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P Golstein

Publications and source records attributed to P Golstein.

At least 19 recordsLinked to original sources
PubMed2006

A necrotic cell death model in a protist.

While necrotic cell death is attracting considerable interest, its molecular bases are still poorly understood. Investigations in simple biological models, taken for instance outside the animal kingdom, may benefit from less interference from other cell death mechanisms and from better experimental accessibility, while providing phylogenetic information. Can necrotic cell death occur outside the animal kingdom? In the protist Dictyostelium, developmental stimuli induced in an autophagy mutant a stereotyped sequence of events characteristic of necrotic cell death. This sequence included swift mitochondrial uncoupling with mitochondrial 2',7'-dichlorofluorescein diacetate fluorescence, ATP depletion and increased oxygen consumption. This was followed by perinuclear clustering of dilated mitochondria. Rapid plasma membrane rupture then occurred, which was evidenced by time-lapse videos and quantified by FACS. Of additional interest, developmental stimuli and classical mitochondrial uncouplers triggered a similar sequence of events, and exogenous glucose delayed plasma membrane rupture in a nonglycolytic manner. The occurrence of necrotic cell death in the protist Dictyostelium (1) provides a very favorable model for further study of this type of cell death, and (2) strongly suggests that the mechanism underlying necrotic cell death was present in an ancestor common to the Amoebozoa protists and to animals and has been conserved in evolution.

Animals↗
PubMed2005

Redundant cell death mechanisms as relics and backups.

Here we review recent observations indicating the existence of redundant cell death mechanisms. We speculate that this redundancy reflects a particular evolutionary history for cellular demise. Autophagic or apoptotic elements might have been added to a primordial death mechanism, initially improving cell dismantling and later acquiring the ability to act themselves as death effectors. The resulting redundancy of cell death mechanisms has pathophysiological implications.

Animals↗
PubMed2003

Endoscopic histoacryl obliteration vs. propranolol in the prevention of esophagogastric variceal rebleeding: a randomized trial.

BACKGROUND AND STUDY AIMS: The obliteration of esophageal and/or gastric varices using Histoacryl is highly effective in controlling active bleeding. However, it is not known whether repeated injections are useful for the long-term eradication of esophagogastric varices. The aim of the study was to compare endoscopic Histoacryl obliteration with propranolol in the secondary prevention of esophagogastric variceal bleeding. PATIENTS AND METHODS: Between August 1995 and February 1999, 41 patients with a first bleeding from esophageal (n = 31) or gastric (n = 10) varices were included in the study. After primary hemostasis with obliteration using Histoacryl, patients were randomly allocated either to undergo complete Histoacryl obliteration of the remaining varices (group A, n = 21) or to long-term propranolol administration (group B, n = 20), for the prevention of rebleeding. RESULTS: The two groups were well matched for age, sex, etiology of cirrhosis, Child-Pugh score, renal function, and infection at the time of admission. The median follow-up was 31.9 months (4.8 - 74.7) for group A and 23.2 months (3.0 - 70.0) for group B. Initial hemostasis was achieved in 40/41 patients (97 %). No significant difference was observed between groups A and B with regard to the incidence of early rebleeding (during the first 6 weeks; 5/21 and 3/20), bleeding-related deaths by 6 weeks (3/21 and 6/20), long-term rebleeding (11/21 and 5/20), or overall number of deaths (9/21 and 9/20). The incidence of complications was higher in group A (10/21) than group B (2/20) (P < 0.03). CONCLUSIONS: Repeated injections of Histoacryl with the aim of eradicating esophagogastric varices are associated with more complications compared with beta-blocker administration, with similar results in terms of rebleeding rate and survival in the long term.

Adult↗
PubMed2001

Individual variations in the correlation between erythemal threshold, UV-induced DNA damage and sun-burn cell formation.

