p16 also known as cyclin-dependent kinase inhibitor 2A, multiple tumor suppressor, is a tumor suppressor protein, that in humans is encoded by the CDKN2A gene.
CDK4/6 binds cyclin D and forms an active protein complex that phosphorylates retinoblastoma protein (pRB).
Once phosphorylated, pRB dissociates from the transcription factor E2F1, liberating it from its bound state in the cytoplasm and allows it to enter the nucleus.
In the nucleus, E2F1 promotes the transcription of target genes that are essential for transition from G1 to S phase.
The G1 to S phase pathway connects the processes of tumor oncogenesis and senescence, fixing them on opposite ends of a spectrum.
Plays an important role in cell cycle regulation by decelerating cells progression from G1 phase to S phase, and therefore acts as a tumor suppressor that is implicated in the prevention of cancers, notably melanoma, oropharyngeal squamous cell carcinoma, cervical cancer, and esophageal cancer.
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 to reduce cell senescence.
A deletion 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 many types of cancer.
Mutations resulting in reduction of function of the CDKN2A gene are associated with increased risk of a wide range of cancers.
Pancreatic adenocarcinoma is often associated with mutations in the CDKN2A gene.
Carriers of germline mutations in CDKN2A have 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.
Homozygous deletions of p16 are frequently found in esophageal cancer and gastric cancer cell lines.
Germline mutations in CDKN2A are associated with an increased susceptibility to develop skin cancer.
There is an increased frequency of DNA methylation of the p16 gene in esophageal cancer.
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.
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, DNA damage, or senescence leads to the buildup of p16 in tissues and is implicated in the aging of cells.
CDKN2A gene generates several transcript variants that differ in their first exons.
This gene is frequently mutated or deleted in a wide variety of tumors and is known to be an important tumor suppressor gene.
p16 can be used as a biomarker to improve the histological diagnostic accuracy of grade 3 cervical intraepithelial neoplasia (CIN).
The CDKN2A gene is frequently mutated or deleted in a wide variety of tumors.
An inhibitor of cyclin dependent kinases such as CDK4 and CDK6.
CDK4 and CDK6 kinases phosphorylate retinoblastoma protein (pRB) which eventually results in progression from G1 phase to S phase.
p16 is encoded by the CDKN2A gene, which is located on chromosome 9 (9p21.3).
p16 is a protein with 148 amino acids and a molecular weight of 16 kDa.The name of p16 is derived from its molecular weight, and the alternative name p16INK4a refers to its role in inhibiting cyclin-dependent kinase CDK4.
A gene that is frequently mutated or deleted in a wide variety of tumors.
An important tumor suppressor gene.
p16 is also implicated in the prevention of melanoma, oropharyngeal squamous cell carcinoma, cervical cancer, vulvar cancer and esophageal cancer.
With aging the expression of p16 increases to reduce the proliferation of stem cells, protecting against cancer while increasing the risks associated with cellular senescence.
Increased expression of the p16 gene occurs with age reducing the proliferation of stem cells.
This reduction in stem cells proliferation protects against cancer while increasing the risks associated with cellular senescence.
p16 is a cyclin-dependent kinase (CDK) inhibitor.
p16 slows down the cell cycle by prohibiting progression from G1 phase to S phase.
CDK4/6 binds cyclin D and forms an active protein complex that phosphorylates retinoblastoma protein (pRB).
Once phosphorylated, pRB disassociates from the transcription factor E2F1, liberating E2F1 from its cytoplasm bound state allowing 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.
p16 acts as a tumor suppressor by binding to CDK4/6 and preventing its interaction with cyclin D.
This interaction ultimately inhibits the downstream activities of transcription factors, such as E2F1, and arrests cell proliferation.
This pathway connects the processes of tumor oncogenesis and senescence, fixing them on opposite ends of a spectrum.
The hypermethylation, mutation, or deletion of p16 leads to downregulation of the gene and can lead to cancer through the dysregulation of cell cycle progression.
