P53 upregulated modulator of apoptosis
Encyclopedia
The p53 upregulated modulator of apoptosis (PUMA) also known as Bcl-2-binding component 3 (BBC3), is a pro-apoptotic
protein, member of the Bcl-2
protein family. In humans, the Bcl-2-binding component 3 protein
is encoded by the BBC3 gene
.
The expression of PUMA is regulated by the tumor suppressor p53
. PUMA is involved in p53
-dependent and -independent apoptosis
induced by a variety of signals, and is regulated by transcription factors, not by post-translational modifications. After activation, PUMA interacts with antiapoptotic Bcl-2
family members, thus freeing Bax
and/or Bak
which are then able to signal apoptosis
to the mitochondria
. Following mitochondrial dysfunction, the caspase cascade is activated ultimately leading to cell death.
family proteins. This group of proteins only share sequence similarity in the BH3 domain, which is required for interactions with Bcl-2-like proteins, such as Bcl-2
and Bcl-xL
. Structural analysis has shown that PUMA directly binds to antiapoptotic Bcl-2 family proteins via an amphiphatic α-helical structure which is formed by the BH3 domain. The mitochondrial localization of PUMA is dictated by a hydrophobic domain on its C-terminal portion. No posttranslational modification of PUMA has been discovered yet.
, Bcl-2
, Mcl-1, Bcl-w
, and A1, inhibiting their interaction with the proapoptotic molecules, Bax and Bak. When the inhibition of these is lifted, they result in the translocation of Bax
and activation of mitochondrial dysfunction resulting in release of mitochondrial apoptogenic proteins cytochrome c
, SMAC
, and apoptosis-inducing factor
(AIF) leading to caspase activation and cell death.
Because PUMA has high affinity for binding to Bcl-2
family members, another hypothesis is that PUMA directly activates Bax and/or Bak and through Bax multimerization triggers mitochondrial translocation and with it induces apoptosis
. Various studies have shown though, that PUMA does not rely on direct interaction with Bax/Bak to induce apoptosis
.
occurs through activation of the tumor suppressor protein p53
. p53 is activated by survival signals such as glucose deprivation and increases expression levels of PUMA. This increase in PUMA levels induces apoptosis
through mitochondrial dysfunction. p53, and with it PUMA, is activated due to DNA damage caused by a variety of genotoxic agents. Other agents that induce p53 dependent apoptosis are neurotoxins, proteasome inhibitor
s, microtubule poisions, and transcription inhibitors
.
PUMA apoptosis
may also be induced independently of p53 activation by other stimuli, such as oncogenic stress growth factor
and/or cytokine
withdrawal and kinase
inhibition, ER
stress, altered redox
status, ischemia
, immune modulation, and infection
.
cells. Additionally, many human tumors contain p53
mutations, which results in no induction of PUMA, even after DNA damage induced through irradiation
or chemotherapy
drugs. Other cancers, which exhibit overexpression of antiapotptic Bcl-2
family proteins, counteract and overpower PUMA-induced apoptosis
. Even though PUMA function is compromised in most cancer
cells, it does not appear that genetic inactivation of PUMA is a direct target of cancer. Many cancers do exhibit p53 gene mutations, making gene therapies that target this gene impossible, but an alternate pathway may be to focus on therapeutic to target PUMA and induce apoptosis in cancer cells. Animal studies have shown that PUMA does play a role in tumor
suppression, but lack of PUMA activity alone does not translate to spontaneous formation of malignancies. Inhibiting PUMA induced apoptosis may be an interesting target for reducing the side effects of cancer treatments, such as chemotherapy, which induce apoptosis in rapidly dividing healthy cells in addition to rapidly dividing cancer cells.
PUMA can also function as an indicator of p53 mutations. Many cancers exhibit mutations in the p53 gene, but this mutation can only be detected through extensive DNA sequencing. Studies have shown that cells with p53 mutations have significantly lower levels of PUMA, making it a good candidate for a protein marker of p53 mutations, providing a simpler method for testing for p53 mutations.
patients are emerging. PUMA inducers target cancer
or tumor
cells, while PUMA inhibitors can be targeted to normal, healthy cells to help alleviate the undesired side effects of chemo
and radiation therapy
.
or irradiation
is highly toxic to cancer cells, specifically lung, head and neck, esophagus, melanoma, malignant glioma, gastric glands, breast and prostate. In addition, studies have shown that PUMA adenovirus seems to induce apoptosis more so than p53 adenovirus. This is beneficial in combating cancers that inhibit p53
activation and therefore indirectly decrease PUMA expression levels.
