Eukaryotic translation elongation factor 1-alpha 1 inhibits p53 and p73 dependent apoptosis and chemotherapy

Alvaro Blanch1, Fiona Robinson, Ian R Watson

  • 1Department of Paediatrics and Cell Biology Program, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.

Plos One
|June 27, 2013
PubMed

Insights

Eukaryotic translation elongation factor 1-alpha 1 (eEF1A1) interacts with p53 and p73, inhibiting apoptosis and causing chemoresistance. Silencing eEF1A1 enhances chemotherapy sensitivity, revealing a new target for cancer treatment.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Cell Death Pathways

Background:

  • The p53 family of transcription factors are critical regulators of cell proliferation and apoptosis.
  • Eukaryotic translation elongation factor 1-alpha 1 (eEF1A1) has known roles in translation and emerging translation-independent functions in cancer.

Purpose of the Study:

  • To identify novel interacting proteins of the p53 family.
  • To investigate the role of eEF1A1 in p53- and p73-mediated apoptosis and chemoresistance.

Main Methods:

  • Co-immunoprecipitation to identify protein interactions.
  • Overexpression and short-interfering RNA (siRNA) silencing of eEF1A1 in cancer cell lines.
  • Assessment of apoptosis induction and chemosensitivity.
  • Analysis of p53 and p73 activity.

Main Results:

  • eEF1A1 was identified as a novel interacting protein of p53 and p73.
  • Overexpression of eEF1A1 inhibited p53-, p73-, and chemotherapy-induced apoptosis, leading to chemoresistance.
  • Silencing eEF1A1 increased chemosensitivity in cells with wild-type p53 but not in p53-null cells.
  • eEF1A1 silencing partially rescued chemoresistance in p53 or p73 knockdown cells, indicating eEF1A1 is a negative regulator of p53/p73 pro-apoptotic functions.

Conclusions:

  • eEF1A1 possesses anti-apoptotic properties within the context of p53-family signaling.
  • eEF1A1 represents a novel mechanism regulating p53 family proteins.
  • Targeting eEF1A1 could sensitize tumors to chemotherapy by modulating p53-family-mediated apoptosis.

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.
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...
The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
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...