The role of apoptosis in non-mammalian host-parasite relationships
G. F. Wiegertjes, G. Flik in Host-Parasite Interactions, 2004
APAF1 (apoptotic protease activating factor 1) has been identified as the mammalian homologue of Ced-4 (Li et al., 1997). Functionally there are similarities between APAF1 and Ced-4, particularly that they both act to activate Ced-3/caspases. However, there are also important differences: Ced-4 appears to interact directly with the apoptosis inhibitor Ced-9, but this does not appear to be the case for APAF1 and the mammalian Ced-9 homologue Bcl-2 (Hausmann et al., 2000). In general, the correspondence between the C. elegans pathway and the mammalian apoptosis pathways are not exact, with the mammalian apoptosis pathways displaying substantially more complexity: Ced-3 in C. elegans has a whole family of homologues, the caspases, in mammalian cells; similarly, Ced-9 in C. elegans has a whole family of homologues in mammalian cells, i.e. the Bcl-2 family.
Tissue injury and repair
C. Simon Herrington in Muir's Textbook of Pathology, 2020
The intrinsic pathway involves mitochondria. In normal cells, there are anti-apoptotic molecules present in the membranes of mitochondria. These belong to the Bcl-2 family of proteins, most notably Bcl-2 itself and Bcl-x. Their presence is stimulated by growth factors and other normal survival signals. Under circumstances of cellular stress or where the cell is deprived of its normal survival signals, there is a loss of the anti-apoptotic proteins and these are replaced by pro-apoptotic members of the same family such as Bax. A shift in the balance between pro- and anti-apoptotic Bcl-2 family members to favour apoptosis causes the mitochondrial membranes to become leaky (so-called mitochondrial permeability transition). One of the proteins that then escapes from the mitochondria is cytochrome C, an enzyme involved in respiration. In the cytosol, this protein binds to another protein Apaf-1 (apoptosis-activating factor 1), which is capable of activating caspases. Other proteins leak out from the mitochondria, which further encourages apoptosis.
Diffuse axonal injury
Hemanshu Prabhakar, Charu Mahajan, Indu Kapoor in Essentials of Anesthesia for Neurotrauma, 2018
Mitochondrial damage after diffuse axonal damage is the result of the excessive calcium influx and intracellular overload, which leads to changes in permeability in the mitochondrial membrane, swelling, and breakage of the mitochondrial crest and membrane.42 The mitochondrial death is followed by an energy failure, ionic imbalance, and disconnection; however, this mitochondrial damage may also lead to the release of cytochrome c (cyto-c), which then activates caspases with significant adverse intra-axonal consequences.43 Caspase-activation by cyto-c mediates degradation of spectrin and increases permeability in plasma membranes.44 After cytochrome c is released from damaged mitochondria, in conjunction with Apaf-1, which contains a caspase recruitment domain, it activates caspase-3, the primary-effect enzyme in neuronal and axonal apoptosis.45 Once the apoptotic process is initiated, other propapoptotic factors can be released or activated, such as caspase -2,-3 and -9, as well a a57kDa flavoprotein, capable of directly activating caspase-3.43,45
Apoptotic resistance in chronic lymphocytic leukemia and therapeutic perspectives
Published in Critical Reviews in Clinical Laboratory Sciences, 2019
Cristina Bagacean, Ciprian Tomuleasa, Adrian Tempescul, Ravnit Grewal, Wesley H. Brooks, Christian Berthou, Yves Renaudineau
Acting as an integrator of the cellular response to DNA damage, tumor transformation, and growth factor withdrawal, the tumor suppressor p53 is a main cellular guardian that can promote the execution of the intrinsic apoptotic pathway, cell growth arrest, and DNA repair. Under normal conditions, p53 is a short-lived protein that needs to be stabilized to be active, and then its half-life shifts from minutes (6–20 min) to hours. p53, via the intrinsic pathway, promotes apoptosis through (i) transcription of the pro-apoptotic genes Puma, Noxa, Bax; (ii) transcription of the apoptosome partner, Apaf-1; and (iii), MOMP, by acting directly in mitochondria by forming complexes with Bcl-2 and Bcl-XL, which allows Bak activation by releasing Bid and Bim in a direct and transcriptional independent manner [16].
Overexpression of NDRG2 promotes the therapeutic effect of pazopanib on ovarian cancer
Published in Journal of Receptors and Signal Transduction, 2021
Ying Cui, Guihua Shen, Linlin Ma, Qiubo Lv
Caspase-9 is a key regulator in the intrinsic pathway involved under multiple stimuli, including chemotherapies, stress agents, and radiation. Dysfunction of caspase-9 activation leads to the development of degenerative disease and cancer. Activation of caspase-9 requires the binding with APAF-1 [44]. APAF-1 is known to bind with caspase-9 through CARD domains, which provides an indispensable complementary interface for activation of caspase-9 [45]. A previous study found that activation of caspase-9 and caspase-3 are present at the end stage of the disease, suggesting that activation of caspases might contribute to the apoptosis of cells [46], this result showed that caspase-9 is required for the maintaining of cellular homeostasis via regulation of apoptosis. Other studies showed that activated caspase-9 further induce the cleave of caspase-3, which binds with the apoptosome and performs as an executor of the apoptosis process [47].
Possible modifier genes in the variation of neurofibromatosis type 1 clinical phenotypes
Published in Journal of Neurogenetics, 2018
Apoptosis can be initiated in the intrinsic and extrinsic pathways. Both pathways induce cell death by activating caspases. One of the important proteins in the intrinsic pathway is apoptotic protease activating factor-1 (Apaf-1), and any loss of expression of this protein can result in tumor development (Igney & Krammer, 2002). Hepatocellular carcinoma antigen 66 (HCA66) is one of the proteins that interacts with Apaf-1 and can regulate apoptosis. The HCA66 gene, located on chromosome 17q11.2, is one of the genes that is deleted in NF1-microdeletion syndrome (De Raedt et al., 2004). Patients with NF1-microdeletion syndrome have a distinct phenotype with a poor prognosis characterized by a low IQ, dysmorphic features, and numerous neurofibromas (Leppig et al., 1997). Piddubnyak et al. (2007) examined the effect of the modulated expression of HCA66 on the apoptosis of cell lines derived from NF1-microdeleted patients. In this study, they showed that HCA66 seems to regulate apoptosis at the level of the Apaf-1-induced activation of caspase-9 in the apoptosome following cytochrome c/dATP stimulation. Likewise, they presumed that the binding of HCA66 can also induce a conformational change that would increase the recruitment of caspase-9. Therefore, the reduced expression of HCA66 could make cell lines derived from NF1-microdeleted patients less susceptible to apoptosis. Accordingly, not only the HCA66 gene but also all of the proteins involved in the apoptotic pathway should be considered as possible modifiers in NF1 tumors.
Related Knowledge Centers
- Alternative Splicing
- Apoptosome
- Atpase
- Autocatalysis
- Cytochrome C
- Apoptosis
- Card
- Deoxyadenosine Triphosphate
- Caspase-9
- Protein–Protein Interaction