Control of Activating Transcription Factor 4 (ATF4) Persistence by Multisite Phosphorylation Impacts Cell Cycle Progression and Neurogenesis

Organogenesis is a highly integrated process with a fundamental requirement for precise cell cycle control. Mechanistically, the cell cycle is composed of transitions and thresholds that are controlled by coordinated post-translational modifications. In this study, we describe a novel mechanism cont...

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Bibliographic Details
Published in:The Journal of biological chemistry 2010-10, Vol.285 (43), p.33324-33337
Main Authors: Frank, Christopher L., Ge, Xuecai, Xie, Zhigang, Zhou, Ying, Tsai, Li-Huei
Format: Article
Language:English
Subjects:
Activating transcription factor 4
Activating Transcription Factor 4 - genetics
Activating Transcription Factor 4 - metabolism
Animals
Cell Biology
Cell Cycle
Cell Differentiation
Cortex
Development
Differentiation
Female
G1 Phase - physiology
HeLa Cells
Humans
Mice
Mutation
Neocortex - cytology
Neocortex - embryology
Neurodevelopment
Neurogenesis
Neurogenesis - physiology
Neuroprogenitor Cell
NIH 3T3 Cells
Organogenesis
Phosphorylation
Phosphorylation - physiology
Post-translation
Protein Phosphorylation
Protein Synthesis and Degradation
Protein Turnover
Transcription Factors
Ubiquitination
Ubiquitination - physiology
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Summary:Organogenesis is a highly integrated process with a fundamental requirement for precise cell cycle control. Mechanistically, the cell cycle is composed of transitions and thresholds that are controlled by coordinated post-translational modifications. In this study, we describe a novel mechanism controlling the persistence of the transcription factor ATF4 by multisite phosphorylation. Proline-directed phosphorylation acted additively to regulate multiple aspects of ATF4 degradation. Stabilized ATF4 mutants exhibit decreased β-TrCP degron phosphorylation, β-TrCP interaction, and ubiquitination, as well as elicit early G1 arrest. Expression of stabilized ATF4 also had significant consequences in the developing neocortex. Mutant ATF4 expressing cells exhibited positioning and differentiation defects that were attributed to early G1 arrest, suggesting that neurogenesis is sensitive to ATF4 dosage. We propose that precise regulation of the ATF4 dosage impacts cell cycle control and impinges on neurogenesis.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M110.140699