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Apoptosis

Programmed cell death or apoptosis is an important physiological process in multicellular organisms. The equilibrium between cell growth and division and the rate at which cells undergo cell death allows for dynamic adjustment of the cell number depending on internal or external parameters. For example, during the development of the vertebrate nervous system about half of the cells undergo apoptosis shortly after they have been formed. In an adult organism, this equilibrium is essential to maintain for example the size and function of organs and tissues. Dysregulation of this equilibrium oftentimes leads to cancer. Unlike necrosis which causes a potentially damaging inflammatory response after affected cells burst, apoptosis unfolds in a very organized way: the cell shrinks and condenses while the internal structures are disassembled and the DNA is fragmented. The dying cell is then rapidly phagocytosed by neighboring cells or macrophages.

At the core of the apoptotic process are caspases, a family of cysteine proteases. They are produced as pro-caspases which are rendered active subsequently to cleavage by other caspases. This caspase cascade is triggered when initiator procaspases (e.g. procaspases 8, 9, 10) are aggregated with the help of adaptor proteins, thus facilitating mutual activation due to low protease activity or conformational changes of the procaspases. The activated caspases are then free to activate effector caspases (e.g. caspases 3, 6, and 7) and promote apoptosis. Their effect is further regulated by Bcl-2 family proteins (e.g. Bcl-2, Bcl-xL) and IAPs (inhibitors of apoptosis, e.g. BIRC1, XIAP).

Apoptotic processes follow several pathways. Extrinsic death receptor pathways are induced through ligands that bind to a family of death receptor proteins (e.g. the FAS and TRAIL receptors) containing a cytoplasmic death domain. The intrinsic pathway is engaged in response to DNA damage or mitochondrial stress and is particularly relevant in cancer. Besides these canonical apoptotic pathways there are also caspase independent pathways, triggered e.g. by granzyme B and A. These caspase independent pathways are thought to have evolved in response to viruses that inhibit caspases.

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Caspases

Mitochondrial

BCL2 (B-Cell CLL/lymphoma 2):

This gene encodes an integral outer mitochondrial membrane protein that blocks the apoptotic death of some cells such as lymphocytes. Constitutive expression of BCL2, such as in the case of translocation of BCL2 to Ig heavy chain locus, is thought to be the cause of follicular lymphoma. Two transcript variants, produced by alternate splicing, differ in their C-terminal ends. [provided by...   More...

BCL2L1 (BCL2-Like 1):

The protein encoded by this gene belongs to the BCL-2 protein family. BCL-2 family members form hetero- or homodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. The proteins encoded by this gene are located at the outer mitochondrial membrane, and have been shown to regulate outer mitochondrial membrane channel (VDAC) opening. VDAC...   More...

Inhibitor of Apoptosis

BIRC2 (Baculoviral IAP Repeat Containing 2):

The protein encoded by this gene is a member of a family of proteins that inhibits apoptosis by binding to tumor necrosis factor receptor-associated factors TRAF1 and TRAF2, probably by interfering with activation of ICE-like proteases. This encoded protein inhibits apoptosis induced by serum deprivation and menadione, a potent inducer of free radicals. Alternatively spliced transcript variants...   More...

EPR1 (Early-Phytochrome-Responsive1):

Receptor

CRADD (CASP2 and RIPK1 Domain Containing Adaptor with Death Domain):

DR4 (Drought-Repressed 4 Protein):

RIPK1 (Receptor (TNFRSF)-Interacting serine-threonine Kinase 1):

TNFRSF10C (Tumor Necrosis Factor Receptor Superfamily, Member 10c, Decoy Without An Intracellular Domain):

TNFRSF10D (Tumor Necrosis Factor Receptor Superfamily, Member 10d, Decoy with Truncated Death Domain):

Cytoplasmatic

YWHAQ (Tyrosine 3-Monooxygenase/tryptophan 5-Monooxygenase Activation Protein, theta Polypeptide):

YWHAZ (Tyrosine 3-Monooxygenase/tryptophan 5-Monooxygenase Activation Protein, zeta Polypeptide):

Endoplasmatic Reticulum

CAPNL1 (Calpain 1, Large Subunit):

The calpains, calcium-activated neutral proteases, are nonlysosomal, intracellular cysteine proteases. The mammalian calpains include ubiquitous, stomach-specific, and muscle-specific proteins. The ubiquitous enzymes consist of heterodimers with distinct large, catalytic subunits associated with a common small, regulatory subunit. This gene encodes the large subunit of the ubiquitous enzyme,...   More...

TREX1 (three Prime Repair Exonuclease 1):

This gene encodes a nuclear protein with 3' exonuclease activity. The encoded protein may play a role in DNA repair and serve as a proofreading function for DNA polymerase. Mutations in this gene result in Aicardi-Goutieres syndrome, chilblain lupus, Cree encephalitis, and other diseases of the immune system. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep...   More...

SET (SET Nuclear Oncogene):

Granzyme

Gzmb - GZMB

Cytolytic T lymphocytes (CTL) and natural killer (NK) cells share the remarkable ability to recognize, bind, and lyse specific target cells. They are thought to protect their host by lysing cells bearing on their surface 'nonself' antigens, usually peptides or proteins resulting from infection by intracellular pathogens. The protein encoded by this gene is crucial for the rapid induction of...

GZMA (Granzyme A (Granzyme 1, Cytotoxic T-Lymphocyte-Associated serine Esterase 3)):

Nuclear

PARP1 (Poly (ADP-Ribose) Polymerase 1):

This gene encodes a chromatin-associated enzyme, poly(ADP-ribosyl)transferase, which modifies various nuclear proteins by poly(ADP-ribosyl)ation. The modification is dependent on DNA and is involved in the regulation of various important cellular processes such as differentiation, proliferation, and tumor transformation and also in the regulation of the molecular events involved in the recovery...   More...

DFFB (DNA Fragmentation Factor, 40kDa, beta Polypeptide (Caspase-Activated DNase)):

DNA damage

ABL1 (C-Abl Oncogene 1, Non-Receptor tyrosine Kinase):

The ABL1 protooncogene encodes a cytoplasmic and nuclear protein tyrosine kinase that has been implicated in processes of cell differentiation, cell division, cell adhesion, and stress response. Activity of c-Abl protein is negatively regulated by its SH3 domain, and deletion of the SH3 domain turns ABL1 into an oncogene. The t(9\;22) translocation results in the head-to-tail fusion of the...   More...

ATR (Ataxia Telangiectasia and Rad3 Related):

Apoptosis Markers

ANXA5 - Annexin V

The protein encoded by this gene belongs to the annexin family of calcium-dependent phospholipid binding proteins some of which have been implicated in membrane-related events along exocytotic and endocytotic pathways. Annexin 5 is a phospholipase A2 and protein kinase C inhibitory protein with calcium channel activity and a potential role in cellular signal transduction, inflammation, growth...   More...

EPR1 (Early-Phytochrome-Responsive1):

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