Activation of p16 through DNA damage, or senescence leads to the builds up p16 in tissues
Activation of p16 is implicated in aging of cells.
The regulation of p16 involves the interaction of several transcription factors, as well as several proteins involved in epigenetic modification through methylation and repression of the promoter region.
Such 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.
These mechanisms cause the downregulation of gene expression that leads to decreased levels of the p16 protein, and may be responsible for the development of various forms of cancer serving as an alternative process to gene deletion or mutation.
PRC1 and PRC2 are two protein complexes that modify the expression of p16 that can repress transcription of p16.
These pathways are activated to reduce cell senescence.
Mutations resulting in deletion or reduction of function of the CDKN2A gene are associated with increased risk of cancers.
Changes of the gene are frequently seen in cancer cell lines.
Pancreatic adenocarcinoma is often associated with mutations in the CDKN2A gene.
Carriers of germline mutations in CDKN2A have high risks of melanoma also increased risks of pancreatic, lung, laryngeal, skin cancers and oropharyngeal cancers, and tobacco smoking exacerbates carriers’ susceptibility for such non-melanoma cancers.
Homozygous deletion of p16 are frequently associated with esophageal cancer and gastric cancers.
Increased frequency of DNA methylation of p16 gene associated with esophageal cancer.
p16 deletion detected in surface epithelial mesothelial proliferations is predictive of underlying invasive mesothelioma.
High grade squamous intraepithelial lesion show strong p16 staining.
p16 is a widely used immunohistochemical marker in gynecologic pathology.
Cytoplasmic and nuclear expression of p16 in squamous cell carcinomas (SCC) of the female genital tract is strongly associated with high-risk human papilloma virus (HPV) infection and neoplasms of cervical origin.: The majority of SCCs of uterine cervix express p16.
More than a third of urinary bladder SCCs express p16.
SCCs of urinary bladder express p16 independent of gender.
Concentrations of p16INK4a increase dramatically as tissue ages.
p16INK4a, along with senescence-associated beta-galactosidase, is regarded to be a biomarker of cellular senescence.
p16INK4a is implicated in the maintenance of cognitive functions during aging.
p16 protein is 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 seen in familial melanoma.
p16 deletion, mutation, hypermethylation, or overexpression is now associated with various cancers.
Methylation can physically inhibit the transcription of the gene or methylation can lead to the recruitment of transcription factors that repress transcription downregulated of gene expression that leads to decreased levels of the p16 protein.
This process is responsible for the development of various forms of cancer serving as an alternative process to gene deletion or mutation.
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 prognosis.
p16 positivity has been shown to be favorably prognostic in oropharyngeal squamous cell carcinoma.
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% in the HPV-positive subgroup and 57.1% in the HPV-negative subgroup, and the 3-year rates of progression-free survival were 73.7% and 43.4%, respectively.
status is so prognostic that the AJCC staging system has been revised to include p16 status in oropharyngeal squamous cell cancer group staging.
Cancers that overexpress p16 are usually caused by the human papillomavirus (HPV), whereas cancers in which p16 is downregulated will usually have other causes.
With oropharyngeal squamous cell carcinoma, the immunohistochemistry detection in the presence of the p16 biomarker has been shown to be the strongest indicator of disease course.
The presence of the biomarker p16 is associated with a more favorable prognosis as measured by cancer-specific survival, recurrence-free survival, locoregional control as well as other measurements.
Cytoplasmic and nuclear expression of p16 in squamous cell carcinomas are strongly associated with high-risk human papilloma virus (HPV) infection and neoplasms of cervical origin.
The majority of squamous cell carcinomas of uterine cervix express p16.
More than a third of urinary bladder squamous cell carcinomas express p16.
Concentrations of p16INK4a increase significantly as tissue ages.
Mutation or deletion in the gene was implicated in human cancer cell lines.