Evidence for a mitochondrial localization of the retinoblastoma protein

<p>Abstract</p> <p>Background</p> <p>The retinoblastoma protein (Rb) plays a central role in the regulation of cell cycle, differentiation and apoptosis. In cancer cells, ablation of Rb function or its pathway is a consequence of genetic inactivation, viral oncoprotein binding or deregulated hyperphosphorylation. Some recent data suggest that Rb relocation could also account for the regulation of its tumor suppressor activity, as is the case for other tumor suppressor proteins, such as p53.</p> <p>Results</p> <p>In this reported study, we present evidence that a fraction of the total amount of Rb protein can localize to the mitochondria in proliferative cells taken from both rodent and human cells. This result is also supported by the use of Rb siRNAs, which substantially reduced the amount of mitochondrial Rb, and by acellular assays, in which [³⁵S]-Methionine-labeled Rb proteins bind strongly to mitochondria isolated from rat liver. Moreover, endogenous Rb is found in an internal compartment of the mitochondria, within the inner-membrane. This is consistent with the protection of Rb from alkaline treatment, which destroys any interaction of proteins that are weakly bound to mitochondria.</p> <p>Conclusion</p> <p>Although a few data regarding an unspecific cytosolic localization of Rb protein have been reported for some tumor cells, our results are the first evidence of a mitochondrial localization of Rb. The mitochondrial localization of Rb is observed in parallel with its classic nuclear location and paves the way for the study of potential as-yet-unknown roles of Rb at this site.</p

Mitochondrial control of apoptosis

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Mitochondria and apoptosis

International audienceProgrammed cell death serves as a major mechanism for the precise regulation of cell numbers and as a defense mechanism to remove unwanted and potentially dangerous cells. Despite the striking heterogeneity of cell death induction pathways, the execution of the death program is often associated with characteristic morphological and biochemical changes, and this form of programmed cell death has been termed apoptosis. Genetic studies in Caenorhabditis elegans had led to the identification of cell death genes (ced). The genes ced-3 and ced-4 are essential for cell death; ced-9 antagonizes the activities of ced-3 and ced-4, and thereby protects cells that should survive from any accidental activation of the death program. Caspases (cysteine aspartases) are the mammalian homologues of CED-3. CED-9 protein is homologous to a family of many members termed the Bcl-2 family (Bcl-2s) in reference to the first discovered mammalian cell death regulator. In both worm and mammalian cells, the antiapoptotic members of the Bcl-2 family act upstream of the execution caspases somehow preventing their proteolytic processing into active killers. Two main mechanisms of action have been proposed to connect Bcl-2s to caspases. In the first one, antiapoptotic Bcl-2s would maintain cell survival by dragging caspases to intracellular membranes (probably the mitochondrial membrane) and by preventing their activation. The recently described mammalian protein Apaf-1 (apoptosis protease-activating factor 1) could be the mammalian equivalent of CED-4 and could be the physical link between Bcl-2s and caspases. In the second one, Bcl-2 would act by regulating the release from mitochondria of some caspases activators: cytochrome c and/or AIF (apoptosis-inducing factor). This crucial position of mitochondria in programmed cell death control is reinforced by the observation that mitochondria contribute to apoptosis signaling via the production of reactive oxygen species. Although for a long time the absence of mitochondrial changes was considered as a hallmark of apoptosis, mitochondria appear today as the central executioner of programmed cell death. In this review, we examine the data concerning the mitochondrial features of apoptosis. Furthermore, we discuss the possibility that the mechanism originally involved in the maintenance of the symbiosis between the bacterial ancestor of the mitochondria and the host cell precursor of eukaryotes, provided the basis for the actual mechanism controlling cell survival

Mitochondrial reactive oxygen species and apoptosis

International audienceProgrammed cell death (PCD) serves as a major mechanism for the precise regulation of cellnumbers, and as a defense mechanism to remove unwanted and potentially dangerous cells. Despitethe striking heterogeneity of cell death induction pathways, the execution of the death program isoften associated with characteristic morphological and biochemical changes termed apoptosis.The central components of the intrinsic apoptotic pathway involve specific proteases (i.e.caspases) and mitochondria (Nunez et al., 1998; Raff, 1998). Although for a long time the absenceof mitochondrial changes was considered as a hallmark of apoptosis, mitochondria appear today asthe central executioner of programmed cell death. This crucial position of mitochondria inprogrammed cell death control is not due to a simple loss of function (deficit in energy supplying),but rather to an active process in the regulation of effector mechanisms. This role is reinforced bythe observation that mitochondria contribute to PCD signaling via the production of reactive oxygenspecies, as shown in TNF-α or ceramide-induced cell death during which increased mitochondrialROS production appears as an early event of the induction phase. Recent other reviews cover theabundant literature dealing with the role of mitochondrion in cell death (Bernardi et al., 1998;Bernardi et al., 1999; Mignotte and Kroemer, 1999; Mignotte and Vayssière, 1998; Mignotte andVayssière, 1999; Reed et al., 1998; Susin et al., 1998). In this chapter, we examine on the one handthe data concerning the mitochondrial proteins involved in PCD, and on the other hand the role ofreactive oxygen species (ROS) in mitochondrial features of apoptosis

