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The roles of translation initiation regulation in ultraviolet light-induced apoptosis

Suzanne H Parker1, Todd A Parker, Kimberly S George

  • 1Department of Chemistry and Biochemistry and Edison Biotechnology Institute, Ohio University, Athens, OH 45701, USA.

Molecular and Cellular Biochemistry
|June 21, 2006
PubMed

Insights

Ultraviolet light (UV) triggers apoptosis by activating eIF2alpha kinases. Phosphorylation of eukaryotic initiation factor 2 alpha (eIF2alpha) impacts PARP expression and influences UV-induced cell death, with PERK playing a key role.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Biochemistry

Background:

  • Ultraviolet (UV) light exposure activates specific kinases, leading to the phosphorylation of eukaryotic initiation factor 2 alpha (eIF2alpha), which inhibits translation initiation.
  • Two key kinases, PERK and GCN2, are known to phosphorylate eIF2alpha at Serine-51 in response to UV irradiation.

Purpose of the Study:

  • To investigate the role of eIF2alpha phosphorylation in UV-induced apoptosis.
  • To elucidate the specific contributions of PERK and GCN2 kinases in UV-induced cellular responses.

Main Methods:

  • Comparison of UV sensitivity and apoptosis in wild-type mouse embryo fibroblasts (MEF(s/s)) versus cells with a non-phosphorylatable eIF2alpha (MEF(A/A)).
  • Analysis of PARP cleavage and expression in response to UV irradiation.
  • Assessment of UV sensitivity in knockout cell lines (MEF(GCN2-/-) and MEF(PERK-/-)).
  • Evaluation of UV resistance in MCF-7 cells with a deleted PERK kinase domain (MCF-7-PERKDeltaC) and cells overexpressing wild-type PERK.

Main Results:

  • MEF(A/A) cells, lacking eIF2alpha phosphorylation, exhibited reduced sensitivity to UV-induced apoptosis compared to MEF(s/s) cells.
  • PARP cleavage was observed in MEF(s/s) cells but not in MEF(A/A) cells post-UV irradiation, with differential impacts on PARP expression.
  • MEF(GCN2-/-) cells showed increased UV sensitivity, while MEF(PERK-/-) cells demonstrated decreased UV sensitivity.
  • MCF-7 cells expressing a dominant-negative PERK mutant (PERKDeltaC) were more resistant to UV-induced apoptosis, whereas overexpression of wild-type PERK sensitized cells to UV.

Conclusions:

  • The level of eIF2alpha phosphorylation significantly influences PARP expression and subsequent apoptosis following UV irradiation.
  • Both eIF2alpha-dependent and independent pathways involving PERK and GCN2 likely mediate UV-induced apoptosis.

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