Stress-dependent changes in the properties of p53 complexes by the alternative translation product p53/47

Darren J Powell1, Roman Hrstka, Marco Candeias

  • 1INSERM U716, Institut de Génétique Moléculaire, Paris, France.

Insights

The protein p53, crucial for cancer prevention, has a variant called p53/47. This variant influences p53

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • The tumor suppressor protein p53 is vital for cellular responses to DNA damage and cancer prevention.
  • p53 activation leads to altered expression of numerous genes, but mechanisms differentiating damage types and cellular outcomes (apoptosis, cell cycle arrest, DNA repair) remain unclear.
  • The p53 gene translates into multiple protein products via alternative initiation, including p53/47, which lacks Mdm2 binding and transactivation domain I but retains oligomerization capacity.

Purpose of the Study:

  • To investigate the role of the p53 alternative translation product, p53/47, in modulating p53 complex formation and function.
  • To determine how p53/47 influences p53 properties in a cell stress-dependent manner.
  • To elucidate the specific mechanisms by which p53/47 affects gene expression, such as p21 induction.

Main Methods:

  • Investigated the functional impact of p53/47 on p53 complex folding, oligomerization, and post-translational modifications.
  • Analyzed the effect of p53/47 on gene expression, specifically p21, under various cellular stress conditions.
  • Examined the recruitment of p53/47 to target gene promoters, such as the p21 promoter, following DNA damage.

Main Results:

  • p53/47 was found to control the folding, oligomerization, and post-translational modification of p53 complexes.
  • p53/47 diversifies p53 properties in a cell stress-dependent manner.
  • p21 expression, normally unaffected by p53/47, was induced 18-fold after doxorubicin treatment, accompanied by p53/47 recruitment to the p21 promoter.

Conclusions:

  • p53/47 plays a significant role in diversifying p53 functions in response to cellular stress.
  • The alternative translation product p53/47 actively participates in regulating gene expression, exemplified by its role in p21 induction after DNA damage.
  • These findings highlight a novel regulatory mechanism involving p53 isoforms in cellular responses to DNA damage and cancer prevention.

Related Concept Videos

Covalently Linked Protein Regulators02:04

Covalently Linked Protein Regulators

Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein.
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...
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...
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...