A linear correlation between erythema intensity and DNA damage upon exposure to UV has not been firmly established. Many of the deleterious effects of UV exposure do occur after exposure to suberythemal doses. After DNA damage, cells undergo DNA repair. It is commonly accepted that when the burden of damage is beyond the repair capacities, the cell undergoes programmed cell death or apoptosis. The aim of this study is to quantify the amount of UV-induced DNA damage (estimated via the measurement of DNA repair or unscheduled DNA synthesis or UDS) and cellular damage (estimated via the determination of the density of sunburn cells or SBC). If DNA damage and erythema are correlated, similar intensity of UDS and similar density of SBC should be found in volunteers irradiated with a UV dose equal to two minimal erythema doses (MED). Our results show that in 15 different individuals the same relative dose (2 MEDs) provokes UDS values, which vary within a factor of 4. An even larger variability affects SBC counts after the same relative dose. When DNA damage or SBC are plotted versus the absolute dose (i.e. the dose expressed in J/m(2)), there is a rough correlation (with several exceptions) between dose and extent of UDS and SBC counts. It seems possible to divide the volunteers into two subpopulations with different susceptibilities to UV damage. It is well known that UDS and SBC measurements are often affected by large experimental indeterminacy, yet, the analysis of our results makes it plausible to suggest that for the triggering of erythema, a common threshold value for DNA damage or for SBC count are not to be found. In conclusion, the erythema response seems to be loosely correlated with DNA damage. This suggests that the protection offered by the sunscreens against DNA damage, the molecular basis of UV-induced mutagenesis, might not be related to the sun protection factor (SPF) indicated on the label of sunscreens, which is evaluated using the erythema as an endpoint.

Abnormalities, Radiation-Induced↗
PubMed2000

Signal transduction. FasL binds preassembled Fas.

The binding of a ligand to its receptor has always been viewed as the trigger for signal transduction to ensue. However, as Golstein explains in his Perspective, new findings (Chan et al. and Siegel et al.) suggest that the Fas receptor preassembles into trimers without the help of its ligand, and that this preassembly conditions ligand binding, and thus subsequent signal transduction of a death signal.

Animals↗
PubMed1999

Interdigital cell death can occur through a necrotic and caspase-independent pathway.

Programmed cell death in animals is usually associated with apoptotic morphology and requires caspase activation. Necrosis and caspase-independent cell death have been reported, but mostly in experimental conditions that lead some to question their existence it in vivo. Loss of interdigital cells in the mouse embryo, a paradigm of cell death during development [1], is known to include an apoptotic [2] and caspase-dependent [3] [4] mechanism. Here, we report that, when caspase activity was inhibited using drugs or when apoptosis was prevented genetically (using Hammertoe mutant mice, or mice homozygous for a mutation in the gene encoding APAF-1, a caspase-activating adaptor protein), interdigital cell death still occurred. This cell death was negative for the terminal-deoxynucleotidyl-mediated dUTP nick end-labelling (TUNEL) assay and there was no overall cell condensation. At the electron microscopy level, peculiar 'mottled' chromatin alterations and marked mitochondrial and membrane lesions, suggestive of classical necrotic cell death, were observed with no detectable phagocytosis and no local inflammatory response. Thus, in this developmental context, although caspase activity confers cell death with an apoptotic morphotype, in the absence of caspase activity an underlying mechanism independent of known caspases can also confer cell death, but with a necrotic morphotype. This cell death can go undetected when using apoptosis-specific methodology, and cannot be blocked by agents that act on caspases.

Amino Acid Chloromethyl Ketones↗
PubMed1999

WW domain-containing FBP-30 is regulated by p53.

A subtractive cloning approach was used to clone genes transcriptionally induced in thymocytes undergoing programmed cell death after gamma-irradiation. We thus identified about 60 upregulated genes. One of these genes encodes a WW domain previously briefly reported by others, which defines this gene as FBP-30. cDNA sequencing showed FBP-30 to be remarkably conserved in mammals. FBP-30 expression, essentially restricted to T cells, was regulated by p53 since it increased (1) after gamma-irradiation in wild-type but not in p53-/- thymocytes and (2) in cells transfected with a conditional temperature-sensitive p53 mutant, less than 1 h after shifting to permissive temperature. Upregulation of FBP-30 expression thus depends upon p53 protein expression and correlates with cell death induction in these systems. While the kinetics of its induction are rapid, the observed increased expression of FBP-30 in the presence of protein synthesis inhibitors suggests that FBP-30 gene expression is indirectly regulated by p53, through downregulation of a labile inhibitor of FBP-30 expression.

