Apoptosis(凋亡)
As one of the cellular death mechanisms, apoptosis, also known as programmed cell death, can be defined as the process of a proper death of any cell under certain or necessary conditions. Apoptosis is controlled by the interactions between several molecules and responsible for the elimination of unwanted cells from the body.
Many biochemical events and a series of morphological changes occur at the early stage and increasingly continue till the end of apoptosis process. Morphological event cascade including cytoplasmic filament aggregation, nuclear condensation, cellular fragmentation, and plasma membrane blebbing finally results in the formation of apoptotic bodies. Several biochemical changes such as protein modifications/degradations, DNA and chromatin deteriorations, and synthesis of cell surface markers form morphological process during apoptosis.
Apoptosis can be stimulated by two different pathways: (1) intrinsic pathway (or mitochondria pathway) that mainly occurs via release of cytochrome c from the mitochondria and (2) extrinsic pathway when Fas death receptor is activated by a signal coming from the outside of the cell.
Different gene families such as caspases, inhibitor of apoptosis proteins, B cell lymphoma (Bcl)-2 family, tumor necrosis factor (TNF) receptor gene superfamily, or p53 gene are involved and/or collaborate in the process of apoptosis.
Caspase family comprises conserved cysteine aspartic-specific proteases, and members of caspase family are considerably crucial in the regulation of apoptosis. There are 14 different caspases in mammals, and they are basically classified as the initiators including caspase-2, -8, -9, and -10; and the effectors including caspase-3, -6, -7, and -14; and also the cytokine activators including caspase-1, -4, -5, -11, -12, and -13. In vertebrates, caspase-dependent apoptosis occurs through two main interconnected pathways which are intrinsic and extrinsic pathways. The intrinsic or mitochondrial apoptosis pathway can be activated through various cellular stresses that lead to cytochrome c release from the mitochondria and the formation of the apoptosome, comprised of APAF1, cytochrome c, ATP, and caspase-9, resulting in the activation of caspase-9. Active caspase-9 then initiates apoptosis by cleaving and thereby activating executioner caspases. The extrinsic apoptosis pathway is activated through the binding of a ligand to a death receptor, which in turn leads, with the help of the adapter proteins (FADD/TRADD), to recruitment, dimerization, and activation of caspase-8 (or 10). Active caspase-8 (or 10) then either initiates apoptosis directly by cleaving and thereby activating executioner caspase (-3, -6, -7), or activates the intrinsic apoptotic pathway through cleavage of BID to induce efficient cell death. In a heat shock-induced death, caspase-2 induces apoptosis via cleavage of Bid.
Bcl-2 family members are divided into three subfamilies including (i) pro-survival subfamily members (Bcl-2, Bcl-xl, Bcl-W, MCL1, and BFL1/A1), (ii) BH3-only subfamily members (Bad, Bim, Noxa, and Puma9), and (iii) pro-apoptotic mediator subfamily members (Bax and Bak). Following activation of the intrinsic pathway by cellular stress, pro‑apoptotic BCL‑2 homology 3 (BH3)‑only proteins inhibit the anti‑apoptotic proteins Bcl‑2, Bcl-xl, Bcl‑W and MCL1. The subsequent activation and oligomerization of the Bak and Bax result in mitochondrial outer membrane permeabilization (MOMP). This results in the release of cytochrome c and SMAC from the mitochondria. Cytochrome c forms a complex with caspase-9 and APAF1, which leads to the activation of caspase-9. Caspase-9 then activates caspase-3 and caspase-7, resulting in cell death. Inhibition of this process by anti‑apoptotic Bcl‑2 proteins occurs via sequestration of pro‑apoptotic proteins through binding to their BH3 motifs.
One of the most important ways of triggering apoptosis is mediated through death receptors (DRs), which are classified in TNF superfamily. There exist six DRs: DR1 (also called TNFR1); DR2 (also called Fas); DR3, to which VEGI binds; DR4 and DR5, to which TRAIL binds; and DR6, no ligand has yet been identified that binds to DR6. The induction of apoptosis by TNF ligands is initiated by binding to their specific DRs, such as TNFα/TNFR1, FasL /Fas (CD95, DR2), TRAIL (Apo2L)/DR4 (TRAIL-R1) or DR5 (TRAIL-R2). When TNF-α binds to TNFR1, it recruits a protein called TNFR-associated death domain (TRADD) through its death domain (DD). TRADD then recruits a protein called Fas-associated protein with death domain (FADD), which then sequentially activates caspase-8 and caspase-3, and thus apoptosis. Alternatively, TNF-α can activate mitochondria to sequentially release ROS, cytochrome c, and Bax, leading to activation of caspase-9 and caspase-3 and thus apoptosis. Some of the miRNAs can inhibit apoptosis by targeting the death-receptor pathway including miR-21, miR-24, and miR-200c.
