# P16

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Mammalian protein found in humans

For other uses, see [P16 (disambiguation)](/source/P16_(disambiguation)).

CDKN2A Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2A5E, 1A5E, 1BI7, 1DC2,%%s1A5E, 1BI7, 1DC2, 2A5E Identifiers Aliases CDKN2A, CDK4I, CDKN2, CMM2, INK4, INK4A, MLM, MTS-1, MTS1, P14, P14ARF, P16, P16-INK4A, P16INK4, P16INK4A, P19, P19ARF, TP16, cyclin-dependent kinase inhibitor 2A, cyclin dependent kinase inhibitor 2A, Genes, p16, ARF. External IDs OMIM: 600160; MGI: 104738; HomoloGene: 55430; GeneCards: CDKN2A; OMA:CDKN2A - orthologs Gene location (Human) Chr. Chromosome 9 (human)[1] Band 9p21.3 Start 21,967,752 bp[1] End 21,995,301 bp[1] Gene location (Mouse) Chr. Chromosome 4 (mouse)[2] Band 4 C4|4 42.15 cM Start 89,192,708 bp[2] End 89,212,890 bp[2] RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in parotid gland pituitary gland testicle anterior pituitary subthalamic nucleus tongue ventral tegmental area mucosa of pharynx superior surface of tongue external globus pallidus Top expressed in yolk sac stroma of bone marrow morula embryo glossopharyngeal ganglion endothelial cell of lymphatic vessel lumbar subsegment of spinal cord calvaria greater petrosal nerve muscle of thigh More reference expression data BioGPS More reference expression data Gene ontology Molecular function NF-kappaB binding protein binding cyclin-dependent protein serine/threonine kinase inhibitor activity protein kinase binding RNA binding DNA binding p53 binding transcription factor binding MDM2/MDM4 family protein binding ubiquitin-protein transferase inhibitor activity SUMO transferase activity disordered domain specific binding ubiquitin ligase inhibitor activity Cellular component cytoplasm cytosol senescence-associated heterochromatin focus nucleus nuclear body nucleoplasm nucleolus mitochondrion protein-containing complex Biological process positive regulation of smooth muscle cell apoptotic process negative regulation of cyclin-dependent protein serine/threonine kinase activity replicative senescence G1 phase negative regulation of cell-matrix adhesion cellular senescence negative regulation of cell growth positive regulation of cellular senescence positive regulation of macrophage apoptotic process cell cycle Ras protein signal transduction negative regulation of phosphorylation negative regulation of transcription, DNA-templated negative regulation of NF-kappaB transcription factor activity negative regulation of cell population proliferation G1/S transition of mitotic cell cycle negative regulation of G1/S transition of mitotic cell cycle apoptotic process regulation of G2/M transition of mitotic cell cycle regulation of transcription, DNA-templated regulation of protein stability negative regulation of immature T cell proliferation in thymus regulation of protein export from nucleus negative regulation of protein kinase activity negative regulation of proteolysis involved in cellular protein catabolic process protein K63-linked ubiquitination positive regulation of signal transduction by p53 class mediator somatic stem cell division protein stabilization protein polyubiquitination positive regulation of protein sumoylation transcription, DNA-templated positive regulation of transcription, DNA-templated autophagy of mitochondrion apoptotic mitochondrial changes regulation of protein targeting to mitochondrion protein destabilization negative regulation of ubiquitin-protein transferase activity positive regulation of apoptotic process rRNA processing negative regulation of ubiquitin-dependent protein catabolic process mitochondrial depolarization positive regulation of DNA damage response, signal transduction by p53 class mediator negative regulation of B cell proliferation activation of cysteine-type endopeptidase activity involved in apoptotic process regulation of apoptotic DNA fragmentation positive regulation of transcription by RNA polymerase II positive regulation of protein localization to nucleus protein sumoylation positive regulation of gene expression negative regulation of ubiquitin protein ligase activity amyloid fibril formation negative regulation of protein neddylation Sources:Amigo / QuickGO Orthologs Species Human Mouse Entrez 1029 12578 Ensembl ENSG00000147889 ENSMUSG00000044303 UniProt P42771 Q8N726 P51480 Q64364 RefSeq (mRNA) NM_000077 NM_001195132 NM_058195 NM_058196 NM_058197 NM_001363763 NM_001040654 NM_009877 RefSeq (protein) NP_000068 NP_001182061 NP_478102 NP_478104 NP_001350692 NP_478102.2 NP_001035744 NP_034007 NP_034007.1 Location (UCSC) Chr 9: 21.97 – 22 Mb Chr 4: 89.19 – 89.21 Mb PubMed search [3] [4] Wikidata View/Edit Human View/Edit Mouse

