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p21 in cancer: intricate networks and multiple activities

Key Points

  • p21 came into the spotlight as a mediator of p53 tumour suppressor activity and as an inhibitor of cell cycle progression owing to its ability to inhibit the activity of cyclin-dependent kinase (CDK)–cyclin complexes and proliferating cell nuclear antigen (PCNA).

  • The tumour suppressor activity of p21 stems from its role in inducing growth arrest, differentiation or senescence. Recently, it has become apparent that p21 is stimulated by many pathways that are independent of p53.

  • p21 directly regulates gene expression and other cellular events through protein–protein interactions that are independent of CDKs and PCNA.

  • Multiple transcription factors, ubiquitin ligases, and protein kinases regulate the transcription, stability and cellular localization of p21 thereby regulating its activity.

  • Recent data suggest a tumorigenic role of p21 in certain contexts that relies on its ability to suppress apoptosis and promote the assembly of type-D cyclins with CDK4 and CDK6.

  • Given that p21 is a tumour suppressor, but that it behaves as an oncogene in certain cellular contexts, targeting p21 or factors regulating its activity for therapeutic intervention is a promising but challenging task.

Abstract

One of the main engines that drives cellular transformation is the loss of proper control of the mammalian cell cycle. The cyclin-dependent kinase inhibitor p21 (also known as p21WAF1/Cip1) promotes cell cycle arrest in response to many stimuli. It is well positioned to function as both a sensor and an effector of multiple anti-proliferative signals. This Review focuses on recent advances in our understanding of the regulation of p21 and its biological functions with emphasis on its p53-independent tumour suppressor activities and paradoxical tumour-promoting activities, and their implications in cancer.

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Figure 1: The central role of p21 in sensing and responding to a plethora of stimuli.
Figure 2: The molecular basis of p21 function in cancer.
Figure 3: Transcriptional regulation of CDKN1A (the gene encoding p21).
Figure 4: The p21 degradation cycle.

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Acknowledgements

Owing to the extensive literature concerning the regulation and activity of p21, it was impossible to account for many interesting findings in a single Review. We therefore apologize to colleagues whose work was not cited. This work was supported by grants from the National Institutes of Health (Cancer Training Grant T32CA009109 for T.A. and R01CA89406 for A.D.).

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Glossary

Senescence

A state of permanent growth arrest in G1 that is associated with changes in cell shape, cell adhesion and gene expression.

Cyclin-dependent kinase

(CDK). In association with their cyclin regulatory subunits, CDKs control progression through key cell cycle transitions.

Activation segment

The phosphorylation at a specific amino acid is required for maximal enzymatic activity of many kinases. In human cyclin-dependent kinases 1 and 2, the residues are Thr161 and Thr160, respectively, and are located within the T loop of kinase subdomain VIII.

p300–CREBBP

(p300–CREB-binding protein). Two transcriptional co-activators, each possessing a histone acetyltransferase and a bromodomain (which binds acetylated lysines), that interact with many transcription factors and activate gene transcription.

DNMT1

(DNA (cytosine-5)-methyltransferase 1). An enzyme that has a significant role in methylating cytosine residues shortly after replication and DNA repair, and in the regulation of tissue-specific patterns of methylated cytosines.

Mismatch repair

Corrects DNA replication errors (base–base or insertion or deletion mismatches) caused by DNA polymerase errors.

Base excision repair

A DNA repair pathway that operates on small DNA lesions such as oxidized or reduced bases, fragmented or non-bulky adducts, or those produced by methylating agents.

Translesion DNA synthesis

A mechanism during DNA replication in which the standard DNA polymerase is temporarily exchanged for a specialized polymerase that can synthesize DNA across base damage on the template strand.

Nucleotide excision repair

A process that removes large DNA adducts or base modifications that distort the double helix and uses the opposite strand as template for repair.

CRL4

A cullin–RING ubiquitin ligase (CRL), composed of DDB1 (DNA damage-binding protein 1), a CUL4A or CUL4B E3 ligase subunit, and RBX1. CRLs recognize their substrates by interacting with one of many substrate recognition factors collectively called DDB1- and CUL4-associated factors.

GC boxes

GC-rich sequences and related GT or CACCC boxes. Krüppel-like transcription factors bind with varying affinities to these sequences (also termed as SP1 sites) to regulate gene transcription.

F box protein

F box proteins contain at least one protein–protein interaction F-box motif (about 50 amino acids). SKP2, the first identified F-box protein, is one of the three SCF complex components that recognize substrates for destruction through the SCFSKP2 E3 ubiquitin ligase.

Substrate recognition factor

(SRF). SRFs are integral components of some cullin–RING ubiquitin ligase complexes and dictate substrate specificity. For example, SKP2 and CDT2 are p27 and p21 SRFs for the CRL1 (cullin–RING ubiquitin ligase 1) and CRL4 ubiquitin ligase complexes respectively.

Microsatellite instability

A condition manifested by damaged DNA due to defects in the normal DNA repair process and characterized by unstable sequences of repeating units 1–4 base pairs in length.

T cell leukaemia virus type 1

A retrovirus that is believed to be the cause of a rare cancer of T cells, adult T cell leukaemia–lymphoma.

Histone deacetylase

Histone deacetylases are enzymes that regulate chromatin structure and function through the removal of the acetyl group from the lysine residues of core nucleosomal histones.

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Abbas, T., Dutta, A. p21 in cancer: intricate networks and multiple activities. Nat Rev Cancer 9, 400–414 (2009). https://doi.org/10.1038/nrc2657

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