P21

Last updated
CDKN1A
PDB 1axc EBI.jpg
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases CDKN1A , CAP20, CDKN1, CIP1, MDA-6, P21, SDI1, WAF1, p21CIP1, cyclin-dependent kinase inhibitor 1A, cyclin dependent kinase inhibitor 1A
External IDs OMIM: 116899 MGI: 104556 HomoloGene: 333 GeneCards: CDKN1A
Orthologs
SpeciesHumanMouse
Entrez

1026

12575

Ensembl

ENSG00000124762

ENSMUSG00000023067

UniProt

P38936

P39689

RefSeq (mRNA)

NM_078467
NM_000389
NM_001220777
NM_001220778
NM_001291549

Contents

NM_001111099
NM_007669

RefSeq (protein)

NP_001104569
NP_031695

Location (UCSC) Chr 6: 36.68 – 36.69 Mb Chr 17: 29.31 – 29.32 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

p21Cip1 (alternatively p21Waf1), also known as cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1, is a cyclin-dependent kinase inhibitor (CKI) that is capable of inhibiting all cyclin/CDK complexes, [5] though is primarily associated with inhibition of CDK2. [6] [7] p21 represents a major target of p53 activity and thus is associated with linking DNA damage to cell cycle arrest. [8] [9] [10] This protein is encoded by the CDKN1A gene located on chromosome 6 (6p21.2) in humans. [11]

Function

CDK inhibition

p21 is a potent cyclin-dependent kinase inhibitor (CKI). The p21 (CIP1/WAF1) protein binds to and inhibits the activity of cyclin-CDK2, -CDK1, and -CDK4 /6 complexes, and thus functions as a regulator of cell cycle progression at G1 and S phase. [12] [13] 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. [6] 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 a region that blocks its ability to complex with cyclins and thus prevent CDK activation. [14]

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 G0/quiescent state, whilst those with low p21 continue to proliferate. [15] 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. [16]

PCNA inhibition

p21 interacts with proliferating cell nuclear antigen (PCNA), a DNA polymerase accessory factor, and plays a regulatory role in S phase DNA replication and DNA damage repair. [17] [18] [19] Specifically, p21 has a high affinity for the PIP-box binding region on PCNA, [20] 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). [21] As such, p21 acts as an effective inhibitor of S-phase DNA synthesis though permits NER, leading to the proposal that p21 acts to preferentially select polymerase processivity factors depending on the context of DNA synthesis. [22]

Apoptosis inhibition

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. [23] The ability of p21 to inhibit apoptosis in response to replication fork stress has also been reported. [24]

Regulation

p53 dependent response

Studies of p53 dependent cell cycle arrest in response to DNA damage identified p21 as 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. [25] Dulcic et al. also found that γ-irradiation of fibroblasts induced a p53 and p21 dependent cell cycle arrest, here p21 was found bound to inactive cyclin E/CDK2 complexes. [26] 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. [27] [13] 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 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. [28] 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; [29] this responsible for the bifurcation in CDK2 activity observed in Spencer et al.. [15]

Degradation

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 Skp2 induces degradation of p21. [30] [31] Studies have also demonstrated that the E3 ubiquitin ligase complex CRL4 Cdt2 degrades p21 in a PCNA dependent manner over S-phase, necessary to prevent p21 dependent re-replication, [32] as well as in response to UV irradiation. [33] Recent work has now found that in human cell lines SCFSkp2 degrades p21 towards the end of G1 phase, allowing cells to exit a quiescent state, whilst CRL4Cdt2 acts to degrade p21 at a much higher rate than SCFSkp2 over the G1/S transition and subsequently maintain low levels of p21 throughout S-phase. [29]

Clinical significance

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 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. [34]

p21 mediates the resistance of hematopoietic cells to an infection with HIV [35] 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 the HIV life cycle inside CD4 T cells, significantly limiting production of new viruses. [36]

Metastatic canine mammary tumors display increased levels of p21 in the primary tumors but also in their metastases, despite increased cell proliferation. [37] [38]

Mice that lack the p21 gene gain the ability to regenerate lost appendages. [39]

Interactions

P21 has been shown to interact with:

Related Research Articles

<span class="mw-page-title-main">Cell cycle</span> Series of events and stages that result in cell division

The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA and some of its organelles, and subsequently the partitioning of its cytoplasm and other components into two daughter cells in a process called cell division.

