CDKN2A

Last updated

CDKN2A
Protein CDKN2A PDB 1a5e.png
Available structures
PDB Ortholog search: PDBe RCSB
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
Orthologs
SpeciesHumanMouse
Entrez

1029

12578

Ensembl

ENSG00000147889

ENSMUSG00000044303

UniProt

P42771
Q8N726

P51480
Q64364

RefSeq (mRNA)

NM_001040654
NM_009877

RefSeq (protein)

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

CDKN2A, also known as cyclin-dependent kinase inhibitor 2A, is a gene which in humans is located at chromosome 9, band p21.3. [5] It is ubiquitously expressed in many tissues and cell types. [6] The gene codes for two proteins, including the INK4 family member p16 (or p16INK4a) and p14arf. [7] Both act as tumor suppressors by regulating the cell cycle. p16 inhibits cyclin dependent kinases 4 and 6 (CDK4 and CDK6) and thereby activates the retinoblastoma (Rb) family of proteins, which block traversal from G1 to S-phase. p14ARF (known as p19ARF in the mouse) activates the p53 tumor suppressor. Somatic mutations of CDKN2A are common in the majority of human cancers, with estimates that CDKN2A is the second most commonly inactivated gene in cancer after p53. Germline mutations of CDKN2A are associated with familial melanoma, glioblastoma and pancreatic cancer. [8] The CDKN2A gene also contains one of 27 SNPs associated with increased risk of coronary artery disease. [9]

Contents

Structure

Gene

The CDKN2A gene resides on chromosome 9 at the band 9p21 and contains 8 exons. [10] This gene encodes two proteins, p16 and p14ARF, which are transcribed from the same second and third exons but alternative first exons: p16 from exon 1α and ARF from exon 1β. As a result, they are translated from different reading frames and therefore possess completely different amino acid sequences. [11] In addition to p16 and ARF, this gene produces 4 other isoforms through alternative splicing. [12]

Proteins

p16

This protein belongs to the CDKN2 cyclin-dependent kinase inhibitor family. [12] p16 comprises four ankyrin repeats, each spanning a length of 33 amino acid residues and, in the tertiary structure, forming a helix-turn-helix motif. One exception is the second ankyrin repeat, which contains only one helical turn. These four motifs are connected by three loops such that they are oriented perpendicular to the helical axes.

According to its solvent-accessible surface representation, p16 features clustered charged groups on its surface and a pocket located on the right side with a negatively charged left inner wall and a positively charged right inner wall. [13]

p14ARF

The size of this protein is 14 kDa in humans. [14] Within the N-terminal half of ARF are highly hydrophobic domains that serve as mitochondrial import sequences.

Function

P14ARF

P14ARF is a central actor of the cell cycle regulation process as it participates to the ARF-MDM2-p53 pathway and the Rb-E2F-1 pathway. [15] It is the physiological inhibitor of MDM2, an E3 ubiquitin ligase controlling the activity and stability of P53, and loss of P14ARF activity may have a similar effect as loss of P53. [16] P14ARF induces cell cycle arrest in G2 phase and subsequent apoptosis in a P53-dependent and P53-independent manner, and thus is regarded as a tumor suppressor. [17] [18] [19] [20] In addition, P14ARF could down-regulate E2F-dependent transcription and plays a role in the control of the G1 to S phase transition as well. [21]

P16（INK4A）

P16 interacts with Rb and controls the G1 to S transition. It binds to CDK4/6 inhibiting its kinase activity and prevents Rb phosphorylation. Therefore, Rb remains associated with transcription factor E2F1, preventing transcription of E2F1 target genes which are crucial for the G1/S transition. During this process, a feedback loop exists between P16 and Rb, and P16 expression is controlled by Rb. [22] [23] P16/Rb pathway collaborates with the mitogenic signaling cascade for the induction of reactive oxygen species, which activates the protein kinase C delta, leading to an irreversible cell cycle arrest. Thus P16 participates not only in the initiation but also in the maintenance of cellular senescence, as well in tumor suppression. [24] [25] On the other hand, some specific tumors harbor high levels of P16, and its function in limitation of tumorigenic progression has been inactivated via the loss of Rb. [25] [26]

Clinical relevance

In human cancer cell lines derived from various tumor types, a high frequency of genetic and epigenetic alterations (e.g., promoter hyper-methylation, homozygous deletion or mutation) in the CDKN2A gene has been observed. Accordingly, epigenetic/genetic modulation of changes in CDKN2A might be a promising strategy for prevention or therapy of cancer.

