Topic 7 - Key Terms

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adult stem cells - Undifferentiated cells found in various tissues throughout the body that divide to generate cells that repair and replace cells in that tissue. (T7P2)

AMP-activated protein kinase (AMPK) - A protein kinase that plays a central role in cellular energy homeostasis. AMPK is activated when the cytosolic concentration of adenosine monophosphate (AMP) increases. (T7P1)

anti-apoptotic - The term used to describe events, or regulatory proteins, that inhibit apoptosis. (T7P1)

Apaf-1 - Apoptotic protease activating factor-1. A cytosolic protein that plays a critical role in formation of the apoptosome. Apaf-1 binds cytochrome c and dATP to form the apoptosome, which acts as a caspase-activation scaffold for procaspase 9. (T7P1)

apoptosis - A type of programmed cell death that removes cells without causing inflammation. Characterised by cell shrinkage, membrane blebbing, chromatin condensation, DNA fragmentation and activation of caspase enzymes. (T7P1)

apoptosome - A multi-protein complex formed by the association of cytochrome c, dATP and Apaf-1. The binding of procaspase 9 to the apoptosome leads to dimerisation and activation of procaspase 9 monomers, thereby triggering the caspase activation cascade. (T7P1)

autophagy - A process by which cells can self-digest themselves under conditions of stress or nutrient starvation. Cellular contents destined for degradation are encapsulated by lipid membranes to form characteristic double-walled vesicles (autophagosomes) that then fuse with lysosomes. Hydrolases present in the lumen of lysosomes degrade the cellular material. (T5P2 and T7P1)

Bak - A pro-apoptotic member of the Bcl-2 protein family. Bak is resident at the mitochondrial outer membrane. When activated by the binding of a member of the BH3-only Bcl-2 family proteins, Bak oligomerises to form pores in the mitochondrial outer membrane that allow the release of cytochrome c, which is necessary for apoptosome formation. (T7P1)

Bax - [Bax family] One group of pro-apoptotic Bcl-2 family members. (T7P1)

Bcl-2 family - (B cell lymphoma 2) A family of proteins that play pivotal roles in the regulation of apoptosis. There are both anti- and pro-apoptotic Bcl-2 family members. (T7P1)

BH3-only proteins - A subgroup of the Bcl-2 family members that contain a single BH3 domain. These proteins act as sentinels for cell damage and provoke apoptotic cell death. The BH3-only proteins cause the activation of Bax and Bak by direct or indirect effects. The expression, localisation and function of BH3-only proteins are altered by various forms of cell stress. (T7P1)

Bid - A pro-apoptotic, BH3-only, member of the Bcl-2 family. The expression of Bid is upregulated by the active form of the tumour suppressor protein p53. Bid can be activated by cleavage via caspase 8. The truncated form of Bid interacts with, and activates, Bax and Bak resulting in apoptosis. (T7P1)

blebbing - In relation to cell membranes - the formation of membrane protrusions, involving detachment of the cell membrane from cytoskeletal components. A feature of apoptotic cell death and, in some cases, necrotic cell death. (T7P1)

caspase recruitment domains (CARD) - Domains that are contained within the pro-domains of initiator procaspases 2 and 9. CARD domains enable proteins to associate via homotypic interactions. The CARD domain of procaspase 9 allows it to bind to Apaf-1 in the apoptosome. The binding of procaspase 9 to Apaf-1 leads to caspase activation and apoptosis. (T7P1)

caspases - Cysteine-dependent aspartate-directed proteases. A family of proteases that all contain cysteine at their catalytic sites, and cleave their protein substrates on the carboxyl side of aspartate residues. Caspases are present in cells as inactive precursors (zymogens) known as procaspases. Initiator caspases activate effector caspases, which in turn hydrolyse specific proteins thereby committing a cell to die. (T7P1)

ced - For cell death defective; the name given to some genes detected in mutant C. elegans in which the usual pattern of cell death did not take place, or in which extra cells died. (T7P1)