p53 has the ability to activate intrinsic and extrinsic pathways of apoptosis by inducing transcription of several proteins like Puma, Bid, Bax, TRAIL-R2, and CD95.
Some inhibitors of apoptosis proteins (IAPs) can inhibit apoptosis indirectly (such as cIAP1/BIRC2, cIAP2/BIRC3) or inhibit caspase directly, such as XIAP/BIRC4 (inhibits caspase-3, -7, -9), and Bruce/BIRC6 (inhibits caspase-3, -6, -7, -8, -9).
Any alterations or abnormalities occurring in apoptotic processes contribute to development of human diseases and malignancies especially cancer.
References:
1.Yağmur Kiraz, Aysun Adan, Melis Kartal Yandim, et al. Major apoptotic mechanisms and genes involved in apoptosis[J]. Tumor Biology, 2016, 37(7):8471.
2.Aggarwal B B, Gupta S C, Kim J H. Historical perspectives on tumor necrosis factor and its superfamily: 25 years later, a golden journey.[J]. Blood, 2012, 119(3):651.
3.Ashkenazi A, Fairbrother W J, Leverson J D, et al. From basic apoptosis discoveries to advanced selective BCL-2 family inhibitors[J]. Nature Reviews Drug Discovery, 2017.
4.McIlwain D R, Berger T, Mak T W. Caspase functions in cell death and disease[J]. Cold Spring Harbor perspectives in biology, 2013, 5(4): a008656.
5.Ola M S, Nawaz M, Ahsan H. Role of Bcl-2 family proteins and caspases in the regulation of apoptosis[J]. Molecular and cellular biochemistry, 2011, 351(1-2): 41-58.
Products for Apoptosis
- Caspase(79)
- 14.3.3 Proteins(1)
- Apoptosis Inducers(41)
- Bax(7)
- Bcl-2 Family(98)
- Bcl-xL(8)
- c-RET(9)
- IAP(24)
- KEAP1-Nrf2(56)
- MDM2(12)
- p53(104)
- PC-PLC(4)
- PKD(6)
- RasGAP (Ras- P21)(1)
- Survivin(5)
- Thymidylate Synthase(10)
- TNF-α(100)
- Other Apoptosis(885)
- APC(5)
- PD-1/PD-L1 interaction(46)
- ASK1(3)
- PAR4(2)
- RIP kinase(44)
- FKBP(19)
- Pyroptosis(15)
- Cat.No. 产品名称 Information
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GC26092
Z-LEHD-FMK TFA
Z-LEHD-FMK TFA (Caspase-9 Inhibitor) is a cell-permeable, competitive and irreversible inhibitor of enzyme caspase-9, which helps in cell survival.
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GC25743
PIM447 (LGH447)
PIM447 (LGH447) is a novel pan-PIM kinase inhibitor with Ki values of 6 pM, 18 pM, 9 pM for PIM1, PIM2, PIM3 respectively. It also inhibits GSK3β, PKN1, and PKCτ, but at a significantly lower potency with IC50 between 1 and 5 μM (>105-fold differential relative to the Ki on PIMs). PIM447 induces apoptosis.
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GC25691
OTS514 hydrochloride
OTS514 is a highly potent TOPK(T-LAK cell-originated protein kinase) inhibitor with an IC50 value of 2.6 nM. OTS514 induces cell cycle arrest and apoptosis.
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GC25673
Obatoclax (GX15-070)
Obatoclax (GX15-070) is an antagonist of Bcl-2 with an Ki of 0
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GC25428
Foscenvivint (ICG-001)
Foscenvivint (ICG-001) antagonizes Wnt/β-catenin/TCF-mediated transcription and specifically binds to CREB-binding protein (CBP) with IC50 of 3 μM, but is not the related transcriptional coactivator p300. ICG-001 induces apoptosis.
