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Assessment of Mitochondrial Functions and Cell Viability in Renal Cells Overexpressing Protein Kinase C Isozymes
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PKCε promotes oncogenic functions of ATF2 in the nucleus while blocking its apoptotic function at mitochondria

Eric Lau1, Harriet Kluger, Tal Varsano

  • 1Signal Transduction Program, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.

Cell
|February 7, 2012
PubMed

Insights

The transcription factor ATF2 acts as a tumor suppressor in skin cancer by localizing to mitochondria. However, high PKCε levels in melanoma block this function, promoting cancer progression.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Cancer Research

Background:

  • The transcription factor ATF2 exhibits dual roles, acting as an oncogene in melanoma and a tumor suppressor in nonmalignant skin cancer.
  • Understanding the mechanisms governing ATF2's distinct functions is crucial for developing targeted cancer therapies.

Purpose of the Study:

  • To elucidate how the subcellular localization of ATF2 dictates its oncogenic or tumor suppressor activities.
  • To investigate the role of Protein Kinase C epsilon (PKCε) in regulating ATF2 localization and function.

Main Methods:

  • Investigated ATF2 localization in response to genotoxic stress.
  • Examined the interaction between ATF2 and PKCε.
  • Analyzed the effect of ATF2 mitochondrial localization on mitochondrial permeability and apoptosis.
  • Correlated PKCε levels with ATF2 function and patient prognosis in melanoma samples.

Main Results:

  • ATF2's tumor suppressor function depends on its mitochondrial localization, which is regulated by PKCε.
  • Genotoxic stress promotes ATF2 nuclear export to the mitochondria, where it perturbs the HK1-VDAC1 complex, increasing mitochondrial permeability and apoptosis.
  • High PKCε levels in melanoma cells inhibit ATF2 nuclear export, blocking its tumor-suppressive function and promoting resistance to apoptosis.
  • Elevated PKCε levels in melanoma tumors correlate with poor patient prognosis.

Conclusions:

  • Subcellular localization is a key determinant of ATF2's oncogenic or tumor suppressor functions.
  • PKCε plays a critical role in modulating ATF2's cellular fate and its impact on cancer development.
  • Targeting the ATF2-PKCε axis could offer novel therapeutic strategies for melanoma.

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