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Biomedical subjects

D R Green

Publications and source records attributed to D R Green.

At least 37 records · Page 2Linked to original sources
PubMed2001

The machinery of programmed cell death.

Apoptosis or programmed cell death is an essential physiological process that plays a critical role in development and tissue homeostasis. However, apoptosis is also involved in a wide range of pathological conditions. Apoptotic cells may be characterized by specific morphological and biochemical changes, including cell shrinkage, chromatin condensation, and internucleosomal cleavage of genomic DNA. At the molecular level, apoptosis is tightly regulated and is mainly orchestrated by the activation of the aspartate-specific cysteine protease (caspase) cascade. There are two main pathways leading to the activation of caspases. The first of these depends upon the participation of mitochondria (receptor-independent) and the second involves the interaction of a death receptor with its ligand. Pro- and anti-apoptotic members of the Bcl-2 family regulate the mitochondrial pathway. Cellular stress induces pro-apoptotic Bcl-2 family members to translocate from the cytosol to the mitochondria, where they induce the release of cytochrome c, while the anti-apoptotic Bcl-2 proteins work to prevent cytochrome c release from mitochondria, and thereby preserve cell survival. Once in the cytoplasm, cytochrome c catalyzes the oligomerization of apoptotic protease activating factor-1, thereby promoting the activation of procaspase-9, which then activates procaspase-3. Alternatively, ligation of death receptors, like the tumor necrosis factor receptor-1 and the Fas receptor, causes the activation of procaspase-8. The mature caspase may now either directly activate procaspase-3 or cleave the pro-apoptotic Bcl-2 homology 3-only protein Bid, which then subsequently induces cytochrome c release. Nevertheless, the end result of either pathway is caspase activation and the cleavage of specific cellular substrates, resulting in the morphological and biochemical changes associated with the apoptotic phenotype.

Apoptosis↗
PubMed2001

Stress management - heat shock protein-70 and the regulation of apoptosis.

Apoptosis, molecularly regulated cell death, can be induced by a range of environmental, physical or chemical stresses, and is characterized by a sequence of precisely regulated events that culminate in the self-destruction of a cell. Fascinating biochemical and genetic parallels exist between the cell death pathways of different animal species. However, an even more highly conserved and evolutionarily ancient cellular response can be engaged as a consequence of stress, which functions to maintain cellular survival. This response is mediated by the heat-shock or stress proteins. This article discusses the functional interactions between the stress response and the apoptotic cell death pathway and how these might impact on determining cellular survival.

Animals↗
PubMed2001

Breaking the mitochondrial barrier.

Pro- and anti-apoptotic members of the Bcl-2 family control the permeability of the outer mitochondrial membrane. They could do this either by forming autonomous pores in the membrane or by collaborating with components of the permeability transition pore. Here we discuss why we favour the first of these possibilities.

Animals↗
PubMed2001

The role of Fas ligand in immune privilege.

Immune privilege is a property of some sites in the body, whereby immune responses are limited or prevented. One explanation that has been proposed for this phenomenon is engagement of the pro-apoptotic molecule Fas by its ligand (FasL), which leads to apoptosis, and consequently limits an inflammatory response. This idea has recently been challenged, and here we review the evidence for and against a role for FasL in immune privilege.

Animals↗
PubMed2001

ICE heats up.

Explore the source record for details and available documents.

Animals↗
PubMed2001

Mechanisms of p53-dependent apoptosis.

Cellular stresses, such as growth factor deprivation, DNA damage or oncogene expression, lead to stabilization and activation of the p53 tumour suppressor protein. Depending on the cellular context, this results in one of two different outcomes: cell cycle arrest or apoptotic cell death. Cell death induced through the p53 pathway is executed by the caspase proteinases, which, by cleaving their substrates, lead to the characteristic apoptotic phenotype. Caspase activation by p53 occurs through the release of apoptogenic factors from the mitochondria, including cytochrome c and Smac/DIABLO. Released cytochrome c allows the formation of a high-molecular weight complex, the apoptosome, which consists of the adapter protein Apaf-1 and caspase 9, which is activated following recruitment into the apoptosome. Active caspase 9 then cleaves and activates the effector caspases, such as caspases-3 and -7, which execute the death program. Released Smac/DIABLO facilitates caspase activation through repression of the IAP caspase inhibitor proteins. The release of mitochondrial apoptogenic factors is regulated by the pro- and anti-apoptotic Bcl-2 family proteins, which either induce or prevent the permeabilization of the outer mitochondrial membrane. The mechanism by which p53 signals to the Bcl-2 family proteins is unclear. It was shown that some of the pro-apoptotic family members, such as Bax, Noxa or PUMA, are transcriptional targets of p53. In addition, transcription-independent, pro-apoptotic activities of p53 have been described. The elucidation of the p53-dependent pathway, resulting in mitochondrial outer membrane permeabilization through the pro-apoptotic Bcl-2 family proteins, is a key to unveiling the mechanism of stress-induced apoptosis.

Animals↗
PubMed2001

How cells die: apoptosis pathways.

