Hypoxia suppresses conversion from proliferative arrest to cellular senescence
Olga V Leontieva1, Venkatesh Natarajan, Zoya N Demidenko
1Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Summary
Hypoxia suppresses cellular senescence, a process called geroconversion, by inhibiting the mTOR pathway. This maintains cell quiescence, allowing cells to potentially regain regenerative potential after stimuli removal.
Area of Science:
- Cellular Biology
- Molecular Biology
- Gerontology
Background:
- Cellular senescence is an irreversible state of cell cycle arrest.
- The mammalian target of rapamycin (mTOR) pathway drives the conversion of reversible arrest into senescence (geroconversion).
- Hypoxia is known to inhibit mTOR.
Purpose of the Study:
- To investigate whether hypoxia can suppress geroconversion.
- To determine if hypoxia's effect on geroconversion is dependent on p53 or HIF-1.
Main Methods:
- Inducible p21 expression in HT-p21-9 cells to induce cell cycle arrest and senescence.
- Exposure to hypoxia during p21 induction.
- Treatment with etoposide and nutlin-3a in normal fibroblasts, retinal cells, and cancer cell lines.
- Assessment of senescent morphology, regenerative potential, mTOR pathway activity, and DNA damage response.
Main Results:
- Hypoxia inhibited the mTOR pathway and suppressed geroconversion in p21-induced cells without preventing cell cycle arrest.
- Hypoxia maintained reversible quiescence, allowing cells to restart proliferation after p21 withdrawal.
- Hypoxia suppressed senescence induced by etoposide and nutlin-3a in various cell types, independent of p53 and HIF-1.
- Hypoxia inhibited mTOR and suppressed senescence without affecting DNA damage response or p53/p21 induction.
Conclusions:
- Hypoxia effectively suppresses geroconversion, preventing the establishment of irreversible cellular senescence.
- This suppression is mediated by mTOR inhibition and is independent of p53 and HIF-1.
- Hypoxia offers a potential strategy to maintain cellular quiescence and regenerative potential in diverse cell types and under various senescence-inducing conditions.
Related Concept Videos
02:53Adaptive Mechanisms in Cancer Cells
Cancer cells accumulate genetic changes at an abnormally rapid rate due to the defects in the DNA repair mechanisms. From an evolutionary perspective, such genetic instability is advantageous for cancer development. Mutant cell lines accumulate a series of beneficial mutations that contribute to their progression into cancer.
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
01:24Regulation of Angiogenesis and Blood Supply
Rapidly dividing tumors, embryos, and wounded tissues require more oxygen than usual, lowering the oxygen concentration in the blood. At low oxygen or hypoxic conditions, an oxygen-sensitive transcription factor called the hypoxia-inducible factor 1 or HIF1 is activated. HIF1 is a dimeric protein of alpha (ɑ) and beta (β) subunits. Under optimal oxygen conditions, HIF1β is present in the nucleus while HIF1ɑ remains in the cytosol. HIF1ɑ is hydroxylated by prolyl hydroxylase and factor...
02:15Replicative Cell Senescence
Replicative cell senescence is a property of cells that allows them to divide a finite number of times throughout the organism's lifespan while preventing excessive proliferation. Replicative senescence is associated with the gradual loss of the telomere — short, repetitive DNA sequences found at the end of the chromosomes. Telomeres are bound by a group of proteins to form a protective cap on the ends of chromosomes. Embryonic stem cells express telomerase — an enzyme that adds the telomeric...
02:15Replicative Cell Senescence
Replicative cell senescence is a property of cells that allows them to divide a finite number of times throughout the organism's lifespan while preventing excessive proliferation. Replicative senescence is associated with the gradual loss of the telomere — short, repetitive DNA sequences found at the end of the chromosomes. Telomeres are bound by a group of proteins to form a protective cap on the ends of chromosomes. Embryonic stem cells express telomerase — an enzyme that adds the telomeric...
01:23Hypoxia
Hypoxia is a medical condition characterized by an inadequate oxygen supply to body tissues. It typically manifests as a bluish discoloration of the skin and mucosae, especially in fair-skinned individuals, when hemoglobin (Hb) saturation drops below 75%.
Types of Hypoxia
There are four primary types of hypoxia, each resulting from a different cause:
1. Anemic hypoxia: This type occurs due to insufficient oxygen delivery caused by a lack of red blood cells (RBCs) or RBCs with abnormal or...
Types of Hypoxia
There are four primary types of hypoxia, each resulting from a different cause:
1. Anemic hypoxia: This type occurs due to insufficient oxygen delivery caused by a lack of red blood cells (RBCs) or RBCs with abnormal or...
02:23Abnormal Proliferation
Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the daughter...