Restriction point Animal cell cycle checkpoint

The restriction point (R), also known as the Start or G1/S checkpoint, is a cell cycle checkpoint in the G1 phase of the animal cell cycle at which the cell becomes "committed" to the cell cycle, and after which extracellular signals are no longer required to stimulate proliferation. The defining biochemical feature of the restriction point is the activation of G1/S- and S-phase cyclin-CDK complexes, which in turn phosphorylate proteins that initiate DNA replication, centrosome duplication, and other early cell cycle events. It is one of three main cell cycle checkpoints, the other two being the G2-M DNA damage checkpoint and the spindle checkpoint.

Cell cycle checkpoint Control mechanism in the eukaryotic cell cycle

Cell cycle checkpoints are control mechanisms in the eukaryotic cell cycle which ensure its proper progression. Each checkpoint serves as a potential termination point along the cell cycle, during which the conditions of the cell are assessed, with progression through the various phases of the cell cycle occurring only when favorable conditions are met. There are many checkpoints in the cell cycle, but the three major ones are: the G1 checkpoint, also known as the Start or restriction checkpoint or Major Checkpoint; the G2/M checkpoint; and the metaphase-to-anaphase transition, also known as the spindle checkpoint. Progression through these checkpoints is largely determined by the activation of cyclin-dependent kinases by regulatory protein subunits called cyclins, different forms of which are produced at each stage of the cell cycle to control the specific events that occur therein.

Proliferating cell nuclear antigen

Proliferating cell nuclear antigen (PCNA) is a DNA clamp that acts as a processivity factor for DNA polymerase δ in eukaryotic cells and is essential for replication. PCNA is a homotrimer and achieves its processivity by encircling the DNA, where it acts as a scaffold to recruit proteins involved in DNA replication, DNA repair, chromatin remodeling and epigenetics.

G1/S transition Stage in cell cycle

The G1/S transition is a stage in the cell cycle at the boundary between the G1 phase, in which the cell grows, and the S phase, during which DNA is replicated. It is governed by cell cycle checkpoints to ensure cell cycle integrity and the subsequent S phase can pause in response to improperly or partially replicated DNA. During this transition the cell makes decisions to become quiescent, differentiate, make DNA repairs, or proliferate based on environmental cues and molecular signaling inputs. The G1/S transition occurs late in G1 and the absence or improper application of this highly regulated check point can lead to cellular transformation and disease states such as cancer

Cyclin D

Cyclin D is a member of the cyclin protein family that is involved in regulating cell cycle progression. The synthesis of cyclin D is initiated during G1 and drives the G1/S phase transition. Cyclin D protein is anywhere from 155 to 477 amino acids in length.

Cyclin-dependent kinase 2 Protein-coding gene in the species Homo sapiens

Cyclin-dependent kinase 2, also known as cell division protein kinase 2, or Cdk2, is an enzyme that in humans is encoded by the CDK2 gene. The protein encoded by this gene is a member of the cyclin-dependent kinase family of Ser/Thr protein kinases. This protein kinase is highly similar to the gene products of S. cerevisiae cdc28, and S. pombe cdc2, also known as Cdk1 in humans. It is a catalytic subunit of the cyclin-dependent kinase complex, whose activity is restricted to the G1-S phase of the cell cycle, where cells make proteins necessary for mitosis and replicate their DNA. This protein associates with and is regulated by the regulatory subunits of the complex including cyclin E or A. Cyclin E binds G1 phase Cdk2, which is required for the transition from G1 to S phase while binding with Cyclin A is required to progress through the S phase. Its activity is also regulated by phosphorylation. Multiple alternatively spliced variants and multiple transcription initiation sites of this gene have been reported. The role of this protein in G1-S transition has been recently questioned as cells lacking Cdk2 are reported to have no problem during this transition.

Cyclin-dependent kinase 4 Human protein

Cyclin-dependent kinase 4 also known as cell division protein kinase 4 is an enzyme that in humans is encoded by the CDK4 gene. CDK4 is a member of the cyclin-dependent kinase family.

