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Medical Sciences	50%

Selected Abstracts

Lef-1 isoforms regulate different target genes and reduce cellular adhesion

INTERNATIONAL JOURNAL OF CANCER, Issue 5 2010
Sarah Jesse
Abstract The lymphoid enhancer factor 1 (Lef-1) belongs to the nuclear transducers of canonical Wnt-signalling in embryogenesis and cancer. Lef-1 acts, in cooperation with ,-catenin, as a context-dependent transcriptional activator or repressor, thereby influencing multiple cellular functions such as proliferation, differentiation and migration. Here we report that an increased Lef-1 expression in human pancreatic cancer correlates with advanced tumour stages. In pancreatic tumours, two different transcripts of Lef-1 have been detected in various stages, as demonstrated by RT-PCR analysis. One transcript was identified as the full length Lef-1 (Lef-1 FL), whereas the second, shorter transcript lacked exon VI (Lef-1 ,exon VI) compared to the published sequence. Comparative analysis of these two Lef-1 variants revealed that they exhibit different cellular effects after transient expression in pancreatic carcinoma cells. Forced expression of Lef-1 ,exon VI inhibited E-cadherin expression in a ,-catenin-independent way. Increased amounts of Lef-1 ,exon VI resulted in reduced cellular aggregation and increased cell migration. Expression of Lef-1 FL, but not the newly identified Lef-1 ,exon VI, induced the expression of the cell cycle regulating proteins c-myc and cyclin D1 in cooperation with ,-catenin and it enhanced cell proliferation. Our findings indicate that expression of alternatively spliced Lef-1 isoforms is involved in the determination of proliferative or migratory characteristics of pancreatic carcinoma cells. [source]

Differential targeting of GSH1 and GSH2 is achieved by multiple transcription initiation: implications for the compartmentation of glutathione biosynthesis in the Brassicaceae

THE PLANT JOURNAL, Issue 1 2005
Andreas Wachter
Summary The genome of Arabidopsis thaliana reveals that in this species the enzymes of glutathione biosynthesis, GSH1 and GSH2, are encoded by single genes. In silico analysis predicts proteins with putative plastidic transit peptides (TP) for both genes, but this has not been experimentally verified. Here we report a detailed analysis of the 5,ends of GSH1 and GSH2 mRNAs and demonstrate the subcellular targeting of the proteins encoded by different transcript types. GSH1 transcript analysis revealed two mRNA populations with short and long 5,-UTRs, respectively, both including the entire TP sequence. The ratio of long/total GSH1 transcripts was subject to developmental regulation. Transient transformation experiments with reporter gene fusions, bearing long or short 5,-UTRs, indicated an exclusive targeting of GSH1 to the plastids. Corroborating these results, endogenous and ectopically expressed GSH1 proteins were always present as a single polypeptide species with the size expected for correctly processed GSH1. Finally, the plastidic GSH1 localization was confirmed by immunocytochemistry. Similar to GSH1, multiple transcript populations were found for GSH2. However, here the prevalent shorter transcripts lacked a complete TP sequence. As expected, the large (but less abundant) transcript encoded a plastidic GSH2 protein, whereas GSH2 synthesized from the shorter transcript was targeted to the cytosol. The implications of the results for the compartmentation and regulation of GSH synthesis are discussed. [source]

Definition of three minimal deleted regions by comprehensive allelotyping and mutational screening of FHIT,p16INK4A, and p19ARF genes in nasopharyngeal carcinoma

CANCER, Issue 7 2002
Jenq-Yuh Ko M.D.
Abstract BACKGROUND Recurrent deletion on a chromosomal location in tumor cells can be detected by frequent allelic loss and generally is considered to be an indication of the existence of a tumor suppressor gene (TSG) in the region. In the current study, using fluorescent-labeled, high-density microsatellite markers for allelotyping, the authors pinpointed three minimal deleted regions (MDRs) and screened mutations of putative TSGs on chromosomes 3, 9, and 11 in nasopharyngeal carcinoma (NPC) cases occurring in Taiwan. METHODS A total of 133 informative microsatellite markers were used on chromosomes 3, 9, and 11 with an average marker density of 4 centimorgans (cM) for the allelotyping of genomic DNAs isolated from NPC tissues and their corresponding lymphocytes in 48 patients. The correlation between allelic loss and the clinicopathologic parameters of NPC tissues was examined. In addition, putative TSGs including FHIT, p16INK4a, and p19ARF were selected for mutation screening to investigate their potential participation in NPC tumorigenesis. RESULTS Of 3787 informative allelotyping data, 25 frequent allelic losses (or loss of heterozygosity [LOH]) in 13 cytogenetic loci were identified based on a deletion frequency that was greater than the average of allelic loss on that particular chromosome. Several significant associations were determined after statistical analysis of the correlation between allelic loss and clinicopathologic parameters. The allelic losses by D9S318 and D11S1304 were associated with N2/N3 (P = 0.035 and P = 0.005, respectively), and those by D9S905 and D11S1304 were associated with grouped American Joint Committee on Cancer (AJCC) Stage III/IV samples (P = 0.022 and P = 0.017, respectively) of NPC tissues. In addition, three MDRs were revealed on 3p25.3-24.1 (< 19 cM), 3p23-21.31 (< 9 cM), and 11q22.1-23.2 (< 8 cM). To examine somatic mutations in previously reported TSGs located near these frequent LOH loci, three candidate genes, p16INK4a, p19ARF, and FHIT, were analyzed. Point mutations in the coding region of FHIT and in the intron 1 splicing acceptor site of both p16INK4a and p19ARF were detected in NPC cell lines. Sequence analysis of both p16INK4a and p19ARF transcripts revealed that the point mutation resulted in skipping of exon 2 and the generation of shorter transcripts. CONCLUSIONS High-density allelotyping permitted the discovery of 3 MDRs on 3p25.3-24.1 (< 19 cM), 3p23-21.31 (< 9 cM), and 11q22.1-23.2 (< 8 cM) and a correlation was determined between allelic loss and clinicopathologic parameters of NPC tissues. More important, one somatic mutation in NPC cell lines on the intron 1/exon 2 splicing acceptor site of the INK4a/ARF locus was found to result in exon 2 skipping both p16INK4a and p19ARF transcripts, which presumably inactivates the functions of both the p16INK4a and p19ARF proteins. Cancer 2002;94:1987,96. © 2002 American Cancer Society. DOI 10.1002/cncr.10406 [source]