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GC25351
Dimethyl itaconate
Dimethyl itaconate can reprogram neurotoxic to neuroprotective primary astrocytes through the regulation of LPS-induced Nod-like receptor protein 3 (NLRP3) inflammasome and nuclear factor 2/heme oxygenase-1 (NRF2/HO-1) pathways.
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GC25160
BMS-1001
BMS-1001 is a potent inhibitor of PD-1/PD-L1 interaction with EC50 of 253 nM. BMS-1001 alleviates the inhibitory effect of the soluble PD-L1 on the T-cell receptor-mediated activation of T-lymphocytes.
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GC67969
RIP1/RIP3/MLKL activator 1
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GC67966
Methylstat
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GC67936
Lupiwighteone
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GC67792
NSC49652
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GC67765
p53 Activator 5
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GC67694
PD-1/PD-L1-IN-9 hydrochloride
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GC67680
BIO8898
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GC52516
Erbstatin
A tyrosine kinase inhibitor
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GC52489
Ceramide (hydroxy) (bovine spinal cord)
A sphingolipid
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GC52486
Ceramide Phosphoethanolamine (bovine)
A sphingolipid
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GC52485
Ceramide (non-hydroxy) (bovine spinal cord)
A sphingolipid
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GC52476
Bax Inhibitor Peptide V5 (trifluoroacetate salt)
A Bax inhibitor
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GC52472
Inostamycin A (sodium salt)
A bacterial metabolite with anticancer activity
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GC52469
CL2A-SN-38 (dichloroacetic acid salt)
An antibody-drug conjugate containing SN-38
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GC52467
Cell Death Screening Library
For screening a variety of cell death pathways
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GC52455
Pixantrone-d8 (maleate)
An internal standard for the quantification of pixantrone
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GC52372
Ac-VDVAD-AFC (trifluoroacetate salt)
A fluorogenic substrate for caspase-2
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GC52371
Vimentin (G146R) (139-159)-biotin Peptide
A biotinylated mutant vimentin peptide
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GC52370
Citrullinated Vimentin (R144) (139-159)-biotin Peptide
A biotinylated and citrullinated vimentin peptide
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GC52367
Citrullinated Vimentin (G146R) (R144 + R146) (139-159)-biotin Peptide
A biotinylated and citrullinated mutant vimentin peptide
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GC52364
Vimentin (139-159)-biotin Peptide
A biotinylated vimentin peptide
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GC52358
Malachite Green (chloride)
A triphenylmethane dye
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GC52355
BimS BH3 (51-76) (human) (trifluoroacetate salt)
A Bim-derived peptide
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GC52344
Bak BH3 (72-87) (human) (trifluoroacetate salt)
A Bak-derived peptide
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GC52325
MeTC7
A vitamin D receptor antagonist
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GC52318
Oleic Acid-13C5
An internal standard for the quantification of oleic acid
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GC52293
STAT3 Inhibitor 4m
A STAT3 inhibitor
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GC52291
KAS 08
A STING activator
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GC52288
Fumonisin B1-13C34
An internal standard for the quantification of fumonisin B1
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GC52269
Cinnabarinic Acid-d4
An internal standard for the quantification of cinnabarinic acid
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GC52250
Mevalonate (lithium salt)
An intermediate in the mevalonate pathway
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GC52245
CAY10792
An anticancer agent
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GC52227
5-(3',4'-Dihydroxyphenyl)-γ-Valerolactone
An active metabolite of various polyphenols
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GC67618
α-Tocopherol phosphate disodium
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GC67272
N6-Benzyladenosine
DNPH1i (N6-benzyladenosine,BAPR) is a competitive inhibitor of adenosine deaminase(ADA) from L-1210 cells in axenic culture as well as a potent antiproliferative agent in vitro and in vivo.
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GC66824
D-α-Tocopherol Succinate
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GC66479
GSK2593074A
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GC66462
MGH-CP1
MGH-CP1 is a potent and selective inhibitor of transcriptional enhanced associate domain (TEAD) palmitoylation. MGH-CP1 exhibits dose-dependent and potent inhibition of TEAD2/4 auto-palmitoylation in vitro with IC50 of 710 nM and 672 nM, respectively.
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GC66460
UCB-5307
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GC66403
Z-DEVD-AMC
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GC66394
Penpulimab
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GC66382
Lucatumumab
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GC66378
Serplulimab