p16-INK4a Human
Description
Overview and Molecular Structure
p16-INK4a Human (cyclin-dependent kinase inhibitor 2A, p16) is a tumor suppressor protein encoded by the CDKN2A gene located at chromosome 9p21. It belongs to the INK4 (Inhibitor of CDK4) family and functions as a critical regulator of the cell cycle by inhibiting cyclin-dependent kinases 4 and 6 (CDK4/6) . Structurally, p16-INK4a consists of four ankyrin repeats that mediate its binding to CDK4/6, preventing their interaction with cyclin D1 and subsequent phosphorylation of the retinoblastoma (Rb) protein .
Table 1: Key Features of p16-INK4a
| Property | Detail |
|---|---|
| Gene | CDKN2A |
| Protein Size | 16 kDa |
| Function | Cell cycle arrest, senescence, tumor suppression |
| Key Binding Partners | CDK4, CDK6, Rb pathway |
| Regulatory Mechanisms | Epigenetic silencing, oncogenic stress, DNA damage |
Expression Patterns
p16-INK4a expression is typically low in proliferating tissues but increases under stress conditions such as DNA damage, oncogenic activation, and aging . Its expression is tightly regulated by polycomb repressive complexes (e.g., BMI1, EZH2) and DNA methylation .
Key Tissues with Age-Related p16-INK4a Accumulation
Functional Roles in Cell Cycle Regulation
p16-INK4a enforces G1/S-phase arrest by binding CDK4/6, blocking Rb phosphorylation, and maintaining Rb in its active, growth-suppressive state . This mechanism is pivotal in:
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Senescence: Persistent p16-INK4a expression induces irreversible cell-cycle exit, a hallmark of cellular senescence .
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Tumor Suppression: Loss of p16-INK4a is linked to unchecked proliferation in cancers like melanoma and glioblastoma .
Epigenetic Control
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Polycomb complexes (BMI1, EZH2) repress CDKN2A via H3K27me3 modifications .
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DNA methyltransferase 1 (DNMT1) depletion derepresses CDKN2A under oncogenic stress .
Feedback with p53
p16-INK4a expression is amplified in p53-deficient cells, suggesting compensatory tumor suppression .
Implications in Aging
p16-INK4a accumulates in aging tissues, contributing to reduced regenerative capacity :
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Stem Cell Decline: High p16-INK4a levels correlate with diminished self-renewal in hematopoietic and neural stem cells .
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Senescence-Associated Secretory Phenotype (SASP): Senescent p16-INK4a-positive cells secrete pro-inflammatory factors, exacerbating tissue dysfunction .
Role in Cancer: Dual Paradigms
While p16-INK4a is a tumor suppressor, its overexpression occurs in specific cancers due to viral oncoprotein activity (e.g., HPV E7 in cervical cancer) or Rb pathway inactivation .
Table 2: p16-INK4a Expression in Human Cancers
Biomarker Applications
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Diagnostic: Overexpression in HPV-driven cancers aids in subtyping .
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Prognostic: High p16-INK4a predicts better radiation response in oropharyngeal cancers .
Therapeutic Targeting
CDK4/6 inhibitors (e.g., palbociclib) mimic p16-INK4a’s function and are FDA-approved for HR+/HER2- breast cancer .
Table 3: CDK4/6 Inhibitors in Clinical Trials
| Drug (Company) | Phase | Target Population |
|---|---|---|
| Palbociclib (Pfizer) | III | Breast cancer |
| Ribociclib (Novartis) | II/III | Solid tumors, lymphomas |
Recent Research Findings
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Wnt Pathway Activation: Chronic p16-INK4a expression in mouse epidermis induces Wnt-driven hyperplasia, linking senescence to pre-malignant lesions .
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In Vivo Imaging Models: Transgenic mice with luciferase-tagged CDKN2A enable real-time tracking of p16-INK4a dynamics during aging and oncogenesis .
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Senescence Heterogeneity: Single-cell analyses reveal distinct p16-INK4a-positive subpopulations in aged and injured tissues .
Product Specs
MMGSARVAELLLLHGAEPNCADPATLTRPVHDAAREGFLDTLVVLHRAGARL
DVRDAWGRLPVDLAEELGHRDVARYLRAAAGGTRGSNHARIDAAEGPSDIPD.
Product Science Overview
The CDKN2A gene is quite unique as it encodes two distinct proteins through alternative splicing: p16INK4a and p14ARF. These proteins are transcribed from the same second and third exons but have different first exons, resulting in different reading frames and thus different amino acid sequences .
- p16INK4a: This protein belongs to the INK4 family and consists of four ankyrin repeats, each forming a helix-turn-helix motif. These motifs are connected by loops, creating a structure that is essential for its function as a cyclin-dependent kinase inhibitor .
- p14ARF: Known as p19ARF in mice, this protein plays a role in stabilizing the tumor suppressor protein p53 by interacting with and sequestering MDM2, a protein responsible for p53 degradation .
CDKN2A plays a pivotal role in cell cycle regulation by inhibiting cyclin-dependent kinases 4 and 6 (CDK4 and CDK6). This inhibition prevents the phosphorylation of the retinoblastoma protein (Rb), thereby blocking the transition from the G1 phase to the S phase of the cell cycle . This mechanism is crucial for controlling cell proliferation and preventing uncontrolled cell growth, which can lead to tumor formation.
Mutations and deletions in the CDKN2A gene are commonly associated with various types of cancers. It is considered one of the most frequently inactivated tumor suppressor genes, second only to p53 . Germline mutations in CDKN2A are linked to familial melanoma, glioblastoma, and pancreatic cancer . Additionally, CDKN2A is involved in other diseases, such as coronary artery disease, due to its role in cell cycle regulation and tumor suppression .
Recombinant CDKN2A (Human) is produced using recombinant DNA technology, which allows for the expression of the human CDKN2A gene in a host organism, typically bacteria or yeast. This recombinant protein is used in research to study its function, interactions, and potential therapeutic applications. It is particularly valuable in cancer research, where understanding the mechanisms of CDKN2A can lead to the development of targeted therapies and diagnostic tools.
