1AXC , 2ZVV , 2ZVW , 4RJF , 5E0U
37-429: 1026 12575 ENSG00000124762 ENSMUSG00000023067 P38936 P39689 NM_078467 NM_000389 NM_001220777 NM_001220778 NM_001291549 NM_001111099 NM_007669 NP_001361438 NP_001361439 NP_001361440 NP_001361441 NP_001361442 NP_001104569 NP_031695 p21 (alternatively p21 ), also known as cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1 ,
74-539: A DNA polymerase accessory factor, and plays a regulatory role in S phase DNA replication and DNA damage repair. Specifically, p21 has a high affinity for the PIP-box binding region on PCNA, binding of p21 to this region is proposed to block the binding of processivity factors necessary for PCNA dependent S-phase DNA synthesis, but not PCNA dependent nucleotide excision repair (NER). As such, p21 acts as an effective inhibitor of S-phase DNA synthesis though permits NER, leading to
111-879: A PCNA dependent manner over S-phase, necessary to prevent p21 dependent re-replication, as well as in response to UV irradiation. Recent work has now found that in human cell lines SCF degrades p21 towards the end of G1 phase, allowing cells to exit a quiescent state, whilst CRL4 acts to degrade p21 at a much higher rate than SCF over the G1/S transition and subsequently maintain low levels of p21 throughout S-phase. Cytoplasmic p21 expression can be significantly correlated with lymph node metastasis, distant metastases, advanced TNM stage (a classification of cancer staging that stands for: tumor size, describing nearby lymph nodes, and distant metastasis), depth of invasion and OS ( overall survival rate ). A study on immunohistochemical markers in malignant thymic epithelial tumors shows that p21 expression has
148-479: A biochemical change causes their activation. Each procaspase has an N-terminal large subunit of about 20 kDa followed by a smaller subunit of about 10 kDa, called p20 and p10, respectively. Under normal circumstances, caspases recognize tetra-peptide sequences on their substrates and hydrolyze peptide bonds after aspartic acid residues. Caspase 3 and caspase 7 share similar substrate specificity by recognizing tetra-peptide motif Asp-x-x-Asp. The C-terminal Asp
185-427: A central role in the execution-phase of cell apoptosis . Caspases exist as inactive proenzymes that undergo proteolytic processing at conserved aspartic residues to produce two subunits, large and small, that dimerize to form the active enzyme . This protein cleaves and activates caspases 6 and 7 ; and the protein itself is processed and activated by caspases 8, 9, and 10 . It is the predominant caspase involved in
222-611: A cyclin-dependent kinase inhibitor protein, helps control CDK activity in G1. Also, the INK4 proteins help stop the G1-CDK activity when they encounter anti-proliferative signals within the environment. CKIs help promote the specific inhibitory signals that contain the cell from entering the S phase. In budding yeast, SIC 1 and Roughex, RUX, in Drosophila possess the same contributions that contribute to
259-407: A heterodimer, which in turn interacts with another heterodimer to form the full 12-stranded beta-sheet structure surrounded by alpha-helices that is unique to caspases. When the heterodimers align head-to-tail with each other, an active site is positioned at each end of the molecule formed by residues from both participating subunits, though the necessary Cys-163 and His-121 residues are found on
296-445: A malfunction hinders the successful completion of DNA synthesis in the G1 phase, it triggers a signal that delays or halts the progression to the S phase. Cyclin-dependent kinase inhibitor proteins are essential in the regulation of the cell cycle. If cell mutations surpass the cell cycle checkpoints during cell cycle regulation, it can result in various types of cancer. Cyclin-dependent kinase inhibitor proteins work by inactivating
333-588: A negatively influenced survival and significantly correlated with WHO (World Health Organization) type B2/B3. When combined with low p27 and high p53, DFS (Disease-Free Survival) decreases. p21 mediates the resistance of hematopoietic cells to an infection with HIV by complexing with the HIV integrase and thereby aborting chromosomal integration of the provirus . HIV infected individuals who naturally suppress viral replication have elevated levels of p21 and its associated mRNA. p21 expression affects at least two stages in
