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p19INK4D and cell death
Luz E Tavera-Mendoza1, Tian-Tian Wang, John H White
1Department of Physiology, McGill University, Montreal, Quebec, Canada.
Abstract:
INK4 proteins are members of a family of cyclin-dependent kinase (CDK) inhibitors that function in G(1) to block the activity of CDKs 4 and 6. While they share clear structural similarities, numerous studies have shown that INK4 proteins differ in their expression patterns during development and in the adult, and have differing roles in tumor suppression. A recent study from our laboratory showed that expression of the gene encoding p19(INK4D) is induced by the hormonal form of vitamin D(3) and by retinoids, both of which signal through related nuclear receptor transcription factors. Although vitamin D(3) and retinoids have distinct developmental and physiological functions, both regulate the cell cycle and have been shown to have chemopreventive effects in a range of studies. Induction of p19(INK4D) expression contributed to cell cycle arrest by both ligands. However, knockdown of p19(INK4D) rendered cells sensitive to autophagic cell death, a remarkable phenotype given the hyperproliferative responses to loss of other INK4 proteins. We discuss the relevance of our studies and recent findings of others to the cell death observed in p19(INK4D)-deficient animals and to a possible role for p19(INK4D) induction in chemoprevention.
Insights
The cyclin-dependent kinase inhibitor p19(INK4D) is induced by vitamin D(3) and retinoids, promoting cell cycle arrest. Loss of p19(INK4D) leads to autophagic cell death, suggesting its role in chemoprevention.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- INK4 proteins are cyclin-dependent kinase (CDK) inhibitors regulating cell cycle progression.
- p19(INK4D) is an INK4 protein with distinct expression and roles in tumor suppression.
- Vitamin D(3) and retinoids, signaling via nuclear receptors, exhibit chemopreventive effects.
Purpose of the Study:
- To investigate the regulation and function of p19(INK4D) expression.
- To determine the role of p19(INK4D) in cell cycle arrest and cell death induced by vitamin D(3) and retinoids.
Main Methods:
- Gene expression analysis of p19(INK4D) induction.
- Cellular assays to assess cell cycle arrest and cell death.
- Knockdown studies to evaluate the necessity of p19(INK4D) for observed phenotypes.
Main Results:
- p19(INK4D) gene expression is induced by vitamin D(3) and retinoids.
- p19(INK4D) induction contributes to cell cycle arrest mediated by these ligands.
- Knockdown of p19(INK4D) resulted in sensitivity to autophagic cell death.
Conclusions:
- p19(INK4D) plays a crucial role in mediating cell cycle arrest induced by vitamin D(3) and retinoids.
- p19(INK4D) is essential for preventing autophagic cell death, a novel function for INK4 proteins.
- p19(INK4D) induction may be a key mechanism in the chemopreventive effects of vitamin D(3) and retinoids.
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