Resveratrol
, a plant-derived stilbenoid, is currently investigation as a cancer treatment. Resveratrol acts to inhibit and decrease expression of antiapoptotic Bcl-2
family members while also increasing p53
expression. The combination of these two mechanisms leads to apoptosis
via activation of PUMA, Noxa and other proapoptotic proteins, resulting in mitochondrial dysfunction.
Other approaches focus on inhibiting antiapoptotic Bcl-2
family members just as PUMA does, allowing cells to undergo apoptosis
in response to cancerous activity. Preclinical studies involving these inhibitors, also described as BH3 mimetics, have produced promising results.
therapy is dose-limited by undesired side effects in healthy tissue. PUMA has been shown to be active in inducing apoptosis
in hematopoietic and intestinal tissue following γ-irradiation. Since inhibition of PUMA does not directly cause spontaneous malignancies, therapeutics to inhibit PUMA function in healthy tissue could lessen or eliminate the side effects of traditional cancer therapies.
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
protein, member of the Bcl-2
Bcl-2
Bcl-2 is the founding member of the Bcl-2 family of apoptosis regulator proteins encoded by the BCL2 gene. Bcl-2 derives its name from B-cell lymphoma 2, as it is the second member of a range of proteins initially described in chromosomal translocations involving chromosomes 14 and 18 in...
protein family. In humans, the Bcl-2-binding component 3 protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
is encoded by the BBC3 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
The expression of PUMA is regulated by the tumor suppressor p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
. PUMA is involved in p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
-dependent and -independent apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
induced by a variety of signals, and is regulated by transcription factors, not by post-translational modifications. After activation, PUMA interacts with antiapoptotic Bcl-2
Bcl-2
Bcl-2 is the founding member of the Bcl-2 family of apoptosis regulator proteins encoded by the BCL2 gene. Bcl-2 derives its name from B-cell lymphoma 2, as it is the second member of a range of proteins initially described in chromosomal translocations involving chromosomes 14 and 18 in...
family members, thus freeing Bax
Bcl-2-associated X protein
The Bcl-2–associated X protein, or Bax is a protein of the Bcl-2 gene family. It promotes apoptosis by competing with Bcl-2 proper.The BAX gene was the first identified pro-apoptotic member of the Bcl-2 protein family....
and/or Bak
Bcl-2 homologous antagonist killer
Bcl-2 homologous antagonist/killer is a protein that in humans is encoded by the BAK1 gene. BAK1 orthologs have been identified in most mammals for which complete genome data are available....
which are then able to signal apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
to the mitochondria
Mitochondrion
In cell biology, a mitochondrion is a membrane-enclosed organelle found in most eukaryotic cells. These organelles range from 0.5 to 1.0 micrometers in diameter...
. Following mitochondrial dysfunction, the caspase cascade is activated ultimately leading to cell death.
Structure
The PUMA protein is part of the BH3-only subgroup of Bcl-2Bcl-2
Bcl-2 is the founding member of the Bcl-2 family of apoptosis regulator proteins encoded by the BCL2 gene. Bcl-2 derives its name from B-cell lymphoma 2, as it is the second member of a range of proteins initially described in chromosomal translocations involving chromosomes 14 and 18 in...
family proteins. This group of proteins only share sequence similarity in the BH3 domain, which is required for interactions with Bcl-2-like proteins, such as Bcl-2
Bcl-2
Bcl-2 is the founding member of the Bcl-2 family of apoptosis regulator proteins encoded by the BCL2 gene. Bcl-2 derives its name from B-cell lymphoma 2, as it is the second member of a range of proteins initially described in chromosomal translocations involving chromosomes 14 and 18 in...
and Bcl-xL
Bcl-xL
B-cell lymphoma-extra large is a transmembrane molecule in the mitochondria. It is involved in the signal transduction pathway of the FAS-L. It is one of several anti-apoptotic proteins which are members of the Bcl-2 family of proteins. It has been implicated in the survival of cancer cells. Other...