370-642: A region that blocks its ability to complex with cyclins and thus prevent CDK activation. Experiments looking at CDK2 activity within single cells have also shown p21 to be responsible for a bifurcation in CDK2 activity following mitosis, cells with high p21 enter a G 0 /quiescent state, whilst those with low p21 continue to proliferate. Follow up work, found evidence that this bistability is underpinned by double negative feedback between p21 and CDK2, where CDK2 inhibits p21 activity via ubiquitin ligase activity. p21 interacts with proliferating cell nuclear antigen ( PCNA ),
407-470: A single-cell level have demonstrated that pulsatile p53 activity leads to subsequent pulses of p21, and that the strength of p21 activation is cell cycle phase dependent. Moreover, studies of p21-levels in populations of cycling cells, not exposed to DNA damaging agents, have shown that DNA damage occurring in mother cell S-phase can induce p21 accumulation over both mother G2 and daughter G1 phases which subsequently induces cell cycle arrest; this responsible for
SECTION 10
#1733085915863444-399: A specific site, preventing XIAP from being able to bind to inhibit caspase-9 activity. Caspase 3 has been shown to interact with: Caspase-3 has been found to be necessary for normal brain development as well as its typical role in apoptosis, where it is responsible for chromatin condensation and DNA fragmentation. Elevated levels of a fragment of Caspase-3, p17, in the bloodstream
481-496: 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 present in birds , lizards , lissamphibians , and teleosts . The CASP3 protein is a member of the c ysteine- asp artic acid prote ase ( caspase ) family. Sequential activation of caspases plays
518-533: Is a cyclin-dependent kinase inhibitor (CKI) that is capable of inhibiting all cyclin / CDK complexes , though is primarily associated with inhibition of CDK2 . p21 represents a major target of p53 activity and thus is associated with linking DNA damage to cell cycle arrest. This protein is encoded by the CDKN1A gene located on chromosome 6 (6p21.2) in humans. p21 is a potent cyclin-dependent kinase inhibitor (CKI). The p21 (CIP1/WAF1) protein binds to and inhibits
555-496: Is a protein that inhibits the enzyme cyclin-dependent kinase (CDK) and Cyclin activity by stopping the cell cycle if there are unfavorable conditions, therefore, acting as tumor suppressors . Cell cycle progression is stopped by Cyclin-dependent kinase inhibitor protein at the G1 phase. CKIs are vital proteins within the control system that point out whether the processes of DNA synthesis, mitosis , and cytokines control one another. When
592-550: Is absolutely required while variations at other three positions can be tolerated. Caspase substrate specificity has been widely used in caspase based inhibitor and drug design. Caspase-3, in particular, (also known as CPP32/Yama/apopain) is formed from a 32 kDa zymogen that is cleaved into 17 kDa and 12 kDa subunits. When the procaspase is cleaved at a particular residue, the active heterotetramer can then be formed by hydrophobic interactions, causing four anti-parallel beta-sheets from p17 and two from p12 to come together to make
629-448: Is specific to the part of the cell cycle phase. Each CDK and cyclin can be identified based on the location of the cell cycle. CKIs fall into two categories; those that inhibit CDK1, CDK2, and CDK5 and those that inhibit CDK4 and CDK6. These checkpoints' cell cycle blocks at both the G1/S and G2/M checkpoints are consistent with the inhibition profiles of the enzymes. The discovery of Cyclin-dependent kinase inhibitor proteins in 1990 opened
666-659: Is the introduction of granzyme B , which can activate initiator caspases, into cells targeted for apoptosis by killer T cells . This extrinsic activation then triggers the hallmark caspase cascade characteristic of the apoptotic pathway, in which caspase-3 plays a dominant role. In intrinsic activation, cytochrome c from the mitochondria works in combination with caspase-9 , apoptosis-activating factor 1 ( Apaf-1 ), and ATP to process procaspase-3. These molecules are sufficient to activate caspase-3 in vitro, but other regulatory proteins are necessary in vivo . Mangosteen ( Garcinia mangostana ) extract has been shown to inhibit
703-456: Is to stop cell growth when there are mistakes due to DNA damage. Once a cell is stopped at a checkpoint due to DNA damage, either the damage is repaired or the cell is induced to perform apoptosis. However, if CKI’s mutations don’t stop the cell, Cyclin D is transcribed. It moves into the cytoplasm and eventually activates a specific cyclin-dependent kinase (CDK). The active cyclin/CDK complex then phosphorylates proteins, activates them, and sends