The CDKN2A gene is located on the chromosome 9p21 locus, which is intriguing for several reasons. First, this region is well known in cancer genetics as one of the most common sites of deletions leading to hereditary forms of cutaneous malignant melanoma. [11] [27] Second, genome wide association studies have reported a significant association of chromosome 9p21 with coronary artery disease and myocardial infarction [28] as well as the progression of atherosclerosis. [29]

Furthermore, changes in CDKN2A status are highly variable depending on the type of cancer. In addition to skin cancer such as melanoma, changes of CDKN2A have been described in a wide spectrum of cancer types such as gastric lymphoma, [30] Burkitt's lymphoma, [31] head & neck squamous cell carcinoma, [32] glioma, [33] oral cancer, [34] pancreatic adenocarcinoma, [35] non-small cell lung carcinomas, [36] esophageal squamous cell carcinoma, [37] gastric cancer, [38] bladder cancer, [33] osteosarcoma, [33] colorectal cancer, [39] breast cancer, [33] cervical cancer, [33] epithelial ovarian carcinoma, [40] endometrial cancer [33] and prostate cancer. [41]

Familial melanoma

CDKN2A is made up of four sections of exons – exon 1β, exon 1α, exon 2, and exon 3. These exons are used to create two proteins named p16 and p14ARF. Protein p16, created by exon 1α and exon 2, is responsible for tumor creation of genetic melanoma. When working normally, p16 binds to the cyclin dependent kinases CDK4 to inhibit their ability to create tumors, but when inactivated the suppression no longer occurs. [42] When a mutation occurs in protein p16, it prevents the protein kinase of CDK4, which results in the inactivation of the tumor suppressor gene. [42] This starts the development of melanoma.

Melanoma only occurs in a small proportion of the population. If only two family members have melanoma, there is a 5% chance somebody in the next generation will acquire the mutated gene. Also, there is a 20-40% chance of getting hereditary melanoma in a family if 3 or more people in the past generation had melanoma. For those who carry the hereditary mutated gene CDKN2A, acquiring skin cancer is a lot easier. [43] Those who have the gene are far more likely to get melanoma a second or third time compared to those who don't genetically have this gene. [44] The population that is affected by this mutation has a high familial history of melanoma or atypical moles and birth marks in large numbers, a history of primary melanoma/cancers in general, immunosuppression, skin that burns easily and doesn't tan, freckling, blue eyes, red hair, or a history of blistering. [43] People with these high risk factors are more likely to carry inherited mutations in CDKN2A. [44] For those who have a gene mutation, the severity is also dependent on the environmental surroundings. Out of those who carry the gene, those who express the phenotype and actually developed melanoma have a history of more sun exposure, and light skin compared to those who also had the gene but never actually developed melanoma. [44] This suggests that this gene co-works with ones surrounding environment. If two individuals are selected who carry the CDKN2A mutation, and both genetically have the same probability of acquiring skin cancer, but one is from Australia and the other is from Europe, there is a 58% the European will acquire cancer compared to a 91% chance the Australian will get it. [44] This is because the factors mentioned earlier pertaining to those who are more susceptible to the disease and also dependent on the amount of sunscreen one wears and the UV radiation potency in their environment. [43]

Clinical marker

A multi-locus genetic risk score study based on a combination of 27 loci, including the CDKN2A gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22). [9]

Aging

Activation of the CDKN2A locus promotes the cellular senescence tumor suppressor mechanism, which is a permanent form of growth arrest. As senescent cells accumulate with aging, expression of CDKN2A increases exponentially with aging in all mammalian species tested to date, and has been argued to serve as a biomarker of physiological age. [45] Notably, a recent survey of cellular senescence induced by multiple treatments to several cell lines does not identify CDKN2A as belonging to a "core signature" of senescence markers. [46]

In animals

A variant in the CDKN2A locus present in the founder of Bernese mountain dogs around 200 years ago predisposes the breed to histiocytic sarcoma. [47]

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 sequential series of events that take place in a cell that causes it to divide into two daughter cells. These events include the growth of the cell, duplication of its DNA and some of its organelles, and subsequently the partitioning of its cytoplasm, chromosomes and other components into two daughter cells in a process called cell division.

p53 Mammalian protein found in humans

p53, also known as Tumor protein P53, cellular tumor antigen p53, or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins are crucial in vertebrates, where they prevent cancer formation. As such, p53 has been described as "the guardian of the genome" because of its role in conserving stability by preventing genome mutation. Hence TP53 is classified as a tumor suppressor gene.

<span class="mw-page-title-main">Tumor suppressor gene</span> Gene that inhibits expression of the tumorigenic phenotype

A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or reduction in its function. In combination with other genetic mutations, this could allow the cell to grow abnormally. The loss of function for these genes may be even more significant in the development of human cancers, compared to the activation of oncogenes.

<span class="mw-page-title-main">Dysplastic nevus syndrome</span> Medical condition

Dysplastic nevus syndrome, also known as familial atypical multiple mole–melanoma (FAMMM) syndrome, is an inherited cutaneous condition described in certain families, and characterized by unusual nevi and multiple inherited melanomas. First described in 1820, the condition is inherited in an autosomal dominant pattern, and caused by mutations in the CDKN2A gene. In addition to melanoma, individuals with the condition are at increased risk for pancreatic cancer.

