From 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.
From 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; Departments of Neurosurgery and Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts 02118.
J Biol Chem. 2010 Oct 22;285(43):33324-33337. doi: 10.1074/jbc.M110.140699. Epub 2010 Aug 19.
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 G(1) 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 G(1) 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.
器官发生是一个高度整合的过程，对精确的细胞周期控制有基本的要求。从机制上讲，细胞周期由通过协调的翻译后修饰控制的转变和阈值组成。在这项研究中，我们描述了一种通过多部位磷酸化控制转录因子 ATF4 持久性的新机制。脯氨酸定向磷酸化起附加作用，调节 ATF4 降解的多个方面。稳定的 ATF4 突变体表现出降低的 β-TrCP 降解基序磷酸化、β-TrCP 相互作用和泛素化，以及早期 G1 期停滞。稳定表达的 ATF4 也对发育中的新皮层有显著影响。表达突变 ATF4 的细胞表现出定位和分化缺陷，归因于早期 G1 期停滞，表明神经发生对 ATF4 剂量敏感。我们提出，ATF4 剂量的精确调节影响细胞周期控制，并影响神经发生。