Protein family

Cyclin-dependent kinase inhibitor 2a p19Arf N-terminus Solution structure of the n-terminal 37 amino acids of the mouse arf tumor suppressor protein Identifiers Symbol P19Arf_N Pfam PF07392 InterPro IPR010868 SCOP2 1hn3 / SCOPe / SUPFAM Available protein structures: PDB IPR010868 PF07392 (ECOD; PDBsum) AlphaFold IPR010868 PF07392

**p16** (also known as **p16INK4a**, **cyclin-dependent kinase inhibitor 2A**, **CDKN2A**, **multiple tumor suppressor 1** and numerous other synonyms), is a [protein](/source/Protein) that slows [cell division](/source/Cell_division) by slowing the progression of the cell cycle from the [G1 phase](/source/G1_phase) to the [S phase](/source/S_phase), thereby acting as a [tumor suppressor](/source/Tumor_suppressor). It is encoded by the *[CDKN2A](/source/CDKN2A)* [gene](/source/Gene). A [deletion](/source/Genetics) (the omission of a part of the DNA sequence during replication) in this gene can result in insufficient or non-functional p16, accelerating the cell cycle and resulting in several different types of cancer.[5][6][7]

p16 can be used as a [biomarker](/source/Biomarker) to improve the histological diagnostic accuracy of grade 3 [cervical intraepithelial neoplasia](/source/Cervical_intraepithelial_neoplasia) (CIN). p16 is also implicated in the prevention of [melanoma](/source/Melanoma), [oropharyngeal squamous cell carcinoma](/source/Oropharyngeal_cancer), [cervical cancer](/source/Cervical_cancer), [vulvar cancer](/source/Vulvar_cancer) and [esophageal cancer](/source/Esophageal_cancer).

p16 was discovered in 1993. It is a protein with 148 amino acids and a [molecular weight](/source/Molecular_weight) of 16 [kDa](/source/Kilodalton) that comprises four [ankyrin repeats](/source/Ankyrin_repeat).[8] The name of p16 is derived from its [molecular weight](/source/Molecular_weight), and the alternative name p16INK4a refers to its role in inhibiting [cyclin-dependent kinase](/source/Cyclin-dependent_kinase) CDK4.[8]

## Nomenclature

p16 is also known as:

- p16INK4A

- p16Ink4

- Cyclin-dependent kinase inhibitor 2A (CDKN2A)

- CDKN2

- CDK 4 Inhibitor

- Multiple Tumor Suppressor 1 (MTS1)

- TP16

- ARF

- MLM

- P14

## Gene

In humans, p16 is encoded by the [CDKN2A](/source/CDKN2A) gene, located on [chromosome 9](/source/Chromosome_9_(human)) (9p21.3). This [gene](/source/Gene) generates several [transcript](/source/Transcription_(genetics)) variants that differ in their first [exons](/source/Exon). At least three alternatively [spliced](/source/Splicing_(genetics)) variants encoding distinct proteins have been reported, two of which encode structurally related [isoforms](/source/Protein_isoform) known to function as [inhibitors](/source/Enzyme_inhibitor) of [CDK4](/source/Cyclin-dependent_kinase_4). The remaining transcript includes an alternate exon 1 located 20 [kb](/source/Kilobase) upstream of the remainder of the gene; this transcript contains an [alternate open reading frame (ARF)](/source/P14arf) that specifies a protein that is structurally unrelated to the products of the other variants.[9] The ARF product functions as a stabilizer of the tumor suppressor protein [p53](/source/P53_(protein)), as it can interact with and sequester [MDM2](/source/MDM2), a protein responsible for the degradation of p53.[10][11] In spite of their structural and functional differences, the CDK inhibitor isoforms and the ARF product encoded by this gene, through the regulatory roles of CDK4 and p53 in [cell cycle G1 progression](/source/Cell_cycle#G1_phase), share a common functionality in controlling the G1 phase of the cell cycle. This gene is frequently mutated or deleted in a wide variety of tumors and is known to be an important tumor suppressor gene.[5]

When organisms age, the expression of p16 increases to reduce the proliferation of [stem cells](/source/Stem_cell).[12] This reduction in the division and production of stem cells protects against [cancer](/source/Cancer) while increasing the risks associated with [cellular senescence](/source/Senescence).