Generally speaking, there are 2 types of cell death: apoptosis and necrosis. Necrotic cell death is considered an accidental type of death, caused by gross cell injury, and results in the death of groups of cells within a tissue. In contrast, apoptotic cell death may be induced or is preprogrammed into the cell (eg, during development) and results in the death of the individual cells. Apoptotic cells may be characterized by specific morphologic and biochemical changes orchestrated by a family of cysteine proteases known as caspases. At the molecular level, apoptosis is tightly regulated. There are 2 main pathways to apoptotic cell death. One involves the interaction of a death receptor, such as the TNF receptor-1 or the Fas receptor with its ligand, and the second pathway depends on the participation of mitochondria. Proapoptotic and antiapoptotic members of the Bcl-2 family regulate the mitochondrial pathway. The end result of either pathway is caspase activation and the cleavage of specific cellular substrates, resulting in the morphologic and biochemical changes associated with the apoptotic phenotype.

Antigens, CD↗
PubMed2001

Flake-Austin modification of the STA-Peg arthroereisis: a retrospective study.

The Smith subtalar arthroereisis implant (STA-peg) is used to correct severe collapsing pes valgoplanus in children. Flake and Austin modified the placement of this implant to block the leading wall of the lateral talus. Twenty-one patients with a total of 40 STA-peg procedures were evaluated subjectively and objectively. The average age at the time of surgery was 9.7 years (4 to 16 years). The follow-up period averaged 36 months (12 to 90 months). The subjective, objective, and radiographic results were positive and the complication rate was low. A significant advantage of the Flake-Austin modification of the STA-peg placement in transverse planar dominant foot types is also noted.

Adolescent↗
PubMed2001

Posterior facet talocalcaneal coalition.

Posterior facet talocalcaneal coalition is one of the rarest forms of talocalcaneal coalition. When a posterior facet coalition occurs, it typically involves a majority of the posterior facet articular surface. The authors present a rare form of posterior facet talocalcaneal coalition in an 11- year-old girl. A brief review of the literature is provided, along with the case history, including radiographic findings and intraoperative and postoperative illustrations.

Calcaneus↗
PubMed2000

Granzyme B-mediated cytochrome c release is regulated by the Bcl-2 family members bid and Bax.

Cytotoxic T lymphocytes (CTLs) destroy target cells through a mechanism involving the exocytosis of cytolytic granule components including granzyme B (grB) and perforin, which have been shown to induce apoptosis through caspase activation. However, grB has also been linked with caspase-independent disruption of mitochondrial function. We show here that cytochrome c release requires the direct proteolytic cleavage of Bid by grB to generate a 14-kD grB-truncated product (gtBid) that translocates to mitochondria. In turn, gtBid recruits Bax to mitochondria through a caspase-independent mechanism where it becomes integrated into the membrane and induces cytochrome c release. Our results provide evidence for a new pathway by which CTLs inflict damage and explain the caspase-independent mechanism of mitochondrial dysfunction.

BH3 Interacting Domain Death Agonist Protein↗
PubMed2000

A 'non-canonical' DNA-binding element mediates the response of the Fas-ligand promoter to c-Myc.

Cell number is regulated by maintaining a balance between cell proliferation and cell death through apoptosis. Key regulators of this balance include the oncogene product c-Myc, which promotes either entry into the cell cycle or apoptosis [1]. Although the mechanism of c-Myc-induced apoptosis remains unclear, it is susceptible to regulation by survival factors [2,3] and can proceed through the interaction of Fas ligand (FasL) with its receptor, Fas [4]. Activated T lymphocytes are eliminated by an apoptotic process known as activation-induced cell death (AICD), which requires the transcriptional induction of FasL expression [5-7] and sustained levels of c-Myc [8]. The FasL promoter can be driven by c-Myc overexpression, and functional inhibitors of Myc and its binding partner, Max, inhibit the transcriptional activity of the FasL promoter [9,10]. We identified a non-canonical binding site (ATTCTCT) for c-Myc-Max heterodimers in the FasL promoter, which, when mutated, abolished activity in response to c-Myc. Exchange of the canonical c-Myc responsive elements (CACGTG) in the ornithine decarboxylase (ODC) promoter [11] with the non-canonical sequence in the FasL promoter generated an ODC-FasL promoter that was significantly more responsive to c-Myc than the wild-type ODC promoter. Our findings identify a precise physiological role for c-Myc in the induction of apoptosis as a transcriptional regulator of the FasL gene.

Base Sequence↗
PubMed2000

Changes in endoplasmic reticulum luminal environment affect cell sensitivity to apoptosis.

To test the role of ER luminal environment in apoptosis, we generated HeLa cell lines inducible with respect to calreticulin and calnexin and investigated their sensitivity to drug-dependent apoptosis. Overexpression of calreticulin, an ER luminal protein, resulted in an increased sensitivity of the cells to both thapsigargin- and staurosporine-induced apoptosis. This correlated with an increased release of cytochrome c from the mitochondria. Overexpression of calnexin, an integral ER membrane protein, had no significant effect on drug-induced apoptosis. In contrast, calreticulin-deficient cells were significantly resistant to apoptosis and this resistance correlated with a decreased release of cytochrome c from mitochondria and low levels of caspase 3 activity. This work indicates that changes in the lumen of the ER amplify the release of cytochrome c from mitochondria, and increase caspase activity, during drug-induced apoptosis. There may be communication between the ER and mitochondria, which may involve Ca(2+) and play an important role in conferring cell sensitivity to apoptosis. Apoptosis may depend on both the presence of external apoptosis-activating signals, and, as shown in this study, on an internal factor represented by the ER.

Animals↗