Programmed cell death

Liver regeneration after PH also involves a remodeling process in which apoptosis, or programmed cell death, plays an important role in reconstruction of the infrastructure of hepatic tissue. In a sense, it fine tunes the regenerative process. In general, apoptosis is a form of cell death that permits the removal of damaged, senescent, or unneeded cells in multicellular organisms, without damage to the cellular microenviroment. How do you get a christmas cactus to bloom https://cactus-christian.org/blooming.html.

Alterations in this normal process can result in the disruption of the delicate balance between cell proliferation and cell death and can lead to a variety of diseases. For example, in many forms of cancer, key proapoptotic proteins are mutated or antiapoptotic proteins are upregulated, leading to the accumulation of cells and the inability to respond to harmful mutations, DNA damage or chemotherapeutic agents. Since effective chemotherapy depends on the induction of programmed cell death, cancers with defects in the cell death signaling pathways are particularly difficult to treat.

Signaling pathways of apoptosis. Several mechanisms have been identified in mammalian cells for the induction of apoptosis. Fas is a member of the tumor necrosis factor (TNF) receptor superfamily. Fas ligand (Fas L) transmits signals to Fas on a target cell by inducing trimerization of Fas. Activation of Fas causes the recruitment of Fas-associated protein with death domain (FADD) via interactions between the death domain of Fas and FADD and is followed by pro-caspase-8 binding to FADD via interactions between the death effector domains (DED) of FADD and pro-caspase- 8 leading to the activation of caspase-8, Bid and other caspases that initiate a cascade that ultimately results in apoptosis. Fas-induced apoptosis can be effectively blocked at several stages by either FLICE-inhibitory protein (FLIP), by Bcl-2, as well as a growing list of other factors. In addition, activation of caspase-3 by caspase-9 can be blocked by inhibitor of apoptosis proteins (IAPs). Moreover, the protein kinase, Akt, can be activated by various growth factors and its activity can be blocked by PTEN. Akt functions to promote cell survival through two distinct pathways. Akt inhibits apoptosis by phosphorylating the Bcl-2 family member Bad. Alternatively, Akt activates IKK-α that ultimately leads to NF-kappa B activation and cell survival. Proapoptotic Bcl-2 family members, such as Bax and Bak can promote mitochondrial permeability, while Bcl-2 can inhibit their effects. Upon mitochondrial permeability, apoptogenic factors are released from the mitochondrial inter-membrane space and leak into the cytosol. One factor is cytochrome c, which induces the liberation of protease activators (caspases) that ultimately lead to apoptosis through nuclear damage (DNA fragmentation, DNA mutations). In addition, Smac/Diablo is released and can block IAP inhibition of caspase activity. Mitochondrial permeability is also related to the increased generation of reactive oxygen species (ROS), which plays a role in the degradation phase of apoptosis (i.e. plasma membrane alterations). Reproduced with permission from Sigma.

Cells undergo programmed death in response to both internal surveillance mechanisms and signals sent (or not sent) by other cells. Thus, some cells effectively ‘volunteer’ to die, whereas other cells are ‘nominated’ for death by others. Cells that ‘volunteer’ to die are due to sensing DNA damage and inappropriate signals to proliferate. Cells that are ‘nominated’ for death occur in at least three ways. First, cells are recognized as foreigners or harboring foreign pathogens. Second, the nurturing signals sent by other cells or the extracellular matrix are withheld.

Third, some cells respond to certain growth factors such as TGF-β1. Programmed cell death is an active cellular process that culminates in cell death. This may occur in response to developmental or environmental cues or as a response to physiologic damage detected by the cell’s internal surveillance network. In recent years, the term programmed cell death and apoptosis have come to be viewed as synonymous. However, apoptosis is only one type of programmed cell death and is characterized by a particular pattern of morphologic changes. In fact, some cells that undergo programmed cell death may exhibit no dramatic structure changes. Apoptotic death occurs in two phases.

During the latent phase, the cell looks morphologically normal but is actively making preparations for death. The execution phase is characterized by a series of dramatic structural and biochemical changes that culminate in the fragmentation of the cell into membrane-enclosed apoptotic bodies. The process of programmed cell death occurs in several stages. In the first step, the apoptotic pathway is triggered, which can be accomplished by a wide variety of stimuli, including DNA damage, growth factor withdrawal, toxins and radiation.

Once activated, the signal is transduced by a series of protein–protein interactions that involve a conserved set of signaling modules. In the next stage, cell death is executed by the activation of specific proteases called caspases that cleave multiple substrates, leading to changes characteristic of apoptotic cells such as DNA fragmentation, chromatin condensation, cell shrinkage and membrane blebbing. There are two major pathways leading to programmed cell death. First is the death receptor pathway. The cells express at least six different cell surface molecules that can function as death receptors.

One well-characterized death receptor is called Fas (also known as Apo1 or CD95), a member of the tumor necrosis factor (TNF) receptor family. The Fas ligand interacts with the Fas receptor, which leads to an interaction between the death domain of the cytoplasmic region of the Fas receptor and the death domain of the adaptor protein, FADD. FADD recruits and activates procaspase-8 through interactions between the death effector domains of these two proteins.

Once activated, caspase-8 activates downstream caspases such as caspase-3. The second major pathway involves mitochondria, which are key players in this alternative pathway to cell death. A variety of toxic insults can trigger this pathway. This process requires either Bax or Bak to open a channel and release the electron transport protein cytochrome c and other proteins from the intermembranous space into the cytoplasm. Cytochrome c binds the scaffolding protein Apaf-1, a mammalian homolog of Caenorhabditis elegans CED-4 protein.

This complex molecule interacts with caspases through an N-terminal caspase recruitment domain. Adjacent to this is an ATPase domain. The C-terminal portion of Apaf1 appears to act as a negative regulator. Binding of cytochrome c and deoxyadenosine triphosphate (dATP) removes the negative regulatory influence of C-terminus of Apaf-1, permitting binding and autoactivation of caspase-9. This complex of Apaf-1, cytochrome c and caspase-9 is also called apoptosome. Activated caspase-9 subsequently activate caspase-3 and -7, initiating the cell death cascade. In addition, occurrence of a mitochondrial outer membrane permeabilization plays an important role during apoptosis.

The function of the electron transport chain, which is essential for most mitochondrial function including ATP generation, is lost following permeabilization, and this loss is greatly facilitated by caspase activation. Recent studies have shown that genes involved in apoptosis are actively expressed in the regenerating liver. They include the inducing genes c-fos, c jun, c-myc, p53, Bax, Bad, Bak, and TGF-β; the apoptosis inhibitory genes, Bcl-2, Bcl-XL, TRPM- 2/clusterin; and the retinoblastoma gene. Ironically, some of these genes are also involved in cell proliferation, through regulation of the cell cycle.

To maintain homeostasis, cell death and proliferation must be precisely balanced, and communication between these two distinct signaling pathways is critical. Liver regeneration after PH is a complicated process, and probably involves an orchestrated balance of cell replication, apoptosis and remodeling by a number of molecular players. When the surviving hepatocytes are also injured, the process may be even more complicated and involve additional factors, including stem-cell proliferation.