218 research outputs found
Amyloid Deposition in Transplanted Human Pancreatic Islets : A Conceivable Cause of Their Long-Term Failure
No full textFollowing the encouraging report of the Edmonton group, there was a rejuvenation of the islet transplantation field. After that, more pessimistic views spread when long-term results of the clinical outcome were published. A progressive loss of the beta-cell function meant that almost all patients were back on insulin therapy after 5 years. More than 10 years ago, we demonstrated that amyloid deposits rapidly formed in human islets and in mouse islets transgenic for human IAPP when grafted into nude mice. It is, therefore, conceivable to consider amyloid formation as one potential candidate for the long-term failure. The present paper reviews attempts in our laboratories to elucidate the dynamics of and mechanisms behind the formation of amyloid in transplanted islets with special emphasis on the impact of long-term hyperglycemia.Original Publication:Arne Andersson, Sara Bohman, L A Hakan Borg, Johan Paulsson, Sebastian Schultz, Gunilla Westermark and Per Westermark, Amyloid Deposition in Transplanted Human Pancreatic Islets: A Conceivable Cause of Their Long-Term Failure, 2008, EXPERIMENTAL DIABETES RESEARCH, (2008), 562985.http://dx.doi.org/10.1155/2008/562985Copyright: Author
Platelet-derived growth factor in glioblastoma-driver or biomarker?
No full textThe platelet-derived growth factor (PDGF) family of mitogens exerts vital functions during embryonal development, e.g. in the central nervous system, where PDGF drives the proliferation of oligodendrocyte precursors. PDGF and PDGF receptors are co-expressed in human glioblastoma (GBM). Whether an aberrant activation of the PDGF receptor pathway is a driving force in glioma development has remained an open question. In experimental animals, overexpression of PDGF has convincingly been shown to induce tumors, both in wild-type animals (marmoset, rat, mouse) and in mice with targeted deletions of suppressor genes, e.g. Tp53 or Ink4A. Targeting the PDGF receptor in tumor-bearing mice leads to growth inhibition and reversion of the transformed phenotype. Findings of PDGF receptor amplification or mutations in human GBM are strong indicators of a causative role of the PDGF receptor pathway. However, clinical trials using PDGF receptor antagonists have been disappointing. In conclusion, a PDGF receptor profile may be a biomarker for a subgroup of GBM originating from a PDGF receptor-responsive cell. Although compelling experimental and clinical evidence supports the notion that the PDGF receptor pathway is a driver in GBM, formal proof is still missing.</p
CGGBP1-an indispensable protein with ubiquitous cytoprotective functions
No full textThe human genome contains multiple stretches of CGG trinucleotide repeats, which act as transcription- and translation-regulatory elements but at the same time form secondary structures that impede replication and give rise to sites of chromosome fragility. Proteins binding to such DNA elements may be involved in divergent cellular processes such as transcription, DNA damage, and epigenetic state of the chromatin. We review here the work done on CGG repeats and associated proteins with special focus on a factor called CGGBP1. CGGBP1 presents with an interesting example of factors that do not have any single dedicated function, but participate indispensably in multiple processes. Both experimental results and data from cancer genome sequencing have revealed that any alteration in CGGBP1 that compromises its function is not tolerated by normal or cancer cells alike. Based upon a large amount of published data, information from databases, and unpublished results, we decipher in this review how CGGBP1 is a classic example of the one factor, divergent functions' paradigm of cytoprotection. By taking cues from the studies on CGGBP1, more such factors can be discovered for a better understanding of the evolution of mechanisms of cellular survival.</p
CGGBP1 is a nuclear and midbody protein regulating abscission
No full textAbscission marks the completion of cell division and its failure is associated with delayed cytokinesis and even tetraploidization. Aberrant abscission and consequential ploidy changes can underlie various diseases including cancer. Midbody, a transient structure formed in the intercellular bridge during telophase, contains several proteins including Aurora kinase B (AURKB), which participate in abscission. We report here an unexpected expression pattern and function of the transcription repressor protein CGG triplet repeat-binding protein 1 (CGGBP1), in normal human fibroblasts. We show that CGGBP1, a chromatin-associated protein, trans-localizes to spindle midzone and midbodies in a manner similar to that of AURKB. CGGBP1 depletion resulted in a cell cycle block at G2, characterized by failure of cells to undergo mitosis and also reduced entry into S phase. Consistent with its presence in the midbodies, live microscopy showed that CGGBP1 deficiency caused mitotic failure at abscission resulting in tetraploidy, which could be rescued by CGGBP1 overexpression. These results show that CGGBP1 is a bona fide midbody protein required for normal abscission and mitosis in general.</p
Growth factor‐induced proliferation of human fibroblasts in serum‐free culture depends on cell density and extracellular calcium concentration
No full textReal-Time Monitoring of Apoptosis by Caspase-3-Like Protease Induced FRET Reduction Triggered by Amyloid Aggregation
No full textAmyloid formation is cytotoxic and can activate the caspase cascade. Here, we monitor caspase-3-like activity as reduction of fluorescence resonance energy transfer (FRET) using the contstruct pFRET2-DEVD containing enhanced cyan fluorescent protin (EYFP) linked by the caspase-3 specific cleavage site residues DEVD. Beta-TC-6 cells were transfected, and the fluoorescence was measured at 440 nm excitation and 535 nm (EYFP) and 480 nm (ECFP) emission wavelength. Cells were incubated with recombinant pro lset Amyloid Polypeptide (rec prolAPP) or the processing metabolites of prolAPP; the N-terminal flanking peptide withIAPP (recN+IAPP); IAPP with the C-terminal flanking peptied (recIAPP+C) and lslet Amyloid Polypeptide (recIAPP). Peptides were added in solubilized from (50 mu M) or as performed amyloid-like fibrils, or as a combination of these. FRET was measured and incubation with a mixture of solubilized peptide and performed fibrils resulted in loss of FRET and apoptosis was determined to occurein cells incubated with recproIAPP (49%), recN+IAPP (46%), recIAPP (72%) and recIAPP+C (59%). These results show that proIAPP and the processing intermediates reside the same cell toxic capacity as IAPP, and they can all have a central role in the reduction of beta-cell number in type 2 diabetes.Original Publication:Johan F Paulsson, Sebastian Schultz, Martin Kohler, Ingo Leibiger, Per-Olof Berggren and Gunilla Westermark, Real-Time Monitoring of Apoptosis by Caspase-3-Like Protease Induced FRET Reduction Triggered by Amyloid Aggregation, 2008, EXPERIMENTAL DIABETES RESEARCH, (2008), 865850.http://dx.doi.org/10.1155/2008/865850Copyright: Author
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