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Control of activating transcription factor 4 (ATF4) persistence by multisite phosphorylation impacts cell cycle

Christopher L Frank1, Xuecai Ge1, Zhigang Xie2

  • 1From the Massachusetts Institute of Technology, Picower Institute for Learning and Memory, the Howard Hughes Medical Institute, Cambridge, Massachusetts 02139, the Stanley Center for Psychiatric Research.

The Journal of Biological Chemistry
|August 21, 2010
PubMed

Insights

This study reveals how multisite phosphorylation controls the stability of the ATF4 transcription factor, impacting cell cycle progression and neurogenesis during development.

Area of Science:

  • Cell Biology
  • Developmental Biology
  • Molecular Biology

Background:

  • Organogenesis requires precise cell cycle control, regulated by post-translational modifications.
  • The transcription factor ATF4 plays a role in cellular processes.

Purpose of the Study:

  • To elucidate a novel mechanism controlling ATF4 stability through multisite phosphorylation.
  • To investigate the impact of ATF4 dosage on cell cycle control and neurogenesis.

Main Methods:

  • Investigated multisite phosphorylation of ATF4.
  • Analyzed ATF4 degradation, interaction with β-TrCP, and ubiquitination.
  • Assessed cell cycle progression and neocortex development in response to stabilized ATF4.

Main Results:

  • Multisite proline-directed phosphorylation additively regulates ATF4 degradation.
  • Stabilized ATF4 mutants show reduced β-TrCP interaction and ubiquitination, leading to early G(1) arrest.
  • Expression of stabilized ATF4 causes neocortical cell positioning and differentiation defects.

Conclusions:

  • Precise regulation of ATF4 stability by phosphorylation is crucial for cell cycle control.
  • ATF4 dosage impacts neurogenesis, highlighting its sensitivity to protein levels during development.

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