Cyclin-dependent kinase 6 Protein-coding gene in the species Homo sapiens

Cell division protein kinase 6 (CDK6) is an enzyme encoded by the CDK6 gene. It is regulated by cyclins, more specifically by Cyclin D proteins and Cyclin-dependent kinase inhibitor proteins. The protein encoded by this gene is a member of the cyclin-dependent kinase, (CDK) family, which includes CDK4. CDK family members are highly similar to the gene products of Saccharomyces cerevisiae cdc28, and Schizosaccharomyces pombe cdc2, and are known to be important regulators of cell cycle progression in the point of regulation named R or restriction point.

The Cyclin D/Cdk4 complex is a multi-protein structure consisting of the proteins Cyclin D and cyclin-dependent kinase 4, or Cdk4, a serine-threonine kinase. This complex is one of many cyclin/cyclin-dependent kinase complexes that are the "hearts of the cell-cycle control system" and govern the cell cycle and its progression. As its name would suggest, the cyclin-dependent kinase is only active and able to phosphorylate its substrates when it is bound by the corresponding cyclin. The Cyclin D/Cdk4 complex is integral for the progression of the cell from the Growth 1 phase to the Synthesis phase of the cell cycle, for the Start or G1/S checkpoint.

Eukaryotic DNA replication DNA Replication in eukaryotic

Eukaryotic DNA replication is a conserved mechanism that restricts DNA replication to once per cell cycle. Eukaryotic DNA replication of chromosomal DNA is central for the duplication of a cell and is necessary for the maintenance of the eukaryotic genome.

Cyclin-dependent kinase 1 Mammalian protein found in Homo sapiens

Cyclin-dependent kinase 1 also known as CDK1 or cell division cycle protein 2 homolog is a highly conserved protein that functions as a serine/threonine protein kinase, and is a key player in cell cycle regulation. It has been highly studied in the budding yeast S. cerevisiae, and the fission yeast S. pombe, where it is encoded by genes cdc28 and cdc2, respectively. With its cyclin partners, Cdk1 forms complexes that phosphorylate a variety of target substrates ; phosphorylation of these proteins leads to cell cycle progression.

<span class="mw-page-title-main">CDKN1B</span>

Cyclin-dependent kinase inhibitor 1B (p27Kip1) is an enzyme inhibitor that in humans is encoded by the CDKN1B gene. It encodes a protein which belongs to the Cip/Kip family of cyclin dependent kinase (Cdk) inhibitor proteins. The encoded protein binds to and prevents the activation of cyclin E-CDK2 or cyclin D-CDK4 complexes, and thus controls the cell cycle progression at G1. It is often referred to as a cell cycle inhibitor protein because its major function is to stop or slow down the cell division cycle.

Flap structure-specific endonuclease 1

Flap endonuclease 1 is an enzyme that in humans is encoded by the FEN1 gene.

Cyclin-dependent kinase inhibitor 1C

Cyclin-dependent kinase inhibitor 1C , also known as CDKN1C, is a protein which in humans is encoded by the CDKN1C imprinted gene.

GADD45A

Growth arrest and DNA-damage-inducible protein GADD45 alpha is a protein that in humans is encoded by the GADD45A gene.

CDKN2C Protein-coding gene in the species Homo sapiens

Cyclin-dependent kinase 4 inhibitor C is an enzyme that in humans is encoded by the CDKN2C gene.

CDKN2D Protein-coding gene in the species Homo sapiens

Cyclin-dependent kinase 4 inhibitor D is an enzyme that in humans is encoded by the CDKN2D gene.

CDKN3 Protein-coding gene in the species Homo sapiens

Cyclin-dependent kinase inhibitor 3 is an enzyme that in humans is encoded by the CDKN3 gene.

The CIP/KIP family is one of two families of mammalian cyclin dependent kinase (CDK) inhibitors (CKIs) involved in regulating the cell cycle. The CIP/KIP family is made up of three proteins: p21cip1/waf1, P27kip1, p57kip2 These proteins share sequence homology at the N-terminal domain which allows them to bind to both the cyclin and CDK. Their activity primarily involves the binding and inhibition of G1/S- and S-Cdks; however, they have also been shown to play an important role in activating the G1-CDKs CDK4 and CDK6. In addition, more recent work has shown that CIP/KIP family members have a number of CDK-independent roles involving regulation of transcription, apoptosis, and the cytoskeleton.