Amino Acid Sequence↗
PubMed1998

Apparent caspase independence of programmed cell death in Dictyostelium.

During normal development, cell elimination [1,2] occurs by programmed cell death (PCD) [3], of which apoptosis [4] is the best known morphological type. Activation of cysteine proteases termed caspases [5] is required in many instances of animal PCD [6-9], but its role outside the animal kingdom is as yet unknown. PCD occurs during developmental stages in the slime mold Dictyostelium discoideum [10,11]. Under favorable conditions, Dictyostelium multiplies as a unicellular organism. Upon starvation, a pathway involving aggregation, differentiation and morphogenesis induces the formation of a multicellular fungus-like structure called a sorocarp [12], consisting mainly of spores and stalk cells, the latter being a result of cell death. Dictyostelium cell death is similar to classical apoptosis in that some cytoplasmic and chromatin condensation occurs but differs from apoptosis because it involves massive vacuolisation and, interestingly, lacks DNA fragmentation [11]. We examined whether caspase activity is required for Dictyostelium cell death. We found that caspase inhibitors did not affect cell death, although some caspase inhibitors that did not inhibit cell death impaired other stages in development and could block affinity-labelling of soluble extracts of Dictyostelium cells with an activated caspase-specific reagent. The simplest interpretation of these results is that in Dictyostelium, whether or not caspase-like molecules exist and are required for some developmental steps, caspase activation is not required for cell death itself.

Animals↗
PubMed1998

An insertional mutagenesis approach to Dictyostelium cell death.

Programmed cell death (PCD) in Dictyostelium shows a pattern of ordered degeneration similar to that observed in higher eukaryotes but somewhat different from the most studied form of PCD, i.e. apoptosis. To contribute to a genetic definition of this process, Dictyostelium HMX44A cells have been subjected to insertional mutagenesis, followed by selection based on several rounds of differentiation/regrowth to recover only cells resistant to death. We describe here the approach used, a partial characterization of the first mutant thus obtained called C5 showing some dissociation of cell death signs, and, in this case where plasmid rescue was not possible, as a first step towards identification of the gene at play recovery of genomic flanking sequences via genomic recircularization and PCR. This work demonstrates the feasibility of an insertional mutagenesis approach to obtain death-resistant mutants in Dictyostelium.

Animals↗
PubMed1998

Dismantling in cell death: molecular mechanisms and relationship to caspase activation.

The notion of a cell death programme was introduced in view of the reproducibility of its occurrence in time and space (e.g. in the developing embryo) and of its genetic determination. Programmed cell death can be schematically subdivided into three steps: a signalling phase, an execution phase and a dismantling phase. This review focuses on the latter. Apoptosis is the most studied form of dismantling of animal cells. The molecular pathways leading to certain apoptotic lesions appear to be dependent on the proteolytic activity of caspases. Death itself can, however, be caspase-independent. Also, non-apoptotic forms of cell death exist, even in animal cells; their molecular bases are still unknown. The relationship between cell death, apoptosis and caspases is discussed.

Animals↗
PubMed1997

Cell death: TRAIL and its receptors.

A cell-death signaling system has been described recently that involves the ligand TRAIL and corresponding TRAIL-specific cell-surface receptors. These include two receptors able to transduce a death signal and, as a previously unsuspected control mechanism, two other receptors able to prevent this transduction.

Adaptor Proteins, Signal Transducing↗
PubMed1997

Fas and other cell death signaling pathways.

The Fas system ensures, within the immune system, one of the two main pathways of T-cell mediated cytotoxicity, and, importantly, at least part of the downregulation of immune responses. Recently, Fas has been increasingly implicated in other functions, such as protection of immune privileged tissues and disposal of cells undergoing genomic alterations. The Fas system can be viewed as a cell death signal, linking extracellular information to the cell death execution stage. In this review, the Fas pathway will be described, compared to the other known T-cell mediated cytotoxicity mechanism, and then more generally to other cell death signals. The general features of cell death signaling will be emphasized as well as the peculiarities of the Fas system.

Adaptor Proteins, Signal Transducing↗