CED-3 - A caspase isoform expressed in C. elegans; a homologue of the mammalian caspase interleukin 1�-converting enzyme (ICE) . (T7P1)

clonogenic stem cells - Specified, but uncommitted stem cells that are able to revert back to become a quiescent stem cell. Considered to be an intermediate stage between the stem cell and transit-amplifying cells. (T7P2)

committed - Also commitment and committing. Describes cells that have engaged in a program leading to differentiation. For a stem cell, this means exit from self-renewal. (T7P2)

cytochrome c - A protein that is present in the intermembrane space between the inner and outer mitochondrial membranes. Cytochrome c functions as part of the mitochondrial respiratory chain in living cells. In cells undergoing apoptosis, the outer mitochondrial membrane is permeabilised (a process known as MOMP) as a result of Bax and Bak activation, and cytochrome c can enter the cytosol. Once there, cytochrome c binds to Apaf-1 and stimulates the formation of the apoptosome. (T7P1)

DAMPs - Damage-associated molecular pattern molecules. Inflammatory molecules that are lost from leaky necrotic cells. (T7P1)

death domain - A domain within the intracellular part of a death receptor molecule. (T7P1)

death effector domains (DED) - Domains that are contained within the pro-domains of initiator procaspases and adaptor proteins, and are involved in interactions between the two proteins. (T7P1)

death-inducing signalling complex (DISC) - A multiprotein complex that is formed by recruitment of adaptor proteins to death receptors upon ligand binding. The complex recruits initiator procaspase molecules, which are autoactivated. (T7P1)

death receptors - Cell surface receptors to which ligands that activate the extrinsic apoptotic pathway bind. The ligands may be secreted factors or molecules expressed on the surface of other cells. (T7P1)

direct activation model - A model for activation of Bax or Bak in which BH3-only proteins directly bind. (T7P1)

DNA fragmentation factor - A caspase-activated nuclease that hydrolyses genomic DNA during apoptosis. (T7P1)

ectoderm - Embryonic germ layer which will form nervous system and skin. (T7P2)

effector caspases - Caspases that are activated by initiator caspases and go on to hydrolyse cellular proteins and thereby trigger cell death. (T7P1)

embryonic stem cells (ESCs) - Pluripotent stem cells derived from early embryos before formation of the tissue germ layers; capable of forming any cell of the body. (T7P2)

endoderm - Embryonic germ layer which will form cells of the gut and lungs, and cells lining the liver and pancreas. (T7P2)

executioner caspases - Another term for effector caspases. (T7P1)

Fas ligand (FasL) - A protein expressed on the surface of cytotoxic T lymphocytes. (T7P1)

Fas signalling pathway - An apoptotic signalling pathway. When Fas ligand binds to Fas it triggers the extrinsic apoptosis pathway. (T7P1)

granzyme A - One of the proteolytic enzymes secreted by cytotoxic T lymphocytes, along with perforin and granzyme B, onto the surface of a target cell. It acts by cleaving various cellular proteins including DNA fragmentation factor. (T7P1)

granzyme B - One of the proteolytic enzymes secreted by cytotoxic T lymphocytes, along with perforin and granzyme A, onto the surface of a target cell. It acts by cleaving procaspases, and thereby initiates apoptosis. (T7P1)

homotypic - Interactions that occur between homologous sequences in two proteins (e.g. between two proteins that contain DED domains, or between two proteins that contain CARD domains). (T7P1)

‘immortal strand’ hypothesis - Hypothesis developed by John Cairns in 1975, which proposes that one DNA strand is epigenetically marked such that it is always segregated to the daughter stem cell during asymmetric division of a mother stem cell. (T7P2)

immunological synapse - The interface between a cytotoxic T lymphocyte and a target cell. (T7P1)

indirect activation model - A model for activation of Bax or Bak in which BH3-only proteins do not directly bind, but sequester anti-apoptotic Bcl-2 family proteins. (T7P1)

induced pluripotent stem cells (iPSCs) - Pluripotent stem cells created from fully differentiated cells by the re-expression of a core set of stem cell transcription factors, such as the Yamanaka factors: Klf4, Oct4, Sox2 and c-Myc. (T5P1 and T7P2)

inflammation - Term used to describe the reaction of tissues to harmful stimuli. It generally leads to swelling, irritation and possibly pain within tissues, and can be caused by pro-inflammatory signals from healthy cells, infectious agents or the leakage of cellular molecules following necrotic cell death. (T7P1)

initiator caspases - Caspases that, when activated, trigger apoptosis. They activate effector caspases, which hydrolyse cellular proteins. (T7P1)

interleukin 1�-converting enzyme (ICE) - A caspase homologue involved in cytokine processing and inflammatory responses. (T7P1)

mesenchymal stem cells (MSCs) - Mesoderm-derived multipotent stem cells found in bone marrow, connective tissue, adipose tissue and adult muscle that differentiate into these tissue specific cell types. In addition, given appropriate stimuli, MSCs can differentiate into some ectodermal cell types including nervous system and skin cells. (T7P2)

mesoderm - Embryonic germ layer which will form muscle and connective tissues including bone, cartilage, fat and blood. (T7P2)

mitophagy - A form of autophagy where dysfunctional or unwanted mitochondria are digested. (T7P1)