References

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  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000023067 - Ensembl, May 2017
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  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R, Beach D (1993). "p21 is a universal inhibitor of cyclin kinases". Nature. 366 (6456): 701–4. Bibcode:1993Natur.366..701X. doi:10.1038/366701a0. PMID   8259214. S2CID   4362507.
  6. 1 2 Abbas, Tarek; Dutta, Anindya (2009). "p21 in cancer: intricate networks and multiple activities". Nature Reviews Cancer. 9 (6): 400–414. doi:10.1038/nrc2657. PMC   2722839 . PMID   19440234.
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  8. ↑ el-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW, Vogelstein B (November 1993). "WAF1, a potential mediator of p53 tumor suppression". Cell. 75 (4): 817–25. doi: 10.1016/0092-8674(93)90500-P . PMID   8242752.
  9. ↑ Bunz F, et al. (1998). "Requirement for p53 and p21 to sustain G2 arrest after DNA damage". Science. 282 (5393): 1497–1501. doi:10.1126/science.282.5393.1497. PMID   9822382.
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  11. ↑ "Entrez Gene: CDKN1A cyclin-dependent kinase inhibitor 1A (p21, Cip1)".
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  15. 1 2 Spencer, Sabrina~L.; Cappell, Steven~D.; Tsai, Feng-Chiao; Overton, K.~Wesley; Wang, Clifford~L.; Meyer, Tobias (2013). "The Proliferation-Quiescence Decision Is Controlled by a Bifurcation in CDK2 Activity at Mitotic Exit". Cell. 155 (2): 369–383. doi:10.1016/j.cell.2013.08.062. PMC   4001917 . PMID   24075009.
  16. ↑ Overton, K. W.; Spencer, S. L.; Noderer, W. L.; Meyer, T.; Wang, C. L. (2014). "Basal p21 controls population heterogeneity in cycling and quiescent cell cycle states". Proceedings of the National Academy of Sciences. 111 (41): E4386–E4393. Bibcode:2014PNAS..111E4386O. doi: 10.1073/pnas.1409797111 . PMC   4205626 . PMID   25267623.
  17. ↑ Flores-Rozas H, et al. (1994). "Cdk-interacting protein 1 directly binds with proliferating cell nuclear antigen and inhibits DNA replication catalyzed by the DNA polymerase delta holoenzyme". Proceedings of the National Academy of Sciences. 91 (18): 8655–8659. Bibcode:1994PNAS...91.8655F. doi: 10.1073/pnas.91.18.8655 . PMC   44665 . PMID   7915843.
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  33. ↑ Abbas, T.; Sivaprasad, U.; Terai, K.; Amador, V.; Pagano, M.; Dutta, A. (2008). "PCNA-dependent regulation of p21 ubiquitylation and degradation via the CRL4Cdt2 ubiquitin ligase complex". Genes & Development. 22 (18): 2496–2506. doi:10.1101/gad.1676108. PMC   2546691 . PMID   18794347.
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  40. ↑ Chen W, Sun Z, Wang XJ, Jiang T, Huang Z, Fang D, Zhang DD (June 2009). "Direct interaction between Nrf2 and p21(Cip1/WAF1) upregulates the Nrf2-mediated antioxidant response". Mol. Cell. 34 (6): 663–73. doi:10.1016/j.molcel.2009.04.029. PMC   2714804 . PMID   19560419.
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  42. ↑ Mitsui K, Matsumoto A, Ohtsuka S, Ohtsubo M, Yoshimura A (October 1999). "Cloning and characterization of a novel p21(Cip1/Waf1)-interacting zinc finger protein, ciz1". Biochem. Biophys. Res. Commun. 264 (2): 457–64. doi:10.1006/bbrc.1999.1516. PMID   10529385.
  43. 1 2 3 Abbas T, Sivaprasad U, Terai K, Amador V, Pagano M, Dutta A (September 2008). "PCNA-dependent regulation of p21 ubiquitylation and degradation via the CRL4Cdt2 ubiquitin ligase complex". Genes Dev. 22 (18): 2496–506. doi:10.1101/gad.1676108. PMC   2546691 . PMID   18794347.
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