. Structural analysis has shown that PUMA directly binds to antiapoptotic Bcl-2 family proteins via an amphiphatic α-helical structure which is formed by the BH3 domain. The mitochondrial localization of PUMA is dictated by a hydrophobic domain on its C-terminal portion. No posttranslational modification of PUMA has been discovered yet.
Mechanism of action
Biochemical studies have shown that PUMA interacts with antiapoptotic Bcl-2 family members such as Bcl-xLBcl-xL
B-cell lymphoma-extra large is a transmembrane molecule in the mitochondria. It is involved in the signal transduction pathway of the FAS-L. It is one of several anti-apoptotic proteins which are members of the Bcl-2 family of proteins. It has been implicated in the survival of cancer cells. Other...
, Bcl-2
Bcl-2
Bcl-2 is the founding member of the Bcl-2 family of apoptosis regulator proteins encoded by the BCL2 gene. Bcl-2 derives its name from B-cell lymphoma 2, as it is the second member of a range of proteins initially described in chromosomal translocations involving chromosomes 14 and 18 in...
, Mcl-1, Bcl-w
BCL2L2
Bcl-2-like protein 2 is a protein that in humans is encoded by the BCL2L2 gene.This gene encodes a pro-survival member of the bcl-2 protein family. The proteins of this family form hetero- or homodimers and act as anti- and pro-apoptotic regulators. Expression of this gene in cells has been shown...
, and A1, inhibiting their interaction with the proapoptotic molecules, Bax and Bak. When the inhibition of these is lifted, they result in the translocation of Bax
Bcl-2-associated X protein
The Bcl-2–associated X protein, or Bax is a protein of the Bcl-2 gene family. It promotes apoptosis by competing with Bcl-2 proper.The BAX gene was the first identified pro-apoptotic member of the Bcl-2 protein family....
and activation of mitochondrial dysfunction resulting in release of mitochondrial apoptogenic proteins cytochrome c
Cytochrome c
The Cytochrome complex, or cyt c is a small heme protein found loosely associated with the inner membrane of the mitochondrion. It belongs to the cytochrome c family of proteins. Cytochrome c is a highly soluble protein, unlike other cytochromes, with a solubility of about 100 g/L and is an...
, SMAC
Diablo homolog
Diablo homolog, mitochondrial is a protein that in humans is encoded by the DIABLO gene . DIABLO is also referred to as second mitochondria-derived activator of caspases or SMAC.- Function :...
, and apoptosis-inducing factor
Apoptosis-inducing factor
Apoptosis inducing factor is a flavoprotein.Apoptosis inducing factor is involved in initiating a caspase-independent pathway of apoptosis by causing DNA fragmentation and chromatin condensation. It also acts as an NADH oxidase. Another AIF function is to regulate the permeability of the...
(AIF) leading to caspase activation and cell death.
Because PUMA has high affinity for binding to Bcl-2
Bcl-2
Bcl-2 is the founding member of the Bcl-2 family of apoptosis regulator proteins encoded by the BCL2 gene. Bcl-2 derives its name from B-cell lymphoma 2, as it is the second member of a range of proteins initially described in chromosomal translocations involving chromosomes 14 and 18 in...
family members, another hypothesis is that PUMA directly activates Bax and/or Bak and through Bax multimerization triggers mitochondrial translocation and with it induces apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
. Various studies have shown though, that PUMA does not rely on direct interaction with Bax/Bak to induce apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
.
Induction
The majority of PUMA induced apoptosisApoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
occurs through activation of the tumor suppressor protein p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
. p53 is activated by survival signals such as glucose deprivation and increases expression levels of PUMA. This increase in PUMA levels induces apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
through mitochondrial dysfunction. p53, and with it PUMA, is activated due to DNA damage caused by a variety of genotoxic agents. Other agents that induce p53 dependent apoptosis are neurotoxins, proteasome inhibitor
Proteasome inhibitor
Proteasome inhibitors are drugs that block the action of proteasomes, cellular complexes that break down proteins, like the p53 protein. Proteasome inhibitors are being studied in the treatment of cancer.-Examples:...
s, microtubule poisions, and transcription inhibitors
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
.
