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Cell. 2014 Jan 30;156(3):563-76. doi: 10.1016/j.cell.2013.12.035. Epub 2014 Jan 16.

Redox modification of nuclear actin by MICAL-2 regulates SRF signaling.

Author information

1
Department of Pharmacology, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA.
2
Department of Pharmacology, University of Michigan, Ann Arbor, MI, 48109, USA.
3
Department of Surgery, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA.
4
Vahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.
5
Department of Pharmacology, University of Michigan, Ann Arbor, MI, 48109, USA; Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA.
6
Department of Pharmacology, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA. Electronic address: srj2003@med.cornell.edu.

Abstract

The serum response factor (SRF) binds to coactivators, such as myocardin-related transcription factor-A (MRTF-A), and mediates gene transcription elicited by diverse signaling pathways. SRF/MRTF-A-dependent gene transcription is activated when nuclear MRTF-A levels increase, enabling the formation of transcriptionally active SRF/MRTF-A complexes. The level of nuclear MRTF-A is regulated by nuclear G-actin, which binds to MRTF-A and promotes its nuclear export. However, pathways that regulate nuclear actin levels are poorly understood. Here, we show that MICAL-2, an atypical actin-regulatory protein, mediates SRF/MRTF-A-dependent gene transcription elicited by nerve growth factor and serum. MICAL-2 induces redox-dependent depolymerization of nuclear actin, which decreases nuclear G-actin and increases MRTF-A in the nucleus. Furthermore, we show that MICAL-2 is a target of CCG-1423, a small molecule inhibitor of SRF/MRTF-A-dependent transcription that exhibits efficacy in various preclinical disease models. These data identify redox modification of nuclear actin as a regulatory switch that mediates SRF/MRTF-A-dependent gene transcription.

Comment in

PMID:
24440334
PMCID:
PMC4384661
DOI:
10.1016/j.cell.2013.12.035
[Indexed for MEDLINE]
Free PMC Article

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