## Function

p16 is an inhibitor of cyclin-dependent kinases (CDK). It slows down the cell cycle by prohibiting progression from G1 phase to S phase. Otherwise, CDK4/6 binds cyclin D and forms an active protein complex that phosphorylates [retinoblastoma protein](/source/Retinoblastoma_protein) (pRB). Once phosphorylated, pRB dissociates from the transcription factor [E2F1](/source/E2F1). This liberates E2F1 from its bound state in the cytoplasm and allows it to enter the nucleus. Once in the nucleus, E2F1 promotes the transcription of target genes that are essential for transition from G1 to S phase.[13][14]

This pathway connects the processes of tumor oncogenesis and senescence, fixing them on opposite ends of a spectrum. On one end, p16 hypermethylation, mutation, or deletion leads to downregulation of the gene and can lead to cancer through the dysregulation of cell cycle progression. Conversely, activation of p16 through [reactive oxygen species](/source/Reactive_oxygen_species), DNA damage, or senescence leads to the buildup of p16 in tissues and is implicated in the aging of cells.[13]

## Regulation

Regulation of p16 is complex and involves the interaction of several transcription factors, as well as several proteins involved in epigenetic modification through methylation and repression of the promoter region.[13]

[PRC1](/source/PRC1) and PRC2 are two protein complexes that modify the expression of p16 through the interaction of various transcription factors that execute methylation patterns that can repress transcription of p16. These pathways are activated in the cellular response to reduce senescence.[15][16]

## Clinical significance

### Role in carcinogenesis

Mutations resulting in deletion or reduction of function of the CDKN2A gene are associated with increased risk of a wide range of cancers, and alterations of the gene are frequently seen in cancer [cell lines](/source/Cell_line).[17][18] Examples include:

[Pancreatic adenocarcinoma](/source/Pancreatic_cancer) is often associated with mutations in the CDKN2A gene.[19][20][21]

Carriers of [germline mutations](/source/Germline_mutation) in CDKN2A have, besides their high risks of melanoma, also increased risks of pancreatic, lung, laryngeal and oropharyngeal cancers. Tobacco smoking increases the carriers’ susceptibility for such non-melanoma cancers.[22]

Homozygous deletions of p16 are frequently found in [esophageal cancer](/source/Esophageal_cancer) and [gastric cancer](/source/Gastric_cancer) cell lines.[23]

Germline mutations in CDKN2A are associated with an increased susceptibility to develop [skin cancer](/source/Skin_cancer).[24]

Hypermethylation of tumor suppressor genes has been implicated in various cancers. In 2013, a meta-analysis revealed an increased frequency of DNA methylation of the p16 gene in esophageal cancer. As the degree of tumor differentiation increased, so did the frequency of p16 DNA methylation.

Tissue samples of primary oral squamous cell carcinoma (OSCC) often display hypermethylation in the promoter regions of p16. Cancer cells show a significant increase in the accumulation of methylation in CpG islands in the promoter region of p16. This [epigenetic](/source/Epigenetic) change leads to loss of the tumor suppressor gene function through two possible mechanisms: first, methylation can physically inhibit the transcription of the gene, and second, methylation can lead to the recruitment of transcription factors that repress transcription. Both mechanisms cause the same end result: downregulation of gene expression that leads to decreased levels of the p16 protein. It has been suggested that this process is responsible for the development of various forms of cancer serving as an alternative process to gene deletion or mutation.[25][26][27][28][29][30]

p16 positivity has been shown to be favorably prognostic in oropharyngeal squamous cell carcinoma.[31] In a retrospective trial analysis of patients with Stage III and IV oropharyngeal cancer, HPV status was assessed and it was found that the 3-year rates of overall survival were 82.4% (95% CI, 77.2 to 87.6) in the HPV-positive subgroup and 57.1% (95% CI, 48.1 to 66.1) in the HPV-negative subgroup, and the 3-year rates of progression-free survival were 73.7% (95% CI, 67.7 to 79.8) and 43.4% (95% CI, 34.4 to 52.4), respectively. p16 status is so prognostic that the AJCC staging system has been revised to include p16 status in oropharyngeal squamous cell cancer group staging.[32] However, some people can have elevated levels of p16 but test negative for HPV and vice versa. This is known as discordant cancer. The 5-year survival for people who test positive for HPV and p16 is 81%, for discordant cancer it is 53–55%, and 40% for those who test negative for p16 and HPV.[33][34]

