Reduced transcriptional activity in the p53 pathway of senescent cells revealed by the MDM2 antagonist nutlin-3

Related Experiment Video

Updated: Jun 16, 2026

Yeast As a Chassis for Developing Functional Assays to Study Human P53
14:57

Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

Baoying Huang1, Lyubomir T Vassilev

  • 1Discovery Oncology, Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA. lyubomir.vassilev@roche.com

Aging
|February 17, 2010
PubMed

Insights

Cellular senescence impairs the p53 pathway

Area of Science:

  • Oncology
  • Cell Biology
  • Molecular Biology

Background:

  • The p53 tumor suppressor is crucial for cellular senescence.
  • The p53 pathway's stress response in senescent cells is not well understood.

Purpose of the Study:

  • To investigate the functionality of the p53 pathway in senescent human fibroblasts.
  • To determine how senescence affects p53's transcriptional activity and stress response.

Main Methods:

  • Utilized nutlin-3a, an MDM2 antagonist, to activate p53 in senescent WI-38 fibroblasts.
  • Assessed p53 transcriptional activity on target genes and microRNAs.
  • Compared p53's response to genotoxic stress (doxorubicin) in senescent versus early-passage cells.

Main Results:

  • Senescence reduced nutlin-3a-induced transcriptional activity of p53 target genes and microRNAs.
  • Nutlin-3a partially restored doxorubicin-induced p53 protein and transcriptional activity in senescent cells.
  • Apoptotic response to genotoxic stress remained partially attenuated despite restored p53 activity.

Conclusions:

  • Senescence alters not only p53 protein levels but also its transcriptional activation capacity.
  • Both upstream and downstream signaling modifications contribute to the attenuated p53 response in senescent cells.
  • Understanding these alterations is key to targeting cancer through senolytic therapies.
Keywords:
MDM2apoptosiscancerp53senescence

Related Concept Videos

Abnormal Proliferation02:23

Abnormal 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...
Negative Regulator Molecules01:23

Negative Regulator Molecules

Positive regulators allow a cell to advance through cell cycle checkpoints. Negative regulators have an equally important role as they terminate a cell’s progression through the cell cycle—or pause it—until the cell meets specific criteria.
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
DNA Damage Can Stall the Cell Cycle02:36

DNA Damage Can Stall the Cell Cycle

In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
DNA Damage can Stall the Cell Cycle02:36

DNA Damage can Stall the Cell Cycle

In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...