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CREB1 and ATF1 Negatively Regulate Glutathione Biosynthesis Sensitizing Cells to Oxidative Stress

Lina Zhao1, Wenjun Xia1, Peng Jiang1

  • 1School of Life Sciences, Tsinghua University, Beijing, China.

Frontiers in Cell and Developmental Biology
|June 28, 2021
PubMed

Insights

CREB1 and ATF1 proteins suppress glutathione (GSH) production in tumors by inhibiting key enzymes. This reduces cancer cell detoxification of reactive oxygen species (ROS), increasing oxidative stress and offering new therapeutic targets.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cellular Metabolism

Background:

  • Activating transcription factor 1 (ATF1) and cAMP response element binding protein 1 (CREB1) are implicated in various tumors.
  • The precise mechanisms underlying their role in cancer remain largely unknown.

Purpose of the Study:

  • To elucidate the mechanistic role of CREB1 and ATF1 in tumor biology.
  • To investigate the regulation of glutathione (GSH) biosynthesis by CREB1 and ATF1.

Main Methods:

  • Analysis of CREB1 and ATF1 regulation of glutamate-cysteine ligase modifier subunit (GCLM) and glutathione synthase (GSS) expression.
  • Investigating GCLM and GSS as direct transcriptional targets.
  • Assessing the impact on GSH biosynthesis and reactive oxygen species (ROS) detoxification.

Main Results:

  • CREB1 and ATF1 were found to suppress the expression of GCLM and GSS, key enzymes in GSH biosynthesis.
  • GCLM and GSS are identified as direct transcriptional targets of CREB1 and ATF1.
  • Suppression of GSH biosynthesis leads to reduced ROS detoxification and increased oxidative stress susceptibility.

Conclusions:

  • CREB1 family proteins regulate cellular metabolism by controlling GSH biosynthesis.
  • Targeting GCLM or oxidative stress presents a potential therapeutic strategy for tumors with high CREB1 family protein expression.
Keywords:
ATF1CREB1GSHROSproliferationsurvival

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