoid cell lines, but not in primary fibroblasts, compared with their affected siblings. Protein p53, an additional SMN-interacting protein, is not subject to an SMN-dependent regulation. Surprisingly, Htra2-beta1 is also regulated by this tissue-specific mechanism. A similar regulation was found in all type I-III SMA patients, although at a different protein level than in discordant families. Thus, our data show that reduced SMN protein levels cause a reduction in the amount of its interacting proteins and of Htra2-beta1 in both discordant and non-discordant SMA families. We provide evidence that an intrinsic SMA modifying factor acts directly on the expression of SMN, thus influencing the SMA phenotype. Further insights into the molecular pathway and the identification of SMA modifying gene(s) may help to find additional targets for a therapy approach.

Adult↗

PubMed2003

Combinatorial compound libraries for drug discovery: an ongoing challenge.

Almost 20 years of combinatorial chemistry have emphasized the power of numbers, a key issue for drug discovery in the current genomic era, in which it has been estimated that there might be more than 10,000 potential targets for which it would be desirable to have small-molecule modulators. Combinatorial chemistry is best described as the industrialization of chemistry; the chemistry has not changed, just the way in which it is now carried out, which is principally by exploiting instrumentation and robotics coupled to the extensive use of computers to efficiently control the process and analyse the vast amounts of resulting data. Many researchers have contributed to the general concepts as well as to the technologies in present use. However, some interesting challenges still remain to be solved, and these are discussed here in the context of the application of combinatorial chemistry to drug discovery.

Animals↗

PubMedDate not supplied

Solution-phase parallel synthesis of a library of delta(2)-pyrazolines.

A parallel synthesis of a library (80 members) of 2-pyrazolines in solution phase is described. The 2-pyrazoline core was accessed through the [3 + 2] cycloaddition of nitrilimines with enoyl oxazolidinones. The cycloaddition provided two regioisomers, the major product being the C regioisomer. The oxazolidinone moiety was further reduced to the primary alcohol, producing another library of 5-hydroxymethyl-2-pyrazolines. The Lipinski profiles and calculated ADME properties of the compounds are also reported.

Combinatorial Chemistry Techniques↗