740-680: The ATP out of the aperture of the CDK and deactivates it. Cyclin-dependent kinase inhibitor proteins use ATP as a phosphate contributor to phosphorylate serine and threonine residues. Human cells contain many different cyclins that bind to different CDKs. CDKs and cyclins appear and activate at specific cell cycle phases. Seven cyclin-dependent kinase inhibitor proteins have been identified. They are p15, p16 , p18, p19, p21 , p27, and p57. These cyclin-dependent kinase inhibitor proteins emerge only in their specific cell cycle phase. Each Cyclin/CDK complex
777-414: The peptide bond cleavage of a protein sequence to the carboxy-terminal side of an aspartic acid when it is part of a particular 4-amino acid sequence. This specificity allows caspases to be incredibly selective, with a 20,000-fold preference for aspartic acid over glutamic acid . A key feature of caspases in the cell is that they are present as zymogens , termed procaspases, which are inactive until
SECTION 20
#1733085915863814-524: The CDKs through degradation. The typical inactivation mechanism of the CDK/Cyclin complex is based on binding a CDK inhibitor to the CDK cyclin complex and a partial conformational rotation of the CDK. The cyclin is thus forced to release the T loop and detach from the CDK. Then, the CDK inhibitor initiates a small helix into the cleft, blocking the cleft and blocking the active site of the CDK. Eventually, it releases
851-503: The HIV life cycle inside CD4 T cells, significantly limiting production of new viruses. Metastatic canine mammary tumors display increased levels of p21 in the primary tumors but also in their metastases, despite increased cell proliferation. Mice that lack the p21 gene gain the ability to regenerate lost appendages. P21 has been shown to interact with: Cyclin-dependent kinase inhibitor A cyclin-dependent kinase inhibitor protein ( also known as CKIs, CDIs, or CDKIs )
888-541: The activation of caspase 3 in B-amyloid treated human neuronal cells. One means of caspase inhibition is through the IAP (inhibitor of apoptosis) protein family, which includes c-IAP1, c-IAP2, XIAP , and ML-IAP. XIAP binds and inhibits initiator caspase-9, which is directly involved in the activation of executioner caspase-3. During the caspase cascade, however, caspase-3 functions to inhibit XIAP activity by cleaving caspase-9 at
925-548: The activity of cyclin - CDK2 , - CDK1 , and - CDK4 /6 complexes, and thus functions as a regulator of cell cycle progression at G 1 and S phase . The binding of p21 to CDK complexes occurs through p21's N-terminal domain, which is homologous to the other CIP/KIP CDK inhibitors p27 and p57 . Specifically it contains a Cy1 motif in the N-terminal half, and weaker Cy2 motif in the C-terminal domain that allow it to bind CDK in
962-412: The apoptotic cell both by extrinsic (death ligand) and intrinsic (mitochondrial) pathways. The zymogen feature of caspase-3 is necessary because if unregulated, caspase activity would kill cells indiscriminately. As an executioner caspase, the caspase-3 zymogen has virtually no activity until it is cleaved by an initiator caspase after apoptotic signaling events have occurred. One such signaling event
999-506: The bifurcation in CDK2 activity observed in Spencer et al. . p21 is negatively regulated by ubiquitin ligases both over the course of the cell cycle and in response to DNA damage. Specifically, over the G1/S transition it has been demonstrated that the E3 ubiquitin ligase complex SCF induces degradation of p21. Studies have also demonstrated that the E3 ubiquitin ligase complex CRL4 degrades p21 in
1036-1309: The cell into the next phase of the cell cycle. Since the cell with damaged DNA is not stopped, the cell eventually moves out of the G1 checkpoint and prepares for DNA synthesis. When there is uncontrolled cell growth , it can lead to cancer cells due to the inactivation of the CKIs. CASP3 1CP3 , 1GFW , 1I3O , 1NME , 1NMQ , 1NMS , 1PAU , 1QX3 , 1RE1 , 1RHJ , 1RHK , 1RHM , 1RHQ , 1RHR , 1RHU , 2C1E , 2C2K , 2C2M , 2C2O , 2CDR , 2CJX , 2CJY , 2CNK , 2CNL , 2CNN , 2CNO , 2DKO , 2H5I , 2H5J , 2H65 , 2J30 , 2J31 , 2J32 , 2J33 , 2XYG , 2XYH , 2XYP , 2XZD , 2XZT , 2Y0B , 3DEH , 3DEI , 3DEJ , 3DEK , 3EDQ , 3GJQ , 3GJR , 3GJS , 3GJT , 3H0E , 3ITN , 3KJF , 3PCX , 3PD0 , 3PD1 , 4DCJ , 4DCO , 4DCP , 4EHA , 4EHD , 4EHF , 4EHH , 4EHK , 4EHL , 4EHN , 4JJE , 4JQY , 4JQZ , 4JR0 , 4PRY , 4PS0 , 4QTX , 4QTY , 4QU0 , 4QU5 , 4QU8 , 4QU9 , 4QUA , 4QUB , 4QUD , 4QUE , 4QUG , 4QUH , 4QUI , 4QUJ , 4QUL , 5IC4 836 12367 ENSG00000164305 ENSMUSG00000031628 P42574 P70677 NM_004346 NM_032991 NM_009810 NM_001284409 NP_001341710 NP_001341711 NP_001341712 NP_001341713 NP_001271338 NP_033940 Caspase-3
