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Inhibitors of apoptosis are a group of proteins that mainly act on the intrinsic pathway that block programmed cell death, which can frequently lead to
cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
or other effects for the cell if
mutated In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitos ...
or improperly regulated. Many of these inhibitors act to block
caspase Caspases (cysteine-aspartic proteases, cysteine aspartases or cysteine-dependent aspartate-directed proteases) are a family of protease enzymes playing essential roles in programmed cell death. They are named caspases due to their specific cystei ...
s, a family of
cysteine protease Cysteine proteases, also known as thiol proteases, are hydrolase enzymes that degrade proteins. These proteases share a common catalytic mechanism that involves a nucleophilic cysteine thiol in a catalytic triad or dyad. Discovered by Gopal Chund ...
s that play an integral role in apoptosis. Some of these inhibitors include the
Bcl-2 family The Bcl-2 familyTC# 1.A.21 consists of a number of evolutionarily-conserved proteins that share Bcl-2 homology (BH) domains. The Bcl-2 family is most notable for their regulation of apoptosis, a form of programmed cell death, at the mitochondrion. ...
, viral inhibitor crmA, and IAP's.
Apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
, or programmed cell death, is a highly regulated process used by many multicellular organisms. Like any regulated process, apoptosis is subject to either activation or inhibition by a variety of chemical factors. Apoptosis can be triggered through two main pathways; extrinsic and intrinsic pathways. The extrinsic pathway mostly involves extracellular signals triggering intracellular apoptosis mechanisms by binding to
receptors Receptor may refer to: *Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a n ...
in the
cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...
and sending signals from the outside of the cell. Intrinsic pathways involved internal cell signaling primarily through the
mitochondria A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...
.


Bcl-2 family

The
Bcl-2 Bcl-2 (B-cell lymphoma 2), encoded in humans by the ''BCL2'' gene, is the founding member of the Bcl-2 family of regulator proteins that regulate cell death (apoptosis), by either inhibiting (anti-apoptotic) or inducing (pro-apoptotic) apoptosis. ...
family of proteins can either inhibit or promote apoptosis and members are characterized by the Bcl-2 homologous domains BH1, BH2, BH3, and BH4. The combinations of the domains in the proteins determine its role in the apoptosis process. Members of the family that inhibit apoptosis include Bcl-2 itself, Bcl-XL, and Bcl-w, which possess all four of the domains. Bcl-2 is the most well known of the anti-apoptotic members, and is classified as an
oncogene An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.
. Studies have shown that the Bcl-2 oncogene may inhibit apoptosis in two ways; either by directly controlling the activation of caspases, or by disrupting the channels that allow proapoptotic factors from leaving the mitochondria.


Activity in the cell

Regarding the activation of caspases, there exists a gene called ''ced-9'' in ''C. elegans'' that protects against cell death that is a part of the Bcl-2 family. ''ced-9'' encodes a protein that is structurally similar to Bcl-2 that binds to another protein ''ced-4'', a
homolog In biology, homology is similarity due to shared ancestry between a pair of structures or genes in different taxa. A common example of homologous structures is the forelimbs of vertebrates, where the wings of bats and birds, the arms of prima ...
of
APAF-1 Apoptotic protease activating factor 1, also known as APAF1, is a human homolog of ''C. elegans'' CED-4 gene. Function The protein was identified in the lab of Xiaodong Wang as an activator of caspase-3 in the presense of cytochromeC and dATP ...
in humans, and prevents it from activating caspase ''ced-3'', which is necessary for killing of the cell. In humans APAF-1 actually doesn't interact with Bcl-2; rather it is activated by
cytochrome c The cytochrome complex, or cyt ''c'', is a small hemeprotein found loosely associated with the inner membrane of the mitochondrion. It belongs to the cytochrome c family of proteins and plays a major role in cell apoptosis. Cytochrome c is hig ...
, the release of which from the mitochondria is regulated by Bcl-2. BAX and BAK are multidomain proapoptoic members of the Bcl-2 family that lie in the cytosol and the mitochondria, respectively. After several stimuli leading to cell death are activated, BAX also moves to the mitochondria where it carries out its functions there. Bcl-2 and Bcl-xl have been found to sequester BH3 domain molecules in the mitochondria, which prevents the activation of BAX and BAK.


