Table 1.

Major p16 functions in the variety of biological processes observed in different models and tissues.

Process	Model and/or Tissue	Potential Role/Function	References
Intervertebral disc damage	Mouse and human intervertebral disc tissues	P16 is a potential therapeutic target for intervertebral disc damage relief.	[48]
Wound healing	P16-3MR model (fibroblasts, endothelial cells, and keratinocytes)	Accelerate wound closure and re-epithelialization	[43]
Tumorigenesis and tumor suppression	Skin, bone, lung, liver, and brain cancer patients tissues and immunohistopathology	Implicated in tumor development, progression, and metastasis Predictive and prognostic marker Therapeutic target Increases chemosensitivity	[39,40,41,42,72,105,106,107,108,111,112,134,135,136,150,151,152,153,168,169,170,205,206]
Stem cell self-renewal and differentiation	Skin, lung, bone, brain, and heart stem cells	Balanced expression of p16 is a prerequisite for stem cells proliferation and differentiation. Therapeutic approach for maintenance of regenerative capacity	[46,92,101,115,116,117,118,119,138,149,155,156,179]
Cellular senescence	Primary mouse fibroblasts and melanocytes	Target for oncogene-induced senescence bypass and aging	[37,38]
Bone homeostasis	P16-3MR and p16-INK-ATTAC mouse model	Maintenance of bone mass Orchestration of osteoblast and osteoclast function	[123,132,133]
Bone fracture healing	Geriatric Mouse model (p16-/- and WT)	P16-deletion stimulated osteoblastogenesis and vascularization and accelerated bone fracture healing	[138]
Muscle injury	Acute muscle injury (AIM) mouse model	Tissue regeneration	[45]
Osteoporosis	Ovariectomized p16-/- and WT mice	Potential therapeutic target to prevent estrogen-induced osteoporosis	[124,125,126,127,137]
COPD	Lung alveolar and lung epithelial cells in mice and human	Implicated in COPD severity Potential therapeutic target	[140,141,142,149]
Cervical SCC and pulmonary SCC	Human cancer patients	Discriminating biomarker	[150]
Oxidative stress	Fibroblasts, keratinocytes, and melanocytes	P16 regulates oxidative stress and ROS production as pRB-independent tumor suppression mechanism	[72,204]
Mitochondrial biogenesis	Primary mouse fibroblasts, human melanocytes, A375 melanoma cells	P16 balances mitochondrial structure and function	[111]
Alzheimer’s disease (AD)	Alzheimer’s disease patients and mouse model	Implicated in AD severity and development Therapeutic target	[159,160,161,166]
Lung injury	P16-/- and WT mouse model (lung epithelium)	P16 protects against lungs injury	[154]
Cardiac fibrosis	p16-CreERT2-tdTomato mouse model	P16-positive cells removal induces cardiac fibrosis	[83]
Myocardial Infarction	Mice	Indispensable for maintenance of cardiac function and cardiac remodeling after infarction	[181]
Glucose metabolism and homeostasis	Super-INK4A/ARF mice model	Prevented the development of glucose intolerance with aging Protective role against age-induced insulin resistance	[198]
Liver fibrosis	INK-ATTAC mouse model	Therapeutic approach for treatment of liver fibrosis	[83,88,204]
Fat metabolism	Mouse model and primary hepatocytes	Regulate fasting-induced fatty acid oxidation and lipid droplet accumulation in the liver	[201]
Development	Young mice brain, heart, kidney, and liver	Dynamic p16 expression detected in embryonic mice organs, reflecting a potential role in embryonic development	[120]