1073-484: The cleavage of amyloid-beta 4A precursor protein , which is associated with neuronal death in Alzheimer's disease . Alternative splicing of this gene results in two transcript variants that encode the same protein. Caspase-3 shares many of the typical characteristics common to all currently-known caspases. For example, its active site contains a cysteine residue (Cys-163) and histidine residue (His-121) that stabilize
1110-532: The door in how we think about cell cycle control. It has steered to various other fields of study such as developmental biology , cell biology and cancer research . The discovery of the first CKIs in yeast ( Far1 ) and P21 in mammals has led to research on family of molecules. Further research has demonstrates that Cdks, cyclins and CKIs play essential roles in processes such as transcription , epigenetic regulation , metabolism , stem cell self-renewal, neuronal functions and spermatogenesis . In mammals, p27,
1147-457: The p17 (larger) subunit. The catalytic site of caspase-3 involves the thiol group of Cys-163 and the imidazole ring of His-121. His-121 stabilizes the carbonyl group of the key aspartate residue, while Cys-163 attacks to ultimately cleave the peptide bond. Cys-163 and Gly-238 also function to stabilize the tetrahedral transition state of the substrate-enzyme complex through hydrogen bonding . In vitro , caspase-3 has been found to prefer
p21 - Misplaced Pages Continue
1184-414: The peptide sequence DEVDG (Asp-Glu-Val-Asp-Gly) with cleavage occurring on the carboxy side of the second aspartic acid residue (between D and G). Caspase-3 is active over a broad pH range that is slightly higher (more basic) than many of the other executioner caspases. This broad range indicates that caspase-3 will be fully active under normal and apoptotic cell conditions. Caspase-3 is activated in
1221-408: The primary mediator of downstream cell cycle arrest. Notably, El-Deiry et al. identified a protein p21 (WAF1) which was present in cells expressing wild type p53 but not those with mutant p53, moreover constitutive expression of p21 led to cell cycle arrest in a number of cell types. Dulcic et al. also found that γ-irradiation of fibroblasts induced a p53 and p21 dependent cell cycle arrest, here p21
1258-617: The proposal that p21 acts to preferentially select polymerase processivity factors depending on the context of DNA synthesis. This protein was reported to be specifically cleaved by CASP3 -like caspases , which thus leads to a dramatic activation of CDK2, and may be instrumental in the execution of apoptosis following caspase activation. However p21 may inhibit apoptosis and does not induce cell death on its own. The ability of p21 to inhibit apoptosis in response to replication fork stress has also been reported. Studies of p53 dependent cell cycle arrest in response to DNA damage identified p21 as
1295-416: The stability of G1 cells. They are expressed in higher numbers in G1 cells to make sure that no S or M CDKs are in the cell. In the cyclin-dependent kinase (CDK) family, or CDK, Cyclin, and CKIs, serine/threonine kinases play an integral role in regulating the eukaryotic cell cycle. The structure of CDK2 -CyclinA and p27 is determined by crystallography, demonstrating that the inhibitor of p27 stretches at
1332-545: The top of the Cyclin-CDK complex. The amino terminal of p27 has an RXL motif exhibiting a hydrophobic patch of cyclin A. The carboxyl-terminal end of the p27 fragment interacts with the beta sheet of CDKs, causing interference with the structure; p27 slides into the ATP-binding site of CDK2 and inhibits ATP binding. Role in cancer: Cyclin-dependent kinase inhibitor (CKI) mutants are frequent in human cancers. The function of CKI
1369-449: Was found bound to inactive cyclin E / CDK2 complexes. Working in mouse models, it was also shown that whilst mice lacking p21 were healthy, spontaneous tumours developed and G1 checkpoint control was compromised in cells derived from these mice. Taken together, these studies thus defined p21 as the primary mediator of p53-dependent cell cycle arrest in response to DNA damage. Recent work exploring p21 activation in response to DNA damage at
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