<span class="mw-page-title-main">Mdm2</span> Protein-coding gene in humans

Mouse double minute 2 homolog (MDM2) also known as E3 ubiquitin-protein ligase Mdm2 is a protein that in humans is encoded by the MDM2 gene. Mdm2 is an important negative regulator of the p53 tumor suppressor. Mdm2 protein functions both as an E3 ubiquitin ligase that recognizes the N-terminal trans-activation domain (TAD) of the p53 tumor suppressor and as an inhibitor of p53 transcriptional activation.

p14ARF is an alternate reading frame protein product of the CDKN2A locus. p14ARF is induced in response to elevated mitogenic stimulation, such as aberrant growth signaling from MYC and Ras (protein). It accumulates mainly in the nucleolus where it forms stable complexes with NPM or Mdm2. These interactions allow p14ARF to act as a tumor suppressor by inhibiting ribosome biogenesis or initiating p53-dependent cell cycle arrest and apoptosis, respectively. p14ARF is an atypical protein, in terms of its transcription, its amino acid composition, and its degradation: it is transcribed in an alternate reading frame of a different protein, it is highly basic, and it is polyubiquinated at the N-terminus.

p16 Mammalian protein found in humans

p16, is a protein that slows cell division by slowing the progression of the cell cycle from the G1 phase to the S phase, thereby acting as a tumor suppressor. It is encoded by the CDKN2A gene. A deletion in this gene can result in insufficient or non-functional p16, accelerating the cell cycle and resulting in many types of cancer.

INK4 is a family of cyclin-dependent kinase inhibitors (CKIs). The members of this family (p16INK4a, p15INK4b, p18INK4c, p19INK4d) are inhibitors of CDK4 (hence their name INhibitors of CDK4), and of CDK6. The other family of CKIs, CIP/KIP proteins are capable of inhibiting all CDKs. Enforced expression of INK4 proteins can lead to G1 arrest by promoting redistribution of Cip/Kip proteins and blocking cyclin E-CDK2 activity. In cycling cells, there is a resassortment of Cip/Kip proteins between CDK4/5 and CDK2 as cells progress through G1. Their function, inhibiting CDK4/6, is to block progression of the cell cycle beyond the G1 restriction point. In addition, INK4 proteins play roles in cellular senescence, apoptosis and DNA repair.

<span class="mw-page-title-main">Cyclin D</span> Member of the cyclin protein family

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.

<span class="mw-page-title-main">Cyclin-dependent kinase 4</span> Human protein

Cyclin-dependent kinase 4 (CDK4), also known as cell division protein kinase 4, is an enzyme that is encoded by the CDK4 gene in humans. CDK4 is a member of the cyclin-dependent kinase family, a group of serine/threonine kinases which regulate the cell cycle. CDK4 regulates the G1/S transition by contributing to the phosphorylation of retinoblastoma (RB) protein, which leads to the release of protein factors like E2F1 that promote S-phase progression. It is regulated by cyclins like cyclin D proteins, regulatory kinases, and cyclin kinase inhibitors (CKIs). Dysregulation of the CDK4 pathway is common in many cancers, and CDK4 is a new therapeutic target in cancer treatment.

<span class="mw-page-title-main">Cyclin-dependent kinase 6</span> 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.

<span class="mw-page-title-main">Acute myeloblastic leukemia with maturation</span> Medical condition

Acute myeloblastic leukemia with maturation (M2) is a subtype of acute myeloid leukemia (AML).

<span class="mw-page-title-main">Cyclin-dependent kinase 7</span> Protein-coding gene in the species Homo sapiens

Cyclin-dependent kinase 7, or cell division protein kinase 7, is an enzyme that in humans is encoded by the CDK7 gene.

<span class="mw-page-title-main">CDKN2B</span> Protein-coding gene in humans

Cyclin-dependent kinase 4 inhibitor B also known as multiple tumor suppressor 2 (MTS-2) or p15INK4b is a protein that is encoded by the CDKN2B gene in humans.

<span class="mw-page-title-main">CDKN2C</span> Protein-coding gene in humans

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

<span class="mw-page-title-main">CDKN2D</span> Protein-coding gene in humans

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

<span class="mw-page-title-main">CCNG1</span> Protein-coding gene in the species Homo sapiens

Cyclin-G1 is a protein that in humans is encoded by the CCNG1 gene.

<span class="mw-page-title-main">Cellular senescence</span> Phenomenon characterized by the cessation of cell division

Cellular senescence is a phenomenon characterized by the cessation of cell division. In their experiments during the early 1960s, Leonard Hayflick and Paul Moorhead found that normal human fetal fibroblasts in culture reach a maximum of approximately 50 cell population doublings before becoming senescent. This process is known as "replicative senescence", or the Hayflick limit. Hayflick's discovery of mortal cells paved the path for the discovery and understanding of cellular aging molecular pathways. Cellular senescence can be initiated by a wide variety of stress inducing factors. These stress factors include both environmental and internal damaging events, abnormal cellular growth, oxidative stress, autophagy factors, among many other things.

<span class="mw-page-title-main">Retinoblastoma protein</span> Mammalian protein found in humans

The retinoblastoma protein is a tumor suppressor protein that is dysfunctional in several major cancers. One function of pRb is to prevent excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide. When the cell is ready to divide, pRb is phosphorylated, inactivating it, and the cell cycle is allowed to progress. It is also a recruiter of several chromatin remodeling enzymes such as methylases and acetylases.

References

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