# CDKN2A

## Overview
The CDKN2A gene is a critical component in the regulation of the cell cycle and tumor suppression, encoding the cyclin-dependent kinase inhibitor 2A (p16^INK4a) protein. This protein functions as a cyclin-dependent kinase inhibitor, specifically targeting CDK4 and CDK6, thereby playing a pivotal role in controlling cell proliferation by preventing the phosphorylation of the retinoblastoma protein (pRb) and halting the cell cycle at the G1 phase. Additionally, CDKN2A encodes another protein, p14^ARF, which is involved in the p53 pathway, further contributing to its tumor suppressor functions. Mutations in CDKN2A are associated with increased susceptibility to various cancers, including melanoma and pancreatic cancer, highlighting its clinical significance in hereditary cancer syndromes (Ruas1998The; Danishevich2023CDKN2A).

## Structure
The CDKN2A gene encodes the p16INK4a protein, which is a cyclin-dependent kinase inhibitor involved in cell cycle regulation. The p16INK4a protein is composed of four ankyrin-type repeat motifs, each consisting of a helix-loop-helix structure flanked by beta strands. These repeats form an extended concave surface that interacts with cyclin-dependent kinases CDK4 and CDK6, inhibiting their activity by preventing cyclin binding and phosphorylation (Russo1998Structural; Kannengiesser2009Functional).

The ankyrin repeats are linked by beta hairpins, creating an asymmetric 'L' shape with a limited hydrophobic core, which is crucial for the protein's stability and function (Ruas1999Functional). The interaction of p16INK4a with CDK4 and CDK6 involves key residues such as His-66, Asp-84, and Arg-124, which are important for binding and inhibition (Byeon1998Tumor).

The structure of p16INK4a has been determined using techniques like NMR spectroscopy and X-ray crystallography, providing insights into its interaction with CDK4 and CDK6 (Byeon1998Tumor; Kannengiesser2009Functional). The protein's ability to inhibit these kinases is essential for its role as a tumor suppressor, as it helps regulate the G1-to-S transition in the cell cycle (Ruas1999Functional).

## Function
The CDKN2A gene encodes two critical proteins, p16^INK4a and p14^ARF, which play significant roles in cell cycle regulation and tumor suppression in healthy human cells. p16^INK4a functions as a cyclin-dependent kinase inhibitor, specifically targeting CDK4 and CDK6. By inhibiting these kinases, p16^INK4a prevents the phosphorylation of the retinoblastoma protein (pRb), thereby halting the cell cycle progression from the G1 phase to the S phase. This action serves as a checkpoint to prevent uncontrolled cell proliferation, maintaining cellular homeostasis and genomic stability (Ruas1998The).

p14^ARF, another product of the CDKN2A gene, is involved in the p53 pathway. It stabilizes the p53 protein by sequestering MDM2, a negative regulator of p53, thus promoting cell cycle arrest and apoptosis in response to oncogenic stress (Ruas1998The). The expression of these proteins is regulated by different promoters, and their alternative splicing results in distinct transcripts (Ruas1998The).

In the context of aging, p16^INK4a expression increases, contributing to cellular senescence and a decline in beta cell proliferation, which is associated with age-related diseases such as type 2 diabetes (Kong2016Islet). The regulation of p16^INK4a is influenced by epigenetic modifications, including histone methylation, which change with age (Kong2016Islet).

## Clinical Significance
Mutations in the CDKN2A gene are associated with several hereditary cancer syndromes, most notably melanoma pancreatic syndrome (MPS) and familial atypical multiple mole melanoma (FAMMM). These mutations significantly increase the risk of developing melanoma and pancreatic cancer, with a lifetime melanoma risk ranging from 28% to 67% and a 38-fold increased risk of pancreatic cancer compared to the general population (Danishevich2023CDKN2A). Specific variants, such as c.159G>C, c.71G>C, and c.307_308del, have been linked to familial melanoma, pancreatic cancer, and colorectal cancer (Danishevich2023CDKN2A).

CDKN2A mutations are also implicated in melanoma-astrocytoma syndrome and are associated with an increased risk of other cancers, including lung and breast cancers (Potrony2014Increased). The gene's alterations are prevalent in biliary tract cancers, particularly gallbladder cancer, and are linked to decreased survival rates (Danishevich2023CDKN2A).

In nonmelanoma skin cancers, such as squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), CDKN2A mutations can lead to the inactivation of its encoded proteins, contributing to cancer development (Saridaki2003Mutational). Despite the lack of specific targeted therapies for CDKN2A mutations, CDK4/6 inhibitors used in breast cancer may offer potential benefits in cases with CDKN2A mutations leading to CDK4/6 overexpression (Danishevich2023CDKN2A).

## Interactions
The CDKN2A gene encodes the p16INK4a protein, which plays a crucial role in cell cycle regulation by interacting with cyclin-dependent kinases CDK4 and CDK6. p16INK4a binds to these kinases, inhibiting their interaction with cyclins and preventing the phosphorylation of the retinoblastoma protein (Rb), thereby halting cell cycle progression (Russo1998Structural; Jiao2018Regulation). The binding of p16INK4a to CDK4 and CDK6 is mediated by hydrogen-bond networks involving the ankyrin repeats of p16INK4a, which form a continuous interface with the N and C lobes of the kinases (Russo1998Structural). Specific residues in CDK6, such as Lys 29 and Arg 31, are critical for these interactions, and mutations in these residues can disrupt p16INK4a binding (Russo1998Structural).

