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- Castillejo-Lopez, Casimiro
(författare)
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Repetitive DNA in search of a function - a study of telomeric and centromeric sequences in Chironomus
- 1998
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Repetitive DNA is quantitatively the main component of telomeres and centromeres, structures responsible for maintenance of the eukaryotic chromosome. The telomere is the specialized nucleoprotein complex that terminates linear chromosomes. In most species the DNA component consists of short repeats which are generated by the enzyme complex telomerase. However, there are important exceptions such as the Drosophila melanogaster telomeres which are elongated by retrotransposons and, as documented in the present thesis, a third telomeric system in Chironomus pallidivittatus in the form of arrays of 340 bp long complex tandem repeats which extend to the end of their chromosomes. Complex repeats are not elongated by telomerase and one aim of my work has therefore been to elucidate possible regeneration mechanisms for telomeres with such repeats. I have obtained evidence for DNA increase through DNA sequences of nontelomeric origin being inserted into the telomeric repeat array via gene conversion. Immunolocalization of reverse transcriptase related proteins in the telomeric puff of the related species C. thummi revealed, on the other hand, a possible link between the regeneration of Chironomus telomeric complex repeats and mechanisms used by other eukaryotes. Only seven of the eight pairs of chromosome termini in C. pallidivittatus have 340 bp repeats. The remaining telocentric end contains another repeat, the centromeric 155 bp unit, probably extending to the chromosome end. In the arrays of this repeat, a putative homologue of the mammalian centromeric CENP-B box has been found and characterized. Its interspersed distribution and its surrounding direct repeats suggest a mobile origin. It is present in different recombined forms, which could be related to a role in recombination as has been suggested for the human CENP-B box.
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- Kolliopoulos, Konstantinos, 1986-, et al.
(författare)
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Effect of CD44 on glioma cell progression, invasion and senescence
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Glioblastoma multiforme (GBM) is a lethal brain tumor, characterized by enhanced proliferation rate, increased invasive capacity, and chemoresistance. The expression of the hyaluronan receptor CD44 correlates with GBM progression and poor prognosis. We have initiated studies to elucidate the molecular mechanisms behind the effects of CD44 on tumorigenesis by knocking out (KO) CD44, via employing CRISPR/Cas9 gene editing in U251MG cells. CD44-depleted cells exhibited impaired proliferation rate, as confirmed by decreased cell numbers, Ki67 positive nuclei, diminished p-CREB levels, and increased levels of the cell cycle inhibitor p16 compared to control cells. Furthermore, the CD44 KO cells acquired a pro-senescence state, which was manifested upon serum deprivation. Interestingly, CD44 KO cells showed enhanced migratory and invasive properties, as observed in 2D wound healing and 3D collagen assays, which may be partially attributed to the acquisition of a senescence-associated secretory phenotype (SASP) and activation of the ERK1/2 MAPK pathway. RNA-sequencing analysis of stem-like U251MG cells, grown in spheres, unveiled a CD44-dependency for expression of molecules involved in hyaluronan synthesis and degradation, and of members of the PDGF and PDGF receptor families. These observations highlight the importance of CD44 on GBM progression.
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- Prokunina, Ludmila, et al.
(författare)
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A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans
- 2002
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 32:4, s. 666-669
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Recension (övrigt vetenskapligt/konstnärligt)abstract
- Systemic lupus erythematosus (SLE, OMIM 152700) is a complex autoimmune disease that affects 0.05% of the Western population, predominantly women. A number of susceptibility loci for SLE have been suggested in different populations, but the nature of the susceptibility genes and mutations is yet to be identified. We previously reported a susceptibility locus (SLEB2) for Nordic multi-case families. Within this locus, the programmed cell death 1 gene (PDCD1, also called PD-1) was considered the strongest candidate for association with the disease. Here, we analyzed 2,510 individuals, including members of five independent sets of families as well as unrelated individuals affected with SLE, for single-nucleotide polymorphisms (SNPs) that we identified in PDCD1. We show that one intronic SNP in PDCD1 is associated with development of SLE in Europeans (found in 12% of affected individuals versus 5% of controls; P = 0.00001, r.r. (relative risk) = 2.6) and Mexicans (found in 7% of affected individuals versus 2% of controls; P = 0.0009, r.r. = 3.5). The associated allele of this SNP alters a binding site for the runt-related transcription factor 1 (RUNX1, also called AML1) located in an intronic enhancer, suggesting a mechanism through which it can contribute to the development of SLE in humans.
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