NFkappa B-dependent transcriptional activation during heat shock recovery. Thermolability of the NF-kappaB.Ikappa B complex.

Heat shock induces the accumulation of misfolded proteins and results in the preferential expression of heat shock proteins, which help the cell to recover from thermal damage. Heat shock is a well known transcriptional activator of the human immunodeficiency virus type 1 long terminal repeat (LTR). We report here that mutations or deletions of the LTR kappaB sites impaired the LTR transcriptional activation by heat shock. Further analysis revealed that, during heat shock recovery, the NF-kappaB p65 and p50 subunits migrated into the nucleus of HeLa cells, bound to DNA, and induced kappaB-dependent reporter gene expression. This NF-kappaB activation did not depend on new transcriptional and/or translational events and on the pro-oxidant state generated by heat shock. It was not concomitant with IkappaBalpha phosphorylation and was not abolished by the expression of IkappaB kinase or IkappaBalpha dominant-negative mutants. Moreover, NF-kappaB activation and migration into the nucleus were not concomitant with IkappaBalpha/beta or p105 degradation. However, during heat shock recovery, NF-kappaB was dissociated from its complexing partners, allowing its migration into the nucleus. Hence, we describe here a novel mechanism for activation of NF-kappaB based on the thermolability of the NF-kappaB.IkappaB complex.

Caspase-induced proteolysis of the cyclin-dependent kinase inhibitor p27Kip1 mediates its anti-apoptotic activity.

The caspase-mediated cleavage of a limited number of cellular proteins is a common feature of apoptotic cell death. This cleavage usually inhibits the function of the target protein or generates peptides that actively contribute to the death process. In the present study, we demonstrate that the cyclin-dependent kinase inhibitor p27Kip1 is cleaved by caspases in human leukemic cells exposed to apoptotic stimuli. We have shown recently that p27Kip1 overexpression delayed leukemic cell death in response to cytotoxic drugs. In transient transfection experiments, the p23 and the p15 N-terminal peptides generated by p27Kip1 proteolysis demonstrate an anti-apoptotic effect similar to that induced by the wild-type protein, whereas cleavage-resistant mutants have lost their protective effect. Moreover, stable transfection of a cleavage-resistant mutant of p27Kip1 sensitizes leukemic cells to drug-induced cell death. Altogether, these results indicate that proteolysis of p27Kip1 triggered by caspases mediates the anti-apoptotic activity of the protein.

[Perforation of colonic diverticulum under corticoids: a complication to be known and recognized]. / Perforation de diverticule colique sous corticoïdes: une complication à connaître et à reconnaître.

Glucocorticoids can produce acute perforation of colonic diverticula and peritoneal infection. We report two observations in which patients presented a peritoneal collection with no specific clinical signs. The diagnosis was considered after C-T scan or ultrasans. Residues of contrast liquid, after an earlier X-ray exploration, have made the diagnosis of diverticula easier. In one case, corticosteroids were started as a short cure for the treatment of a myeloma. In the other case, patient received a long term corticosteroid therapy at low dose for an asthmatic disease. The perforation was induced by an increased dosage. Diverticular perforations result from inhibition of synthesis of prostaglandins who have the beneficial property of "cytoprotection" and from the immunosuppressive action of glucocorticoids which favour the diffusion of the peritoneal infection. diffusion of the peritoneal infection.

[Agents inducing cell death of the vascular wall]. / Les inducteurs de mort des cellules de la paroi vasculaire.

Arterial wall is constituted by endothelial cells, smooth muscle cells and fibroblasts. A number of agents are capable of inducing damages in these cells leading either to apoptosis or necrosis involved in various pathologies. Such agents are constituted by: bacterial endotoxins, mediators and modulators of immunitary and/or inflammatory systems, drugs, reactive oxygen metabolites, free radicals, cholesterol oxidation derivatives included or not in lipoproteins. The study of the mechanisms of action implied in cell death would permit a better understanding of vascular diseases and open new therapeutic perspectives.