crmA

crmA, or cytokine response modifier A, is a
cowpox Cowpox is an infectious disease caused by the ''cowpox virus'' (CPXV). It presents with large blisters in the skin, a fever and swollen glands, historically typically following contact with an infected cow, though in the last several decades more ...
serpin Serpins are a Protein superfamily, superfamily of proteins with similar structures that were first identified for their Protease inhibitor (biology), protease inhibition activity and are found in all kingdom (biology), kingdoms of life. The acr ...
that inhibits caspases 1, 6 and 8, forming complexes with these caspases that renders them unable to perform their apoptotic functions. Cowpox is an orthopox virus that increases their chances of survival and infection by inhibition of specific caspases and preventing inflammatory responses and apoptosis. * By inhibiting caspase 1, also known as
interleukin 1β Interleukins (ILs) are a group of cytokines (secreted proteins and signal molecules) that are expressed and secreted by white blood cells (leukocytes) as well as some other body cells. The human genome encodes more than 50 interleukins and related ...
converting enzyme (ICE), crmA prevents cytokines interleukin 1β from being formed, preventing an inflammatory response. Although free floating crmA is relatively unstable, it becomes incredibly stable after binding to caspase 1, forming an irreversible stable complex. * Caspase 8 initiates apoptosis by activating "executioner" caspases, numbered 3, 6, and 7. By inhibiting caspase 8, crmA prevents the other caspases from ever being activated. Inhibition of caspase 8 also prevents cell death signals by ligation of a
TNF Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...
super family member known as ''death receptors'', that signal for apoptosis through caspase 8. Serpins generally inhibit
serine proteases Serine proteases (or serine endopeptidases) are enzymes that cleave peptide bonds in proteins. Serine serves as the nucleophilic amino acid at the (enzyme's) active site. They are found ubiquitously in both eukaryotes and prokaryotes. Serin ...
by a suicide substrate inhibition mechanism, in which the serpin undergoes a drastic change in structure to form an acyl enzyme intermediate. A reactive center loop of the protease is bound to the central beta loop of the serpin, trapping the protease in a state where it is no longer able to perform its catalytic functions. Studies have shown crmA uses a method analogous to serpin inhibition of serine proteases to inhibit cysteine protease caspases.


IAPs

The Inhibitors of apoptosis proteins (IAP) are a family of functionally and structurally related proteins that serve as endogenous inhibitors of programmed cell death (
apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
). A common feature of all IAPs is the presence of a BIR (Baculovirus IAP Repeat, a ~70 amino acid domain) in one to three copies. The human IAP family consists of 8 members, and IAP homologs have been identified in numerous organisms. The first members of the IAPs identified were from the
baculovirus ''Baculoviridae'' is a family of viruses. Arthropod Arthropods (, (gen. ποδός)) are invertebrate animals with an exoskeleton, a Segmentation (biology), segmented body, and paired jointed appendages. Arthropods form the phylum Arthropod ...
IAPs, Cp-IAP and Op-IAP, which bind to and inhibit caspases as a mechanism that contributes to its efficient infection and replication cycle in the host. Later, five more human IAPs were discovered which included
XIAP X-linked inhibitor of apoptosis protein (XIAP), also known as inhibitor of apoptosis protein 3 (IAP3) and baculoviral IAP repeat-containing protein 4 (BIRC4), is a protein that stops apoptotic cell death. In humans, this protein (XIAP) is produ ...
,
cIAP1 cIAP1 (also named BIRC2) is the abbreviation for a human protein, cellular inhibitor of apoptosis protein-1. It belongs to the IAP family of proteins and therefore contains at least one BIR ( baculoviral IAP repeat) domain. cIAP1 is a multi-functi ...
, C-IAP2, NAIP, Livin and
Survivin Survivin, also called baculoviral inhibitor of apoptosis repeat-containing 5 or BIRC5, is a protein that, in humans, is encoded by the ''BIRC5'' gene. Survivin is a member of the inhibitor of apoptosis (IAP) family. The survivin protein functions ...
. The best characterized IAP is
XIAP X-linked inhibitor of apoptosis protein (XIAP), also known as inhibitor of apoptosis protein 3 (IAP3) and baculoviral IAP repeat-containing protein 4 (BIRC4), is a protein that stops apoptotic cell death. In humans, this protein (XIAP) is produ ...
, which binds
caspase-9 Caspase-9 is an enzyme that in humans is encoded by the CASP9 gene. It is an initiator caspase, critical to the apoptotic pathway found in many tissues. Caspase-9 homologs have been identified in all mammals for which they are known to exist, such ...
,
caspase-3 Caspase-3 is a caspase protein that interacts with caspase-8 and caspase-9. It is encoded by the ''CASP3'' gene. ''CASP3'' orthologs have been identified in numerous mammals for which complete genome data are available. Unique orthologs are also p ...
and
caspase-7 Caspase-7, apoptosis-related cysteine peptidase, also known as CASP7, is a human protein encoded by the ''CASP7'' gene. ''CASP7'' orthologs have been identified in nearly all mammals for which complete genome data are available. Unique orthologs a ...
, thereby inhibiting their activation and preventing
apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
. Also cIAP1 and cIAP2 have been shown to bind caspases, although how the IAPs inhibit apoptosis mechanistically at the molecular level is not completely understood. Activity of XIAP is blocked by binding to DIABLO (Smac) and HTRA2 (Omi) proteins released from mitochondria after proapoptotic stimuli. Since the mid-2000s, significant progress has been made into the development of small molecule mimics of the endogenous IAP ligand Smac. One recent example published in 2013 describes the synthesis and testing of peptidomimetics whose structure is based on the AVPI tetrapeptide IAP binding motif present in the N-terminus of mature Smac. These peptidomimetic compounds were specifically noted for their exceptionally high level of binding to Livin, one of the important IAP family members yet to receive much attention from a drug discovery perspective. LCL161 is a drug that promotes cancer cell death by antagonizing IAPs. Clinical trials are ongoing, but have received mixed response. A Phase I clinical trial determined that LCL161 is well tolerated in the treatment of patients with advanced solid tumors, though they experienced
vomiting Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the Human nose, nose. Vomiting can be the result of ailments like Food-poisoning, foo ...
,
nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...
,
fatigue Fatigue describes a state of tiredness that does not resolve with rest or sleep. In general usage, fatigue is synonymous with extreme tiredness or exhaustion that normally follows prolonged physical or mental activity. When it does not resolve ...
, and
loss of appetite Anorexia is a medical term for a loss of appetite. While the term in non-scientific publications is often used interchangeably with anorexia nervosa, many possible causes exist for a loss of appetite, some of which may be harmless, while others i ...
. Another study found that LCL161 reduced survival and promoted endotoxic shock when used in MYC-driven
lymphoma Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). In current usage the name usually refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include enlar ...
. Other clinical trials are still enrolling to determine the drugs efficacy.


