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Review
. 2022 Aug 28;12(9):1332.
doi: 10.3390/life12091332.

P16INK4A-More Than a Senescence Marker

Hasan Safwan-Zaiter  1 , Nicole Wagner  1 , Kay-Dietrich Wagner  1
Affiliations
Review

P16INK4A-More Than a Senescence Marker

Hasan Safwan-Zaiter et al. Life (Basel). .

Abstract

Aging is a biological feature that is characterized by gradual degeneration of function in cells, tissues, organs, or an intact organism due to the accumulation of environmental factors and stresses with time. Several factors have been attributed to aging such as oxidative stress and augmented production or exposure to reactive oxygen species, inflammatory cytokines production, telomere shortening, DNA damage, and, importantly, the deposit of senescent cells. These are irreversibly mitotically inactive, yet metabolically active cells. The reason underlying their senescence lies within the extrinsic and the intrinsic arms. The extrinsic arm is mainly characterized by the expression and the secretory profile known as the senescence-associated secretory phenotype (SASP). The intrinsic arm results from the impact of several genes meant to regulate the cell cycle, such as tumor suppressor genes. P16INK4A is a tumor suppressor and cell cycle regulator that has been linked to aging and senescence. Extensive research has revealed that p16 expression is significantly increased in senescent cells, as well as during natural aging or age-related pathologies. Based on this fact, p16 is considered as a specific biomarker for detecting senescent cells and aging. Other studies have found that p16 is not only a senescence marker, but also a protein with many functions outside of senescence and aging. In this paper, we discuss and shed light on several studies that show the different functions of p16 and provide insights in its role in several biological processes besides senescence and aging.

Keywords: aging; cancer; development; p16; pathologies; senescence.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The structure of the INK4A locus gives rise to several transcripts through alternative splicing. P16INK4A and p19ARF are two transcripts of 3 exons which differ only in the first exon that is E1α for p16 and E1β for p19ARF.
Figure 2
Figure 2
In the p16/pRB pathway, p16 inhibits Cdk4/6–cyclin D complex formation and induces subsequent pRB hypophosphorylation. Similarly, in the p53/p21 pathway, p19ARF traps MDM2 and prevents p53 degradation, which consequently activates p21. This works similarly as p16 but by inhibiting Cdk2–cyclin E complex, and, therefore, induces pRB phosphorylation. Dephosphorylated pRB binds E2F transcription factor at the E2F sites and blocks G1–S phase transition, blocking the cell cycle. However, in the absence of p16 and p21, hyperphosphorylated pRB detaches from E2F transcription factors, which consequently activates S-phase genes and induces progression of the cell cycle.
Figure 3
Figure 3
Schematic illustration that summarizes the major functions or implications of p16 in homeostasis, pathophysiology, and cancer of different organs.
See this image and copyright information in PMC

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