## Clinical use

### Biomarker for cancer types

Expression of p16 is used as a prognostic biomarker for certain types of cancer. The reason for this is different types of cancer can have different effects on p16 expression: cancers that overexpress p16 are usually caused by the [human papillomavirus](/source/Human_papillomavirus) (HPV), whereas cancers in which p16 is downregulated will usually have other causes. For patients with oropharyngeal squamous cell carcinoma, using immunohistochemistry to detect the presence of the p16 biomarker has been shown to be the strongest indicator of disease course. Presence of the biomarker is associated with a more favorable prognosis as measured by cancer-specific survival (CSS), recurrence-free survival (RFS), locoregional control (LRC), as well as other measurements. The appearance of hypermethylation of p16 is also being evaluated as a potential prognostic biomarker for prostate cancer.[35][36][37]

### p16 FISH

p16 [deletion](/source/Deletion_(genetics)) detected by [FISH](/source/FISH_(genetic)) in surface epithelial mesothelial proliferations is predictive of underlying invasive [mesothelioma](/source/Mesothelioma).[38]

### p16 immunochemistry

High grade squamous intraepithelial lesion showing strong p16 staining

To count as positive, p16 immunohistochemistry should show "block" staining, which is strong nuclear and cytoplasmic expression in a continuous segment of cells.[39]

As consensus grows regarding the strength of p16 as a biomarker for detecting and determining prognoses of cancer, p16 immunohistochemistry is growing in importance.[13][35][40]

#### Gynecologic cancers

p16 is a widely used immunohistochemical marker in gynecologic pathology. Strong and diffuse cytoplasmic and nuclear expression of p16 in [squamous cell carcinomas](/source/Squamous_cell_carcinoma) (SCC) of the female genital tract is strongly associated with high-risk [human papilloma virus](/source/Human_papilloma_virus) (HPV) infection and neoplasms of cervical origin. The majority of SCCs of uterine cervix express p16. However, p16 can be expressed in other neoplasms and in several normal human tissues.[41]

### Urinary bladder SCCs

More than a third of urinary bladder SCCs express p16. SCCs of urinary bladder express p16 independent of gender. p16 immunohistochemical expression alone cannot be used to discriminate between SCCs arising from uterine cervix versus urinary bladder.[41]

### Role in cellular senescence

Concentrations of p16INK4a increase dramatically as tissue ages. p16INK4a, along with [senescence-associated beta-galactosidase](/source/Senescence-associated_beta-galactosidase), is regarded to be a [biomarker](/source/Biomarker) of [cellular senescence](/source/Senescence#Cellular_senescence).[42] Therefore, p16INK4a could potentially be used as a blood test that measures how fast the body's tissues are aging at a molecular level.[43] Notably, a recent survey of cellular senescence induced by multiple treatments to several cell lines does not identify p16 as belonging to a "core signature" of senescence markers.[44]

It has been used as a target to delay some aging changes in mice.[45]

### Role in neurogenesis

Increasing p16INK4a expression during aging is associated with reduced progenitor functions from the subventricular zone, which generates throughout life new neurons migrating to the olfactory bulb, thereby reducing olfactory neurogenesis.[46] Deletion of p16INK4a does not affect neurogenesis in the other adult neurogenic niche, the [dentate gyrus](/source/Dentate_gyrus) of the hippocampus.[46] However, recently, it has been demonstrated that p16INK4a protects from depletion after a powerful proneurogenic stimulus—i.e., running— also stem and progenitor cells of the aged dentate gyrus.[47] In fact, after deletion of p16INK4a, stem cells of the dentate gyrus are greatly activated by running, while, in wild-type p16INK4a dentate gyrus stem cells are not affected by running.[47] Therefore, p16Ink4a plays a role in the maintenance of dentate gyrus stem cells after stimulus, by keeping a reserve of their self-renewal capacity during aging. Since the dentate gyrus plays a key role in spatial and contextual memory formation, p16INK4a is implicated in the maintenance of cognitive functions during aging.

## Discovery

Researchers Manuel Serrano, Gregory J. Hannon and David Beach discovered p16 in 1993 and correctly characterized the protein as a cyclin-dependent kinase inhibitor.

## Role in carcinogenesis

Since its discovery, p16 has become significant in the field of cancer research. The protein was suspected to be involved in carcinogenesis due to the observation that mutation or deletion in the gene was implicated in human cancer cell lines. The detection of p16 inactivation in familial melanoma supplied further evidence. p16 deletion, mutation, hypermethylation, or overexpression is now associated with various cancers. Whether mutations in p16 can be considered to be driver mutations requires further investigation.[17]

## Interactions

p16 has been shown to [interact](/source/Protein-protein_interaction) with:

- [CCNG1](/source/CCNG1),[48]

- [CDK4](/source/Cyclin-dependent_kinase_4),[8][49][50][51][52][53]