MOMP - Mitochondrial outer membrane permeabilisation, which occurs when Bax or Bak are activated. Cytochrome c can leave mitochondria following MOMP, and participate in the formation of apoptosomes. (T7P1)

mPT (mitochondrial permeability transition) - mPT or mitochondrial permeability transition marks a sudden increase in the flux of ions and solutes across the inner mitochondrial membrane. This leads to mitochondrial swelling and rupture, which precipitates necrotic cell death. (T7P1)

mTOR - Mechanistic target of rapamycin, a serine/threonine kinase that regulates many cellular processes. (T7P1)

necrosis - Typical response of cells to injury in the form of harmful reagents, infections or wounds. The damaged cell swells because the cell membrane fails to control the passage of ions and water, and finally lyses (bursts), releasing its contents, which in vertebrates can stimulate a potentially damaging inflammatory response. (T7P1)

niche - Cellular microenvironment providing support and stimuli necessary to sustain self-renewal. (T7P2)

p53 - A transcription factor encoded by the p53 gene, p53 is a tumour suppressor protein which, if DNA is damaged, ensures that cell division does not proceed and can trigger apoptosis. p53 stimulates transcription of the p21 gene, which encodes p21, a protein which binds to and inactivates cyclin–cdk complexes. (T7P1 and T8P5)

perforin - A pore-forming protein secreted, together with proteolytic enzymes, by cytotoxic T lymphocytes onto the surface of a target cell. Perforin forms ion channels in the target cell membrane. (T7P1)

potency - The range of commitment options available to a stem cell (of which there are four categories: totipotent, pluripotent, multipotent, unipotent). (T7P2)

pro-apoptotic - The term used to describe events, or regulatory proteins, that promote apoptosis. (T7P1)

procaspases - Procaspases are inactive forms of caspases. They become active caspases following dimerisation and cleavage. (T7P1)

pro-domain - Caspases have a pro-domain in addition to their large and small domains. Initiator caspases have large pro-domains that have CARD or DED domains for homotypic protein interaction. The pro-domain of initiator caspases can be hydrolysed during their activation. (T7P1)

programmed cell death - A type of cell death where particular cells die in a reproducible, controlled manner as a result of the action of proteins encoded by the cells themselves. Because of its predictable nature, this form of death was believed to occur as the result of a death 'programme', and so was named programmed cell death. Well-known examples are the loss of the cells between digits (e.g. during the development of fingers), and in the tail of the tadpole, when it metamorphoses into a frog. In adult tissues, cell death usually balances cell division, ensuring that tissues and organs retain the same size and structure as old cells are replaced. (T7P1)

reactive oxygen species (ROS) - Collective term for both oxygen-based radicals (such as nitric oxide) and reactive non-radical oxidants (such as hydrogen peroxide (H2O2) and lipid peroxide). ROS are generated as by-products of oxidative metabolism and other cellular reactions. They are potentially damaging to cells, because they cause oxidative damage to macromolecules and membranes. (T7P1 and T8P4)

segregating determinants - Proteins that become selectively concentrated on one side of a stem cell prior to cell division. Depending upon the axis of division, the determinants can become segregated into just one of the daughter cells (asymmetric cell division) or can be equally divided between the daughter cells (symmetric division). (T7P2)

specified - Describes a cell that has received signals which result in it adopting a certain phenotype. Specified cells need to commit before they can then differentiate. (T7P2)

transit-amplifying cells - Proliferative stem-cell progeny fated for differentiation. (T7P2)

Yamanaka factors - A group of four transcription factors (Klf4, Oct4, Sox2 and c-Myc ) that are highly expressed in embryonic stem cells (ESCs) and whose over-expression in adult mouse fibroblasts was sufficient to generate ESC-like colonies from these cells. Named after Shinya Yamanaka, one of the researchers who reported this observation. The resulting cells were described as induced pluripotent stem cells (iPSCs). (T7P2)