Mitochondrial reactive oxygen species in cell death signaling

International audienceDuring apoptosis, mitochondrial membrane permeability (MMP) increases and the release into the cytosol of pro-apoptotic factors (procaspases, caspase activators and caspase-independent factors such as apoptosis-inducing factor (AIF)) leads to the apoptotic phenotype. Apart from this pivotal role of mitochondria during the execution phase of apoptosis (documented in other reviews of this issue), it appears that reactive oxygen species (ROS) produced by the mitochondria can be involved in cell death. These toxic compounds are normally detoxified by the cells, failing which oxidative stress occurs. However, ROS are not only dangerous molecules for the cell, but they also display a physiological role, as mediators in signal transduction pathways. ROS participate in early and late steps of the regulation of apoptosis, according to different possible molecular mechanisms. In agreement with this role of ROS in apoptosis signaling, inhibition of apoptosis by anti-apoptotic Bcl-2 and Bcl-x L is associated with a protection against ROS and/or a shift of the cellular redox potential to a more reduced state. Furthermore, the fact that active forms of cell death in yeast and plants also involve ROS suggests the existence of an ancestral redox-sensitive death signaling pathway that has been independent of caspases and Bcl-2

Tickets for p53 journey among organelles

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The Mitochondrial Pathways of Apoptosis

International audienceApoptosis is a process of programmed cell death that serves as a major mechanism for the precise regulation of cell numbers, and as a defense mechanism to remove unwanted and potentially dangerous cells. Studies in nematode, Drosophila and mammals have shown that, although regulation of the cell death machinery is somehow different from one species to another, it is controlled by homologous proteins and involves mitochondria. In mammals, activation of caspases (cysteine pro-teases that are the main executioners of apoptosis) is under the tight control of the Bcl-2 family proteins , named in reference to the fi rst discovered mammalian cell death regulator. These proteins mainly act by regulating the release of caspases activators from mitochondria. Although for a long time the absence of mitochondrial changes was considered as a hallmark of apoptosis, mitochondria appear today as the central executioner of apoptosis. In this chapter, we present the current view on the mitochondrial pathway of apoptosis with a particular attention to new aspects of the regulation of the Bcl-2 proteins family control of mitochondrial membrane permeabilization: the mechanisms implicated in their mitochondrial targeting and activation during apoptosis, the function(s) of the oncosuppressive protein p53 at the mitochondria and the role of the processes of mitochondrial fusion and fi ssion

Apoptose, sénescence cellulaire, vieillissement et mitochondries

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Fhe biochemistry of programmed cell death

International audienceProgrammed cell death (PCD) is involved in the removal of superfluous and damaged cells in most organ systems. The induction phase of PCD or apoptosis is characterized by an extreme heterogeneity of potential PCD-triggering signal transduction pathways. During the subsequent effector phase, the numerous PCD-inducing stimuli converge into a few stereotypical pathways and cells pass a point of no return, thus becoming irreversibly conunitted to death. It is only during the successive degradation phase that vital structures and functions are destroyed, giving rise to the full-blown phenotype of PCD. Evidence is accumulating that cytoplasinic structures, including mitochondria, participate in the critical effector stage and that alterations commonly considered to define PCD (apoptotic morphology of the nucleus and regular, oligonucleosomal chromatin fragmentation) have to be ascribed to the late degradation phase. The decision as to whether a cell will undergo PCD or not may be expected to be regulated by "switches" that, once activated, trigger self-amplificatory metabolic pathways. One of these switches may reside in a perturbation of mitochondrial function. Thus, a decrease in mitochondrial transmembrane potential, followed by mitochondrial uncoupling and generation of reactive oxygen species, precedes nuclear alterations. It appears that molecules that participate in apoptotic decisio

Contrôle mitochondrial de l'apoptose : la mort cellulaire programmée est-elle apparue à la suite de l'évènement endosymbiontique à l'origine des mitochonries ?

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