head and neck squamous cell carcinoma Mutations in the CDKN2A gene are found in up to one-quarter of head and neck squamous cell carcinomas (HNSCC). This type of cancerous tumor occurs in the moist lining of the mouth, nose, and throat. CDKN2A gene mutations associated with this condition are acquired during a person's lifetime and are found only in tumor cells; these changes are known as somatic mutations. Most of these mutations lead to production of little or no functional p16(INK4a) protein. Without p16(INK4a) to regulate cell growth and division, cells can continue to grow and divide without control, which can lead to tumor formation. A different type of alteration involving the CDKN2A gene can result in reduced amounts of the p16(INK4a) or p14(ARF) protein. This alteration, known as promoter hypermethylation, turns off the production of p16(INK4a) or p14(ARF). Without one of these tumor suppressors, cells can grow and divide unchecked, leading to the development of cancer. other cancers Mutations affecting the CDKN2A gene are associated with other cancers, including a type of skin cancer called melanoma, breast cancer, lung cancer, and pancreatic cancer. The mutations associated with these cancers are typically inherited (called germline mutations) and are found in all cells in the body. In some families, CDKN2A gene mutations are associated with development of only one type of cancer. In other families, mutations can lead to a cancer predisposition syndrome, which increases the risk of developing multiple types of cancer. CDKN2A gene mutations involved in cancer impair production of functional p16(INK4a) or, less commonly, p14(ARF), which can result in uncontrolled cell growth and tumor formation.

     The CDKN2A gene provides instructions for making several proteins. The most well-studied are the p16(INK4a) and the p14(ARF) proteins. Both function as tumor suppressors, which means they keep cells from growing and dividing too rapidly or in an uncontrolled way. The p16(INK4a) protein attaches (binds) to two other proteins called CDK4 and CDK6. These proteins help regulate the cell cycle, which is the cell's way of replicating itself in an organized, step-by-step fashion. CDK4 and CDK6 normally stimulate the cell to continue through the cycle and divide. However, binding of p16(INK4a) blocks CDK4's or CDK6's ability to stimulate cell cycle progression. In this way, p16(INK4a) controls cell growth and division. The p14(ARF) protein protects a different protein called p53 from being broken down. The p53 protein is an important tumor suppressor that is essential for regulating cell division and self-destruction (apoptosis). By protecting p53, p14(ARF) also helps prevent tumor formation.

The following transcription factors affect gene expression:

• ER-alpha
• PPAR-gamma1
• p53
• AP-1
• c-Jun
• Sp1
• AML1a
• p300

Tissue specificity:

Widely expressed but not detected in brain or skeletal muscle. Isoform 3 is pancreas-specific.

Caution:

The proteins described here are encoded by the gene CDKN2A, but are completely unrelated in term of sequence and function to tumor suppressor ARF (AC Q8N726) which is encoded by the same gene.

Molecular Function:

• P53 Binding
• Dna Binding
• Cyclin-Dependent Protein Serine/Threonine Kinase Inhibitor Activity
• Transcription Factor Binding
• Sumo Transferase Activity
• Protein Kinase Binding
• Poly(A) Rna Binding
• Nf-Kappab Binding
• Ubiquitin-Protein Transferase Inhibitor Activity
• Mdm2/Mdm4 Family Protein Binding

Biological Processes:

• G1/S Transition Of Mitotic Cell Cycle
• Protein Polyubiquitination
• Mitophagy
• Negative Regulation Of Cell-Matrix Adhesion
• Transcription, Dna-Templated
• Rrna Processing
• Negative Regulation Of Protein Kinase Activity
• Activation Of Cysteine-Type Endopeptidase Activity Involved In Apoptotic Process
• Cell Cycle Arrest
• Ras Protein Signal Transduction
• Negative Regulation Of Cell Proliferation
• Apoptotic Mitochondrial Changes
• Regulation Of G2/M Transition Of Mitotic Cell Cycle
• Protein Sumoylation
• Negative Regulation Of Cell Growth
• Negative Regulation Of B Cell Proliferation
• Regulation Of Protein Stability
• Protein Destabilization
• Negative Regulation Of Nf-Kappab Transcription Factor Activity
• Negative Regulation Of Immature T Cell Proliferation In Thymus
• Positive Regulation Of Protein Sumoylation
• Positive Regulation Of Smooth Muscle Cell Apoptotic Process
• Senescence-Associated Heterochromatin Focus Assembly
• Negative Regulation Of Phosphorylation
• Positive Regulation Of Apoptotic Process
• Positive Regulation Of Dna Damage Response, Signal Transduction By P53 Class Mediator
• Negative Regulation Of Cyclin-Dependent Protein Serine/Threonine Kinase Activity
• Negative Regulation Of Transcription, Dna-Templated
• Positive Regulation Of Transcription, Dna-Templated
• Positive Regulation Of Transcription From Rna Polymerase Ii Promoter
• Regulation Of Protein Export From Nucleus
• Somatic Stem Cell Division
• Protein Stabilization
• Negative Regulation Of Ubiquitin-Protein Transferase Activity
• Mitochondrial Depolarization
• Protein K63-Linked Ubiquitination
• Positive Regulation Of Cell Cycle Arrest
• Cellular Senescence
• Replicative Senescence
• Positive Regulation Of Protein Localization To Nucleus
• Positive Regulation Of Signal Transduction By P53 Class Mediator
• Regulation Of Apoptotic Dna Fragmentation
• Negative Regulation Of Proteolysis Involved In Cellular Protein Catabolic Process
• Regulation Of Protein Targeting To Mitochondrion
• Negative Regulation Of Protein Ubiquitination Involved In Ubiquitin-Dependent Protein Catabolic Process
• Positive Regulation Of Macrophage Apoptotic Process
• Positive Regulation Of Cellular Senescence