Bcl-2-family proteins and the role of mitochondria in apoptosis

Kuwana, Tomomi; Newmeyer, Donald D.

doi:10.1016/j.ceb.2003.10.004

Cited by 562 publications

(446 citation statements)

References 94 publications

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“…139 ER stress can also activate well-known general regulators of mammalian apoptosis, including the Bcl-2 and caspase families of proteins. It has long been known that a pool of endogenous Bcl-2 resides in the ER membrane, 140,141 and while Bcl-2 family members are thought to function principally at the mitochondrial outer membrane, 142 there is ample evidence that they influence homeostasis and apoptosis from the ER as well. 143,144 For example, variants of the antiapoptotic family members Bcl-2 or Bcl-X L targeted specifically to the ER membrane can block apoptosis induced by pharmacological kinase inhibition or by proapoptotic Bcl-2 family members.…”

Section: Esr and Apoptosismentioning

confidence: 99%

Cellular response to endoplasmic reticulum stress: a matter of life or death

2006

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The proper functioning of the endoplasmic reticulum (ER) is critical for numerous aspects of cell physiology. Accordingly, all eukaryotes react rapidly to ER dysfunction through a set of adaptive pathways known collectively as the ER stress response (ESR). Normally, this suite of responses succeeds in restoring ER homeostasis. However, in metazoans, persistent or intense ER stress can also trigger programmed cell death, or apoptosis. ER stress and the apoptotic program coupled to it have been implicated in many important pathologies but the regulation and execution of ER stressinduced apoptosis in mammals remain incompletely understood. Here, we review what is known about the ESR in both yeast and mammals, and highlight recent findings on the mechanism and pathophysiological importance of ER stressinduced apoptosis.

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Section: Esr and Apoptosismentioning

confidence: 99%

Cellular response to endoplasmic reticulum stress: a matter of life or death

2006

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“…95 Upon keratinocyte terminal differentiation, the expression of the Bcl-2 family members is altered. The antiapoptotic Bcl-2 is expressed in undifferentiated keratinocytes, but it is downregulated when the cells leave the basal layer and start to differentiate.…”

Section: Mitochondrial Factors and Apoptosome Formationmentioning

confidence: 99%

Death penalty for keratinocytes: apoptosis versus cornification

et al. 2005

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Homeostasis implies a balance between cell growth and cell death. This balance is essential for the development and maintenance of multicellular organisms. Homeostasis is controlled by several mechanisms including apoptosis, a process by which cells condemned to death are completely eliminated. However, in some cases, total destruction and removal of dead cells is not desirable, as when they fulfil a specific function such as formation of the skin barrier provided by corneocytes, also known as terminally differentiated keratinocytes. In this case, programmed cell death results in accumulation of functional cell corpses. Previously, this process has been associated with apoptotic cell death. In this overview, we discuss differences and similarities in the molecular regulation of epidermal programmed cell death and apoptosis. We conclude that despite earlier confusion, apoptosis and cornification occur through distinct molecular pathways, and that possibly antiapoptotic mechanisms are implicated in the terminal differentiation of keratinocytes.

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“…K x is the partition coefficient for the protonated Bclx L ΔTM to partition into the lipid vesicles. This framework has four assumptions: (i) only protonated Bcl-x L ΔTM [protein(0) above] binds to the lipid vesicles, (ii) membrane-bound protein is not involved in the protonation-deprotonation equilibrium, (iii) the protonation sites are equal and independent, and (iv) no significant contribution arises from the protonationdeprotonation equilibria of the ionizable lipid headgroups in this pH range (3)(4)(5)(6)(7)(8). This last assumption is well-founded (32).…”

Section: Thermodynamic Modelmentioning

confidence: 99%

The N-Terminal Domain of Bcl-x_L Reversibly Binds Membranes in a pH-Dependent Manner

et al. 2006

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Bcl-x L regulates apoptosis by maintaining the integrity of the mitochondrial outer membrane by adopting both soluble and membrane-associated forms. The membrane-associated conformation does not require a conserved, C-terminal transmembrane domain and appears to be inserted into the bilayer of synthetic membranes as assessed by membrane permeabilization and critical surface pressure measurements. Membrane association is reversible and is regulated by the cooperative binding of approximately two protons to the protein. Two acidic residues, Glu153 and Asp156, that lie in a conserved hairpin of Bcl-x L ΔTM appear to be important in this process on the basis of a 16% increase in the level of membrane association of the double mutant E153Q/D156N. Contrary to that for the wild type, membrane permeabilization for the mutant is not correlated with membrane association. Monolayer surface pressure measurements suggest that this effect is primarily due to less membrane penetration. These results suggest that E153 and D156 are important for the Bclx L ΔTM conformational change and that membrane binding can be distinct from membrane permeabilization. Taken together, these studies support a model in which Bcl-x L activity is controlled by reversible insertion of its N-terminal domain into the mitochondrial outer membrane. Future studies with Bcl-x L mutants such as E153Q/D156N should allow determination of the relative contributions of membrane binding, insertion, and permeabilization to the regulation of apoptosis.Bcl-2 proteins act as checkpoints in the regulation of apoptosis by integrating intracellular signals to control the permeability and possibly the morphology of the mitochon-drion (1-9). For many Bcl-2 proteins, this checkpoint involves a change in localization from the cytosol to the mitochondrion (10-13). For example, Bcl-x L displays mixed localization to the cytosol and to organellar membranes, including the mitochondrion. After an apoptotic stimulus, Bcl-x L appears to localize primarily to the mitochondrial outer membrane where it may bind other apoptotic factors such as Bad (10,11,14) or form an ion channel thought to maintain the integrity of the mitochondrial membrane (11,(15)(16)(17). While mixed localization of Bcl-x L is well-established, the relative importance of cytosolic-and membranous-localized protein to the regulation of apoptosis is not. Intriguingly, the membrane activity of Bcl-x L may contribute more to its anti-apoptotic activity than its ability to sequester pro-apoptotic proteins: a mutant

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Bcl-2-family proteins and the role of mitochondria in apoptosis

Cited by 562 publications

References 94 publications

Cellular response to endoplasmic reticulum stress: a matter of life or death

Cellular response to endoplasmic reticulum stress: a matter of life or death

Death penalty for keratinocytes: apoptosis versus cornification

The N-Terminal Domain of Bcl-x_L Reversibly Binds Membranes in a pH-Dependent Manner

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Bcl-2-family proteins and the role of mitochondria in apoptosis

Cited by 562 publications

References 94 publications

Cellular response to endoplasmic reticulum stress: a matter of life or death

Cellular response to endoplasmic reticulum stress: a matter of life or death

Death penalty for keratinocytes: apoptosis versus cornification

The N-Terminal Domain of Bcl-xL Reversibly Binds Membranes in a pH-Dependent Manner

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The N-Terminal Domain of Bcl-x_L Reversibly Binds Membranes in a pH-Dependent Manner