PUMA apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
may also be induced independently of p53 activation by other stimuli, such as oncogenic stress growth factor
Growth factor
A growth factor is a naturally occurring substance capable of stimulating cellular growth, proliferation and cellular differentiation. Usually it is a protein or a steroid hormone. Growth factors are important for regulating a variety of cellular processes....
and/or cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
withdrawal and kinase
Kinase
In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
inhibition, ER
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
stress, altered redox
Redox
Redox reactions describe all chemical reactions in which atoms have their oxidation state changed....
status, ischemia
Ischemia
In medicine, ischemia is a restriction in blood supply, generally due to factors in the blood vessels, with resultant damage or dysfunction of tissue. It may also be spelled ischaemia or ischæmia...
, immune modulation, and infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
.
Degradation
PUMA levels are downregulated through the activation of caspase-3 and a protease inhibited by the serpase inhibitor N-tosyl-L-phenylalanine chloromethyl ketone, in response to signals such as the cytokine TGFβ, the death effector TRAIL or chemical drugs such as anisomycin.Role in cancer
Several studies have shown that PUMA function is affected or absent in cancerCancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
cells. Additionally, many human tumors contain p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
mutations, which results in no induction of PUMA, even after DNA damage induced through irradiation
Irradiation
Irradiation is the process by which an object is exposed to radiation. The exposure can originate from various sources, including natural sources. Most frequently the term refers to ionizing radiation, and to a level of radiation that will serve a specific purpose, rather than radiation exposure to...
or chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
drugs. Other cancers, which exhibit overexpression of antiapotptic Bcl-2
Bcl-2
Bcl-2 is the founding member of the Bcl-2 family of apoptosis regulator proteins encoded by the BCL2 gene. Bcl-2 derives its name from B-cell lymphoma 2, as it is the second member of a range of proteins initially described in chromosomal translocations involving chromosomes 14 and 18 in...
family proteins, counteract and overpower PUMA-induced apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
. Even though PUMA function is compromised in most cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
cells, it does not appear that genetic inactivation of PUMA is a direct target of cancer. Many cancers do exhibit p53 gene mutations, making gene therapies that target this gene impossible, but an alternate pathway may be to focus on therapeutic to target PUMA and induce apoptosis in cancer cells. Animal studies have shown that PUMA does play a role in tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
suppression, but lack of PUMA activity alone does not translate to spontaneous formation of malignancies. Inhibiting PUMA induced apoptosis may be an interesting target for reducing the side effects of cancer treatments, such as chemotherapy, which induce apoptosis in rapidly dividing healthy cells in addition to rapidly dividing cancer cells.
PUMA can also function as an indicator of p53 mutations. Many cancers exhibit mutations in the p53 gene, but this mutation can only be detected through extensive DNA sequencing. Studies have shown that cells with p53 mutations have significantly lower levels of PUMA, making it a good candidate for a protein marker of p53 mutations, providing a simpler method for testing for p53 mutations.
Cancer therapeutics
Therapeutic agents targeting PUMA for cancerCancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
patients are emerging. PUMA inducers target cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
or tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
cells, while PUMA inhibitors can be targeted to normal, healthy cells to help alleviate the undesired side effects of chemo
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
and radiation therapy
Radiation therapy
Radiation therapy , radiation oncology, or radiotherapy , sometimes abbreviated to XRT or DXT, is the medical use of ionizing radiation, generally as part of cancer treatment to control malignant cells.Radiation therapy is commonly applied to the cancerous tumor because of its ability to control...
.
Cancer treatments
Research has shown that increased PUMA expression with or without chemotherapyChemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
or irradiation
Irradiation
Irradiation is the process by which an object is exposed to radiation. The exposure can originate from various sources, including natural sources. Most frequently the term refers to ionizing radiation, and to a level of radiation that will serve a specific purpose, rather than radiation exposure to...
is highly toxic to cancer cells, specifically lung, head and neck, esophagus, melanoma, malignant glioma, gastric glands, breast and prostate. In addition, studies have shown that PUMA adenovirus seems to induce apoptosis more so than p53 adenovirus. This is beneficial in combating cancers that inhibit p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
activation and therefore indirectly decrease PUMA expression levels.