- [CDK6](/source/Cyclin-dependent_kinase_6),[52][54][55]

- [DAXX](/source/Death_associated_protein_6),[56]

- [E4F1](/source/E4F1),[57]

- [MDM2](/source/Mdm2),[56][58][59][60][61]

- [P53](/source/P53),[57][58][59]

- [PPP1R9B](/source/PPP1R9B),[62]

- [RPL11](/source/RPL11),[58] and

- [SERTAD1](/source/SERTAD1).[49][50]

## See also

- [p21](/source/P21)

- [p53](/source/P53)

- [Cyclin-dependent kinase](/source/Cyclin-dependent_kinase)

- [Cyclin D](/source/Cyclin_D)

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## External links

- [Genes,+p16](https://meshb.nlm.nih.gov/record/ui?name=Genes%2C+p16) at the U.S. National Library of Medicine [Medical Subject Headings](/source/Medical_Subject_Headings) (MeSH)

- [*CDKN2A*](https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&singleSearch=knownCanonical&position=CDKN2A) human gene location in the [UCSC Genome Browser](/source/UCSC_Genome_Browser).

- [*CDKN2A*](https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_type=knownGene&hgg_gene=CDKN2A) human gene details in the [UCSC Genome Browser](/source/UCSC_Genome_Browser).

v t e PDB gallery 1a5e: SOLUTION NMR STRUCTURE OF TUMOR SUPPRESSOR P16INK4A, 18 STRUCTURES 1bi7: MECHANISM OF G1 CYCLIN DEPENDENT KINASE INHIBITION FROM THE STRUCTURE OF THE CDK6-P16INK4A TUMOR SUPPRESSOR COMPLEX 1dc2: SOLUTION NMR STRUCTURE OF TUMOR SUPPRESSOR P16INK4A, 20 STRUCTURES 2a5e: SOLUTION NMR STRUCTURE OF TUMOR SUPPRESSOR P16INK4A, RESTRAINED MINIMIZED MEAN STRUCTURE

v t e Cell cycle proteins Cyclin A (A1, A2) B (B1, B2, B3) D (D1, D2, D3) E (E1, E2) CDK 1 2 3 4 5 6 7 8 9 10 11A 11B 12 13 14 CDK-activating kinase CDK inhibitor INK4a/ARF (p14arf/p16, p15, p18, p19) cip/kip (p21, p27, p57) P53 p63 p73 family p53 p63 p73 Other Cdc2 Cdc25 Cdc42 Cellular apoptosis susceptibility protein E2F Maturation promoting factor Wee Cullin (CUL7) Phases and checkpoints Interphase G1 phase S phase G2 phase M phase Mitosis (Preprophase Prophase Prometaphase Metaphase Anaphase Telophase) Cytokinesis Cell cycle checkpoints Restriction point Spindle checkpoint Postreplication checkpoint Other cellular phases Apoptosis G0 phase Meiosis

v t e Tumor suppressor genes and oncogenes Ligand Growth factors ONCO c-Sis/PDGF HGF Receptor Wnt signaling pathway TSP CDH1 Hedgehog signaling pathway TSP PTCH1 TGF beta signaling pathway TSP TGF beta receptor 2 Receptor tyrosine kinase ONCO ErbB/c-ErbB HER2 HER3 c-Met c-Ret JAK-STAT signaling pathway ONCO c-Kit Flt3 Intracellular signaling P+Ps Wnt signaling pathway ONCO Beta-catenin TSP APC TGF beta signaling pathway TSP SMAD2 SMAD4 Akt/PKB signaling pathway ONCO c-Akt TSP PTEN Hippo signaling pathway TSP Neurofibromin 2/Merlin MAPK/ERK pathway ONCO c-Ras HRAS c-Raf TSP Neurofibromin 1 Other/unknown ONCO c-Src TSP Maspin Nucleus Cell cycle ONCO CDK4 Cyclin D Cyclin E TSP p53 pRb WT1 p16/p14arf DNA repair/Fanconi TSP BRCA1 BRCA2 Ubiquitin ligase ONCO CBL MDM2 TSP VHL Transcription factor ONCO AP-1 c-Fos c-Jun c-Myc TSP KLF6 Mitochondrion Apoptosis inhibitor SDHB SDHD Other/ungrouped c-Bcl-2 Notch Stathmin

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Adapted from the Wikipedia article [P16](https://en.wikipedia.org/wiki/P16) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/P16?action=history)). Available under [Creative Commons Attribution-ShareAlike 4.0 International](https://creativecommons.org/licenses/by-sa/4.0/). Changes may have been made.