See also

*
Bcl-2 Bcl-2 (B-cell lymphoma 2), encoded in humans by the ''BCL2'' gene, is the founding member of the Bcl-2 family of regulator proteins that regulate cell death (apoptosis), by either inhibiting (anti-apoptotic) or inducing (pro-apoptotic) apoptosis. ...
*
Caspase Caspases (cysteine-aspartic proteases, cysteine aspartases or cysteine-dependent aspartate-directed proteases) are a family of protease enzymes playing essential roles in programmed cell death. They are named caspases due to their specific cystei ...
*
cIAP1 cIAP1 (also named BIRC2) is the abbreviation for a human protein, cellular inhibitor of apoptosis protein-1. It belongs to the IAP family of proteins and therefore contains at least one BIR ( baculoviral IAP repeat) domain. cIAP1 is a multi-functi ...
* cIAP2 *
Inhibitor of apoptosis domain The inhibitor of apoptosis domain -- also known as IAP repeat, Baculovirus Inhibitor of apoptosis protein Repeat, or BIR -- is a structural motif found in proteins with roles in apoptosis, cytokine production, and chromosome segregation. Proteins ...
*
Survivin Survivin, also called baculoviral inhibitor of apoptosis repeat-containing 5 or BIRC5, is a protein that, in humans, is encoded by the ''BIRC5'' gene. Survivin is a member of the inhibitor of apoptosis (IAP) family. The survivin protein functions ...
*
XIAP X-linked inhibitor of apoptosis protein (XIAP), also known as inhibitor of apoptosis protein 3 (IAP3) and baculoviral IAP repeat-containing protein 4 (BIRC4), is a protein that stops apoptotic cell death. In humans, this protein (XIAP) is produ ...


References


External links

* The
MEROPS MEROPS is an online database for peptidases (also known as proteases, proteinases and proteolytic enzymes) and their inhibitors. The classification scheme for peptidases was published by Rawlings & Barrett in 1993, and that for protein inhibitor ...
online database for peptidases and their inhibitors
I32.002
* {{DEFAULTSORT:Inhibitor Of Apoptosis Cell biology