Resveratrol
Resveratrol
Resveratrol is a stilbenoid, a type of natural phenol, and a phytoalexin produced naturally by several plants when under attack by pathogens such as bacteria or fungi....
, a plant-derived stilbenoid, is currently investigation as a cancer treatment. Resveratrol acts to inhibit and decrease expression of antiapoptotic Bcl-2
Bcl-2
Bcl-2 is the founding member of the Bcl-2 family of apoptosis regulator proteins encoded by the BCL2 gene. Bcl-2 derives its name from B-cell lymphoma 2, as it is the second member of a range of proteins initially described in chromosomal translocations involving chromosomes 14 and 18 in...
family members while also increasing p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
expression. The combination of these two mechanisms leads to apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
via activation of PUMA, Noxa and other proapoptotic proteins, resulting in mitochondrial dysfunction.
Other approaches focus on inhibiting antiapoptotic Bcl-2
Bcl-2
Bcl-2 is the founding member of the Bcl-2 family of apoptosis regulator proteins encoded by the BCL2 gene. Bcl-2 derives its name from B-cell lymphoma 2, as it is the second member of a range of proteins initially described in chromosomal translocations involving chromosomes 14 and 18 in...
family members just as PUMA does, allowing cells to undergo apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
in response to cancerous activity. Preclinical studies involving these inhibitors, also described as BH3 mimetics, have produced promising results.
Side-effect treatment
IrradiationIrradiation
Irradiation is the process by which an object is exposed to radiation. The exposure can originate from various sources, including natural sources. Most frequently the term refers to ionizing radiation, and to a level of radiation that will serve a specific purpose, rather than radiation exposure to...
therapy is dose-limited by undesired side effects in healthy tissue. PUMA has been shown to be active in inducing apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
in hematopoietic and intestinal tissue following γ-irradiation. Since inhibition of PUMA does not directly cause spontaneous malignancies, therapeutics to inhibit PUMA function in healthy tissue could lessen or eliminate the side effects of traditional cancer therapies.
See also
- ApoptosisApoptosisApoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
- ApoptosomeApoptosomeThe apoptosome is a large quaternary protein structure formed in the process of apoptosis. Its formation is triggered by the release of cytochrome c from the mitochondria in response to an internal or external cell death stimulus...
- Bcl-2Bcl-2Bcl-2 is the founding member of the Bcl-2 family of apoptosis regulator proteins encoded by the BCL2 gene. Bcl-2 derives its name from B-cell lymphoma 2, as it is the second member of a range of proteins initially described in chromosomal translocations involving chromosomes 14 and 18 in...
- Bcl-2-associated X proteinBcl-2-associated X proteinThe Bcl-2–associated X protein, or Bax is a protein of the Bcl-2 gene family. It promotes apoptosis by competing with Bcl-2 proper.The BAX gene was the first identified pro-apoptotic member of the Bcl-2 protein family....
(BAX) - BH3 interacting domain death agonistBH3 interacting domain death agonistThe BH3 interacting-domain death agonist, or BID, gene is a pro-apoptotic member of the Bcl-2 protein family. Bcl-2 family members share one or more of the four characteristic domains of homology entitled the Bcl-2 homology domains , and can form hetero- or homodimers...
(BID) - Caspases
- Cytochrome cCytochrome cThe Cytochrome complex, or cyt c is a small heme protein found loosely associated with the inner membrane of the mitochondrion. It belongs to the cytochrome c family of proteins. Cytochrome c is a highly soluble protein, unlike other cytochromes, with a solubility of about 100 g/L and is an...
- NoxaNoxaPhorbol-12-myristate-13-acetate-induced protein 1 is a protein that in humans is encoded by the PMAIP1 gene.Noxa is a pro-apoptotic member of the Bcl-2 protein family. Bcl-2 family members can form hetero- or homodimers, and they act as anti- or pro-apoptotic regulators that are involved in a wide...
- MitochondrionMitochondrionIn cell biology, a mitochondrion is a membrane-enclosed organelle found in most eukaryotic cells. These organelles range from 0.5 to 1.0 micrometers in diameter...