Mutations in p16INK4a can affect its ability to bind CDK4 and CDK6, impacting its function as a tumor suppressor. For instance, variants like D84N and D84H impair the protein's ability to bind CDK4 and CDK6 by altering the electrostatic character of the CDK-binding surface (Ruas1999Functional). These interactions are essential for the tumor suppressor function of p16INK4a, and disruptions can contribute to cancer development (Hallett2017Differential).


## References


[1. (Ruas1998The) Margarida Ruas and Gordon Peters. The p16ink4a/cdkn2a tumor suppressor and its relatives. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 1378(2):F115–F177, October 1998. URL: http://dx.doi.org/10.1016/s0304-419x(98)00017-1, doi:10.1016/s0304-419x(98)00017-1. This article has 261 citations.](https://doi.org/10.1016/s0304-419x(98)00017-1)

[2. (Byeon1998Tumor) In-Ja L. Byeon, Junan Li, Karen Ericson, Thomas L. Selby, Anton Tevelev, Hee-Jung Kim, Paul O’Maille, and Ming-Daw Tsai. Tumor suppressor p16ink4a: determination of solution structure and analyses of its interaction with cyclin-dependent kinase 4. Molecular Cell, 1(3):421–431, February 1998. URL: http://dx.doi.org/10.1016/s1097-2765(00)80042-8, doi:10.1016/s1097-2765(00)80042-8. This article has 122 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1016/s1097-2765(00)80042-8)

[3. (Kong2016Islet) Yahui Kong, Rohit B. Sharma, Benjamin U. Nwosu, and Laura C. Alonso. Islet biology, the cdkn2a/b locus and type 2 diabetes risk. Diabetologia, 59(8):1579–1593, May 2016. URL: http://dx.doi.org/10.1007/s00125-016-3967-7, doi:10.1007/s00125-016-3967-7. This article has 71 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1007/s00125-016-3967-7)

[4. (Danishevich2023CDKN2A) Anastasiia Danishevich, Airat Bilyalov, Sergey Nikolaev, Nodirbec Khalikov, Daria Isaeva, Yuliya Levina, Maria Makarova, Marina Nemtsova, Denis Chernevskiy, Olesya Sagaydak, Elena Baranova, Maria Vorontsova, Mariya Byakhova, Anna Semenova, Vsevolod Galkin, Igor Khatkov, Saida Gadzhieva, and Natalia Bodunova. Cdkn2a gene mutations: implications for hereditary cancer syndromes. Biomedicines, 11(12):3343, December 2023. URL: http://dx.doi.org/10.3390/biomedicines11123343, doi:10.3390/biomedicines11123343. This article has 4 citations and is from a peer-reviewed journal.](https://doi.org/10.3390/biomedicines11123343)

[5. (Ruas1999Functional) Margarida Ruas, Sharon Brookes, Neil Q McDonald, and Gordon Peters. Functional evaluation of tumour-specific variants of p16ink4a/cdkn2a: correlation with protein structure information. Oncogene, 18(39):5423–5434, September 1999. URL: http://dx.doi.org/10.1038/sj.onc.1202918, doi:10.1038/sj.onc.1202918. This article has 59 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1038/sj.onc.1202918)

[6. (Hallett2017Differential) Stephen T. Hallett, Martyna W. Pastok, R. Marc L. Morgan, Anita Wittner, Katie L.I.M. Blundell, Ildiko Felletar, Stephen R. Wedge, Chrisostomos Prodromou, Martin E.M. Noble, Laurence H. Pearl, and Jane A. Endicott. Differential regulation of g1 cdk complexes by the hsp90-cdc37 chaperone system. Cell Reports, 21(5):1386–1398, October 2017. URL: http://dx.doi.org/10.1016/j.celrep.2017.10.042, doi:10.1016/j.celrep.2017.10.042. This article has 50 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1016/j.celrep.2017.10.042)

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[9. (Saridaki2003Mutational) Z. Saridaki, T. Liloglou, A. Zafiropoulos, E. Koumantaki, O. Zoras, and D.A. Spandidos. Mutational analysis of cdkn2a genes in patients with squamous cell carcinoma of the skin. British Journal of Dermatology, 148(4):638–648, April 2003. URL: http://dx.doi.org/10.1046/j.1365-2133.2003.05230.x, doi:10.1046/j.1365-2133.2003.05230.x. This article has 44 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1046/j.1365-2133.2003.05230.x)

[10. (Jiao2018Regulation) Yang Jiao, Yunpeng Feng, and Xiuli Wang. Regulation of tumor suppressor gene cdkn2a and encoded p16-ink4a protein by covalent modifications. Biochemistry (Moscow), 83(11):1289–1298, November 2018. URL: http://dx.doi.org/10.1134/S0006297918110019, doi:10.1134/s0006297918110019. This article has 50 citations.](https://doi.org/10.1134/S0006297918110019)

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