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p73-alpha is capable of inducing scotin and ER stress

Alessandro Terrinoni1, Marco Ranalli, Bruno Cadot

  • 1Biochemistry Laboratory, IDI-IRCCS, Department of Experimental Medicine and Biochemical Sciences, University of Rome 'Tor Vergata', 00133 Rome, Italy.

Oncogene
|April 30, 2004
PubMed

Insights

The p73 protein, similar to p53, triggers programmed cell death via endoplasmic reticulum (ER) stress and scotin transactivation. This pathway, involving TAp73alpha and p53 but not DeltaNp73alpha, contributes to apoptosis.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • The tumor suppressor protein p53 and its family member p73 induce programmed cell death (apoptosis) in response to DNA damage.
  • Endoplasmic reticulum (ER) stress is increasingly recognized as a critical component in cellular apoptosis pathways.
  • Scotin, a recently identified protein, has been shown to be a target of p53 and can induce ER stress.

Purpose of the Study:

  • To investigate the role of p73, specifically the TAp73alpha isoform, in inducing programmed cell death through ER stress.
  • To determine if p73, like p53, can transactivate the scotin gene.
  • To elucidate the molecular mechanisms linking p73 activity to ER stress and apoptosis.

Main Methods:

  • Utilized Tet-On inducible Saos 2 osteosarcoma cell lines lacking endogenous p53.
  • Assessed scotin mRNA levels using real-time RT-PCR.
  • Examined ER morphology and calcium levels using calnexin and fluo-3 staining, respectively.
  • Investigated the transcriptional induction of Gadd 153 as a marker for ER stress.

Main Results:

  • TAp73alpha induction in Saos 2 cells led to significant alterations in ER morphology, including changes in calnexin localization.
  • Both TAp73alpha and p53 strongly induced scotin expression, while the transcriptionally deficient DeltaNp73alpha isoform did not.
  • Scotin induction correlated with ER morphological changes, altered intracellular calcium concentrations, and transcriptional induction of Gadd 153, indicating ER stress.
  • The results demonstrate that TAp73alpha and p53, but not DeltaNp73alpha, can elicit scotin transactivation and ER stress.

Conclusions:

  • TAp73alpha and p53 activate scotin transactivation, leading to endoplasmic reticulum stress.
  • This p73-mediated scotin-ER stress pathway is a novel mechanism contributing to apoptosis.
  • The findings highlight a distinct role for the full-length TAp73alpha isoform in apoptosis induction, differentiating it from short isoforms like DeltaNp73alpha.

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